Next Article in Journal
Quality-of-Life Evaluation of Patients with Unresectable Locally Advanced or Locally Recurrent Head and Neck Carcinoma Treated with Head and Neck Photoimmunotherapy
Next Article in Special Issue
Obesity-Related Cross-Talk between Prostate Cancer and Peripheral Fat: Potential Role of Exosomes
Previous Article in Journal
Expression of Nectin-4 in Variant Histologies of Bladder Cancer and Its Prognostic Value—Need for Biomarker Testing in High-Risk Patients?
Previous Article in Special Issue
Active Surveillance in Intermediate-Risk Prostate Cancer: A Review of the Current Data
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment

Department of Anatomical Pathology, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijón, Spain
Research Unit, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijón, Spain
Department of Urology, Hospital Universitario Central de Asturias, Universidad de Oviedo, Avda. de Roma s/n., 33011 Oviedo, Spain
Department of Surgery, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33920 Gijón, Spain
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2022, 14(18), 4412;
Submission received: 11 August 2022 / Revised: 5 September 2022 / Accepted: 6 September 2022 / Published: 11 September 2022



Simple Summary

The crosstalk between prostate stroma and its epithelium is essential to tissue homeostasis. Likewise, reciprocal signaling between tumor cells and the stromal compartment is required in tumor progression to facilitate or stimulate key processes such as cell proliferation and invasion. The aim of the present work was to review the current state of knowledge on the significance of tumor stroma in the genesis, progression and therapeutic response of prostate carcinoma. Additionally, we addressed the future therapeutic opportunities.


Prostate cancer (PCa) is a common cancer among males globally, and its occurrence is growing worldwide. Clinical decisions about the combination of therapies are becoming highly relevant. However, this is a heterogeneous disease, ranging widely in prognosis. Therefore, new approaches are needed based on tumor biology, from which further prognostic assessments can be established and complementary strategies can be identified. The knowledge of both the morphological structure and functional biology of the PCa stroma compartment can provide new diagnostic, prognostic or therapeutic possibilities. In the present review, we analyzed the aspects related to the tumor stromal component (both acellular and cellular) in PCa, their influence on tumor behavior and the therapeutic response and their consideration as a new therapeutic target.

1. Introduction

The prostate and breasts are accessory sexual glands present only in mammals. Cancers of these origins are major health issues of the new century worldwide. Breast cancer accounts for over 25% of women’s cancers universally, implying a high risk (more than 10%) of developing this cancer during a woman’s lifetime [1]. Prostate cancer (PCa) is a common cancer among males [2]. In addition, the number of men diagnosed with PCa is growing all over the world [3,4]. On the other hand, 30–40% of patients with PCa experience biochemical recurrence (BCR) after radical prostatectomy (RP), and approximately 26–30% of these will develop into advanced and metastatic disease within the next five years [5,6]. In this respect, clinical decisions about adjuvant therapy based on a combination of androgen deprivation therapies (ADT) with radiotherapy, chemotherapy and/or immunotherapy [7,8] are important. Furthermore, PCa may display resistance to ADT, which is often accompanied by the occurrence of metastasis [9] and related deaths within 2–4 years [10].
Currently, the prognostic factors established for PCa are the TNM Classification of Malignant Tumors, the surgical margin status, the PSA (prostate-specific antigen) serum level and Gleason’s score. The combination of clinical staging and Gleason score remains the best predictor of a prognosis. However, although the Gleason classification is the most widely used, it persists in being deficient to elucidate the tumor behavior [11]. For all of this, new approaches to tumor biology are required, from which further prognostic evaluations and complementary strategies may be appointed.
Since the 1950s, some studies have supported the hypothesis of biological, genetic and epidemiological similarities between breast cancer and PCa [12,13]. Nevertheless, it is striking that while many studies have been published on the biological implication of the tumor stroma of breast cancer, little research exists on the same aspects in PCa. Figure 1 illustrates the changes in published studies of the stroma in breast cancer and PCa. As can be seen, there are approximately twice as many such works on breast cancer.
In this review, we discuss the relevant aspects of the complex tumor/stroma relationship in PCa, with its possible prognostic and potential therapeutic implications.

2. Normal Prostatic Stroma, Reactive Stroma in Benign Pathologies and in Preneoplastic Lesions

The prostate tissular architecture closely resembles that of the breasts in that it also comprises ducts with epithelial luminal and basal layers and the surrounding stroma tissue (Figure 2A). In normal prostatic tissue, the epithelium and stroma interact to maintain the physiological homeostasis. The stromal compartment is composed of a collagen-rich extracellular matrix (ECM) and cells. The ECM contributes to the establishment, separation and preservation of differentiated tissues. In addition, the ECM has influence on physiological signaling, since cells interact with the ECM by expressing receptors at their cell surfaces [13]. The basement membrane (BM) is an ECM structure that separates the epithelium from the stroma, and it is implicated in tissue resistance [14]. The ECM is configured with structural proteins (elastin and fibronectin), fibrillary proteins (collagens) and hydrated gel-forming macromolecules (proteoglycans or hyaluronic acid) [15]. Nevertheless, the ECM composition can vary considerably according to the tissue type.
The cells components from the stroma include fibroblasts, smooth muscle cells and immune cells, blood vessels and nerves. The crosstalk between epithelial cells and all the adjacent stromal cells is key to preserve the homeostasis in the normal prostatic tissue [16]. Thus, for example, it is known that prostatic androgen-stimulated smooth muscle cells induce the correct differentiation of epithelial cells through the release of regulatory molecular factors [17]. However, the homeostatic regulation capacity of the stroma in the face of tissue injuries or microbial infections can be reduced with the processes associated with aging. In these circumstances, the stromal cells can secrete proinflammatory cytokines (such as CXCL12 and CXCL5) that induce a proliferative activity of the epithelium and cause benign prostate hypertrophy (BPH) [18].
The deregulation of epithelial–stromal interactions is not only considered to be responsible for initiating and/or promoting proliferative diseases such as BPH but also PCa [19,20]. BPH typically happens in the 80–90% of older men in their 70s [21]. The prostate epithelium of BPH maintains its structural organization but characteristically consists of a highly proliferative epithelium, which results in enlarged nodules surrounding the stroma, showing the typical features of fibrotic diseases and reactive stroma with proinflammatory properties [22]. The BPH stroma is primarily composed of proliferating fibroblasts and myofibroblasts secreting ECM proteins, such as collagen type I and tenascin C [22]. Tenascin C is a glycoprotein involved in tissue remodeling such as cell adhesion and migration [23] (Figure 2B).
The morphological and functional changes in stroma progression to premalignant lesions are relevant. Focal atrophic lesions usually occur in the peripheral zone of the prostate [24] and are characterized by enhanced cell proliferation [25]. These types of lesions, characterized by chronic inflammation, are termed proliferative inflammatory atrophy (PIA) (Figure 2C) and can be due to several causes, such as diet type, cell damage (e.g., chemical exposure), infectious agents, hormonal changes or urinary retention [24]. Instead, PIA lesions could be precursors to high-grade prostatic intraepithelial neoplasia (HGPIN) in the peripheral zone (Figure 2D), which may subsequently progress to invasive PCa [24] (Figure 2E). This is attributable to stromal transformations, which lead to starting a tumorigenic process, such as an increase in oxidative stress. Therefore, it is known that, in inflammatory lesions, there is both protumor genomic instability and modifications in the gene expression, which are, in part, provoked due to macrophages releasing reactive oxygen species (ROS) and reactive nitrogen species [24,26]. Interestingly, this stromal transformation is considered to be the preliminary stage of HGPIN and PCa [27]. It was also observed that fibroblasts adjacent to the HGPIN foci are induced to acquire the cancer-associated fibroblasts (CAFs) phenotype via secreted factors by prostate epithelial cells, such as kallikrein-related peptidase-4 (KLK4) [28]. As a result, all these data suggest that induced changes in the stromal component of the prostatic tissue contribute to the progression to invasive PCa.

3. Reactive Stroma in Cancer

Homeostasis derived from a constant and self-regulated epithelial–stromal interaction is definitely disrupted in carcinomas, generating a tumor microenvironment (TME) that promotes tumor progression [29]. In 1986, Dvorak described tumors as “non-healing wounds” and suggested that stromal cells actively interact with epithelial cancerous cells [30]. In this stage, stromal cells often react with a fibrotic reaction around tumors [31].
The term “reactive stroma” consists of a set of alterations in the TME as a reaction to the presence of tumor cells due to an altered ECM deposition, neovascularization and the increased presence of myofibroblast-like CAFs and immune cell infiltration [32]. This concept posits that cancer cells cannot promote the disease by themselves but might recruit and modulate resident cell types to cooperate to promote tumor progression [33,34]. It was even stressed that the presence of a modified TME may be sufficient to promote epithelial cell tumorigenesis, even without genetic alterations [34]. Its influence is such that, if a normal microenvironment is restored, cancer cells may lose their tumorigenic phenotypes and capabilities [33,34].
The composition of the tumor stroma varies across different tumor types and within the same tumor type. The tumor stroma consists of ECM, the nonmalignant cells of the tumor mass and their cell components [35].

3.1. Tumoral Stroma ECM

First, the ECM forms a physical barrier, specially represented by the BM, which is more compact than the interstitial matrix, preventing the invasion of cancer cells and subsequently providing protection [36]. Hence, the interaction between cancer cells and the ECM is the first and key dynamic process in tumor pathobiology [14,37]. This remodeling process is perturbed during cancer with an abnormal ECM deposit, leading to stiffness and tumor progression [37]. In this context, enzymes secreted by tumor cells, such as lysyl oxidases (LOX), are capable of crosslinking collagen and, thus, to building up one collagen I structure that promotes metastasis [32,38,39]. In addition to its structural function, the ECM represents a reservoir for bioactive molecules that may positively impact on several biological basic processes related with tumor progression [14].

3.2. Cell Components of Tumoral Stroma

Different cell types play a role in tumor–stroma interactions. These ones include resident cells, such as CAFs, endothelial cells and pericytes, neural crest cells and mesenchymal stromal/stem cells (MSC). No resident stromal cells comprise immune cells, which infiltrate solid tumors (Figure 3).

3.2.1. Myoepithelial Cells and Fibroblasts

The cell components of the ECM, such as myoepithelial cells or fibroblasts, are characterized by predominantly performing protective functions to inhibit tumor progression. In breast cancer, the disruption of myoepithelial cells appears to be a cardinal milestone in tumor progression. The myoepithelial cells are situated between the stroma and the luminal cells, creating a natural separation between both morphological structures [40,41,42]. In addition, myoepithelial cells reduce the gene expression of MMP-2, MMP-9 and MT1-MMP, thereby reducing cancer cells’ invasive capacities [43]. Myoepithelial cells also inhibit angiogenesis by expressing MMP inhibitor TIMP-1, thrombospondin-1 and bFGF receptors [44,45]. In addition, myoepithelial cells, by expressing high levels of fibronectin, laminin and collagen [46,47], also participate in the accumulation of ECM and BM rather than degrading it. Therefore, all of these data suggest that myoepithelial cells can have multiple positive roles in preventing tumorigenesis.
On the other hand, it has been suggested that stromal fibroblasts might have a protective task involving cancer. Thus, it has been reported that these stromal cells may decrease EMT, invasion and metastasis by secreting factors such as caveolin-1, podoplanin [48], SLIT2 and asporin [49]. Nevertheless, despite all of these protective actions against tumor progression, stromal cells are mainly recognized by their protumor actions.

3.2.2. CAFs and Tumor Progression

Cancer cells secrete cytokines and chemokines, such as TGF-β, involved in CAF recruitment and activation [50,51]. In fact, CAFs represent the most plentiful stromal component in PCa. CAFs are described as spindle-shaped cells but, compared to normal fibroblasts, may be identified by the overexpression of molecular markers such as α-SMA, fibroblast activation protein (FAP), PDGFR-β or fibroblast-specific protein-1 (FSP-1) [52].
Resident fibroblasts can be the source of the CAF population. In this sense, it has recently been reported how Yes-associated protein 1 (YAP1) can convert normal fibroblasts into CAFs in the PCa TME. In addition, silencing YAP1 in tumor stromal cells can inhibit tumor growth in PCa [53]. However, CAFs can also originate from other sources, including MSC, epithelial cells, pericytes, adipocytes and endothelial cells [54]. Consequently, in PCa, the existence of different populations of CAFs has been described, which probably reflects the different cell origins of CAFs. CAFs with high CD90 levels of expression exhibited an increased proportion of numerous genes associated with tumor progress, including TGF-β, the angiogenic factors vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) and the cytokines interleukin (IL)-6 and chemokine (C-X-C motif) ligand 12. In addition, the coexistence of subpopulations of CAFs that do not express and others that express TGF-β receptor II (TGFβRII) has been identified, which seems to contribute to tumor progression and evidence of the heterogeneity of CAFs in PCa [55,56].
Several studies have identified CAFs as promoting tumor cell growth, invasion, epithelial-to-mesenchymal transition (EMT) and ADT resistance in PCa [35]. CAFs may positively influence tumor invasion through indirect or direct actions, such as cell-to-cell contact, which contribute to the regulation of the cancer cell motility through the modulation of Eph-Ephrin signaling [57]. It has also been suggested that direct contact between PCa cells and CAFs enhances tumor growth by activating Notch signaling in stromal cells [58].
CAFs can also influence tumor invasion trough indirect actions such as the overproduction of ECM components (collagen, tenascin-C, fibronectin or hyaluronate) [55,59,60,61] that favor tumor cell proliferation and invasion, leading to metastasis [15,62]. Indeed, it has been described that fibronectin produced by CAFs can establish a fiber-oriented network allowing migration pathways to cancer cells [61]. CAF contractile forces may alter the organization and the physical properties of the BM, making it permissive to tumor invasion [63]. However, there are a lot of data indicating a more complex role of CAFs in tumor progression.
CAFs induce ECM remodeling by secreting matrix proteases such as MMPs and FAP [64]. Especially relevant seems MMPs, secreted by both stromal and cancer cells, which are regulated by tissue inhibitors of matrix metalloproteinases (TIMPs) [65,66]. During PCa development, the overexpression of MMP-1, -2, -7, -9 and -14 was found in stroma and circulation (Gong et al., 2014) [67,68], as well as an imbalance between MMPs and TIMPs, which enhances PCa cell invasiveness [66,69]. It has been proposed that the loss of Dickkopf-3 (DKK3) expression, a secreted protein that inhibits TGF-β signaling activity in both prostate epithelial and stromal cells, could explain the increased expression of MMPs in PCa. In addition, DKK3 silencing is associated with an increase release of MMP-2 and MMP-9 [70,71].
There are other mechanisms for which MMP activity also promote other key aspects of tumor progression, such as cell proliferation, apoptosis and angiogenesis [65,66], and the cleavage of growth factors with known tumorigenic properties, such as FGFs, TGF-β and HGF [72]. In turn, MMPs cause a clear EMT in cancer cells, as well as increased tumor growth and the development of metastases [73].
CAFs construct a metabolic symbiosis with PCa cells, bestowing cancer aggressiveness through a lactate shuttle. A crucial role of tumor mitochondria as a sensor and energy transducer of CAF-dependent metabolic reprogramming has been revealed. This underscores the dependence of cancer cells on CAF catabolic activity and mitochondria exchange [74]. Its activation relates to the reverse Warburg effect, a phenomenon occurring in several tumors, including PCa, in which CAFs performed aerobic glycolysis and provide lactate, as well as amino acids such as glutamine and ketone bodies, to oxidative tumor cells, which are able to use these nutrients as an energy source or incorporate them as metabolic precursors necessary for tumor development [75]. This shows that tumor cells depend, to some extent, on the stroma to maintain their metabolism and growth. CAFs have also been shown to improve immunosuppression in the TME partly through cytokine secretion, such as TGF-β and CXCL12, but equally across the expression of inhibitory molecules such as PD-L1. Moreover, CAFs can also promote the angiogenesis process by secreting factors such as VEGF-A, FGF2, PDGFC and CXCL12. There is another interesting mechanism lately described by which CAFs may protect cancer cells as they progress towards metastasis. Duda et al. indicated that CAFs can migrate with circulating tumor cells (CTCs) as wandering cell clusters. This mass migration unit boosts tumor cell survival and colonization in far-flung organs [76]. So much so that there is a correlation between the number of CAFs and disease progression in breast, colon and prostate cancer [77]. These results suggest the use of heterotypic clusters of CTCs and CAFs as potential markers of cancer progression, as well as potential targets in metastatic disease [78].

3.2.3. CAFs and Therapy Response

CAFs can not only promote cancer progression but also its survival by creating a “protective niche” that keeps tumor cells alive by inducing a resistance to cancer therapy. There are several mechanisms by which CAFs may influence the efficacy of chemotherapeutic drugs. These stromal cells regulate the interstitial fluid pressure in the TME and therefore affect drug transport from the vasculature to tumor interstitium. In this regard, CAFs could reduce drug accessibility, especially at the center of the tumor [79]. In addition, various mechanisms were described by which CAFs can induce a resistance to different chemotherapeutic agents in PCa. There are data indicating that CAFs producing IL-6 inhibit doxorubicin-induced cell death by inhibiting p53 induction in PCa cells [80] but also through the release of glutathione, which decreases the ROS levels and avoids drug accumulation in cancer cells [81]. CAF-derived exosomes carrying miR-423-5p can also increase the resistance of PCa to taxane by blocking GREM2 through the TGF-β pathway [82].
Several studies found that CAFs are also active in promoting PCa resistance to antiandrogen therapies. AR indirectly inhibits the expression of inflammatory cytokines by CAFs such as CCL2 and CXCL8, known to promote PCa cell motility. CAFs secrete IL-6, which may activate AR transcriptional activity in PCa cells by modulating PI3K/AKT, MAPK and STAT3 signaling in the absence of androgens [83,84]. In a multivariate analysis, fibroblasts were the most significant cell type in determining the prognosis in PCa and associated with castration-resistant prostate cancer (CRPC) [85].
It has been described that ADT stimulates the proliferation of a subpopulation of CAFs, characterized by the expression of CD105, and produces frizzled-related protein 1 (SFRP1), a member of the Wnt signaling pathway, which supports the neuroendocrine differentiation of the adjacent epithelial cells [86]. This seems to indicate that CAFs participate in their progression towards neuroendocrine CRPC [86,87].
Interestingly, we found that one CAF population from PCa presented a higher expression of IL-6, FGF7, MMP2 and MMP11, with a lower expression of FGF10 and IL-17RB than normal prostatic fibroblasts [88], which was consistent with those found in breast cancer [89]. In addition, we also found that, at the same time, FGF7 is primarily expressed in CAFs from localized tumors, whereas MMP-11 and AR are overexpressed in CAFs from metastatic CRPC [88].

3.3. Immune Cells

Inflammatory cascades during PCa tumorigenesis have been extensively discussed [90,91]. The inflammatory process in the prostate gland may be caused by pathogens such as Chlamydia Trachomatis and Neisseria Gonorrhea, or noninfective shooters characterized by diet, urinary reflux or autoimmune processes [92]. Clinical studies detected an increased risk of PCa in men who had experienced infectious prostatitis [90]. Chronic inflammation in normal prostate tissue was evidently related to high-grade prostatic malignant tumors demonstrated by a biopsy [93]. In this setting, chronic inflammation transforms the prostatic microenvironment into a medium rich in immune cells, growth factors and chemokines and in proinflammatory cytokines, concomitantly interacting between them and with epithelial cells to induce proliferation and angiogenesis [94].
Immune cells can be recruited to the tumor by cytokines and chemokines such as CCL2 produced by cancer cells and CAFs [95,96,97]. Tumor-infiltrating leukocytes have been considered as part of the defense mechanism against tumor development [98] and also, in the end, interpreted as a failed attempt by the immune system to refuse the tumor. Instead, currently, it is common knowledge that leukocyte infiltration can promote tumor expansion, angiogenesis and tumor cell encroachment [99,100] due to the secretion of growth factors, proteases, chemokines and cytokines [101,102].
The immune cell infiltrate of tumors (Figure 3) comprises T and B cells, neutrophils and macrophages, among others [99]. Tumor-associated macrophages (TAMs) can exhibit a classically activated (M1) or an alternatively activated (M2) phenotype, defined as a tumor-suppressing or tumor-promoting phenotype, respectively, where the M2 phenotype is related to a worse prognosis [99,103,104]. This is evidenced by a study in which it was shown that TAMs are preferentially polarized as M1-like in colorectal cancer, as opposed to PCa, where TAMs are predominantly M2-like [105]. Likewise, it was reported that the presence of M2 within the TME from PCa is an independent predictor of extracapsular extension [106]. Nevertheless, myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with powerful immunosuppressing activity. MDSCs are classified as polymorphonuclear (PMN-MDSCs) or monocytic (M-MDSCs). PMN-MDSCs infiltrate much more easily into the stromal area than into the epithelial area of the tumor regions, and these stromal cell infiltrates were associated with vascularization in PCa [107]. In contrast, stromal T- and B-lymphocytes contribute to an immunological response that reduces cancer development and progression [108,109,110,111,112,113,114,115,116].
Some studies have attempted to ponder the impact of heterogeneity of the inflammatory component of the stroma on the PCa prognosis. The Cancer Genome Atlas (TCGA) database has provided a set of global gene expression profiles and clinical data on patients worldwide [117]. In addition, the ESTIMATE algorithm was developed to evaluate the expression levels of certain molecular entities in stromal and immune cells of the TME [118]. The immune-activated subtype, characterized by the activation of WNT/TGF-β, TGF-β1 and C-ECM signatures, is present in 14.9–24.3% of patients, which was associated with a good prognosis and a good response to anti-PD-1/PD-L1 therapy. ESTIMATE appears as a novel immune molecular classifier significantly associated with clinical prognosis and provides an innovative perspective on immunotherapeutic strategies for PCa patients [119]. In another, similar study, Zhao et al. found that eight individual differentially expressed genes (DEGs): C6, C7, S100A12, PAX5, FAM162B, MLC1, TCEAL5 and CAMK1G significantly predicted a favorable global survival, and one DEG, EPYC, was associated with immune cell infiltration, immune responses and a low overall survival [120].
The protumor effect of immune cells is mainly transmitted through cytokines. They may contribute to the creation of free radicals that can damage DNA, possibly causing mutations that lead to tumor formation, boosting cell proliferation and reducing apoptosis, stimulating EMT and angiogenesis or permitting tumor cell scape from immune surveillance. In contrast, cytokines can adjust an antitumoral response that seems to be dependent on the balance between pro- and anti-inflammatory cytokines [121] and the stage of tumor development [122]. Inflammatory cells generate high levels of proinflammatory cytokines and chemokines, such as IL-1β, IL-6, IL-8, IL-17, NF-κB, interferon-γ, VEGF and TNF-α. Some of these have been attached to tumorigenesis and prognosis in PCa [123]. High serum levels of TNF were reported in PCa hormone refractory conditions denoting an auspicious feature as a biomarker for CRPC. Elevated concentrations of NF-κB in the PCa microenvironment [124] alter the expression of cell cycle scriptwriters such as c-myc and cyclin-D1 and increases the expression of angiogenic factors, including IL-6, IL-8 and VEGF [125]. IL-6 was outlined as a key driver in PCa pathogenesis. As several studies demonstrated, increased serum levels of IL-6 match with metastatic or hormone-resistant PCa [126,127,128]. In addition, it was reported that targeting IL-6 with Siltuximab improved the disease outcomes in patients with metastatic refractory CRPC to the standard treatment [129]. On the other hand, there are also data showing that increased IL-8 concentrations within the PCa microenvironment increased cancer cell adherence to the endothelium, thereby improving tumor angiogenesis and metastatic propagation [130], as well as in docetaxel-refractory metastatic CRPC [130]. As a result, agents reducing the IL-8 levels such as naphthylamide help it deal with advanced forms of this malignancy [131].

3.4. Endothelial Cells

Endothelial cells (ECs) are pervasive within tumors and required for vessel development and function, particularly blood vessels, vital for providing oxygen and nutrients for tumor growth. The endothelial barrier keeps vascular and tissue homeostasis, and its dysfunction induces vascular permeability, which favors angiogenesis, inflammatory cell infiltration and tumor cell extravasation. Additionally, ECs can impact tumor progression through the secretion of several factors [132,133,134,135], induced by the crosstalk between a tumor and ECs [136]. The phenotypes of ECs differ depending on the tumors, as ECs from highly metastatic tumors exhibit a more proangiogenic phenotype than ECs from low metastatic tumors [137].
Tumor vascularization is characterized by the formation of immature blood vessels that fail covering pericytes [138]. The interaction between tumor cells and the surrounding stromal endothelial cells encourages an “angiogenic shift” by enhancing the proangiogenic factors such as VEGF. Zhao et al. evidenced that ECs are a substantial component of the TME for their contribution to boosting metastatic activity via silencing AR expression and transcriptional activity; therefore, their inhibition could impede PCa progression [120].
On the other hand, studying the phenotype of epithelial cells provides a clearer picture of the prognostic value of the tumor stroma. For example, for breast cancer, MMP-11 expression by ECs was associated with a shorter relapse-free survival, whereas TIMP-3 expression was linked to the small appearance of distant metastasis. Simultaneously, MMP-11 and TIMP-2 expression by ECs was associated with shorter global survival, whereas TIMP-3 expression by ECs was associated with an increased overall survival [139]. These results indicate that a strong MMP/TIMP expression by ECs from breast carcinomas can be due to interactions signaling between tumor cells and their surrounding microenvironment. Similar associations integrating morphology and biology should be explored in PCa.

3.5. Mesenchymal Stromal Cells

It is widely accepted that PCa originates from cancer stem cells (CSCs). Albeit prostate CSCs constitute a smaller percentage of the total tumor mass, there are data pointing out that they have several mechanisms related with PCa progression, such as improved DNA repair, antioxidative stress, autophagy, the initiation of antiapoptotic signaling, resistance to therapy, including radiotherapy, or EMT [140,141].
MSC are also part of the PCa tumor stroma and promote its progression. Essentially, MSC are adult multipotent stromal cells characterized by the expression of surface markers (CD73, CD90 and CD105), with the capability of self-regeneration and differentiation into osteoblasts, chondrocytes and adipocytes [142,143]. In physiological conditions, MSCs interact with the surrounding cells by secreting soluble factors, such as cytokines and growth factors, therefore contributing to tissue homeostasis and immunoregulation. However, MSCs also bear a relevant role in the tumor–stroma crosstalk [144,145]. MSCs can be recruited by neoplastic cells to the tumor site employing chemotactic factors such as MMPs, inflammatory cytokines and growth factors [146]. These steam cells have also shown several protumor behaviors, such as increasing the tumor growth speed [147] and angiogenesis [148] and onset EMT [149], along with modification of the extracellular matrix [150], in order to bolster the migration and implantation of metastasis [151]. MSCs prompt the suppression of immune effector cells [152,153], as well as the expansion of the immune regulatory ones [153,154], thus developing resistances to cancer therapies [155,156]. Specifically, in the TME, besides the MSCs being a source of CAFs, they may be able to transdifferentiate into MDSCs or M2-type macrophages under the influence of cytokines or chemokines [157].
In relation to PCa, there are data that supports the cooperation of CSCs and mesenchymal cells in metastasis development and hormone resistance [158]. Thus, a novel interaction between MSC and PCa cells, through activation of the Jagged1/Notch1 pathway, has recently been shown in promoting tumorigenesis [159]. It has been reported that chronic exposure to MSC abets the selection of PCa cells that are resistant to IL-28-induced apoptosis and treatments such as docetaxel, which depends on the MSC secretion of TGF-β1 [160].

4. Tumor Stroma from Bone Metastasis

Metastasis requires successive steps. First of all, migratory PCa cells invade blood vessels, survive in the circulation, leak and nest in a secondary metastatic site [161]. This is an inefficient process, with a chance rate of only 0.01% of tumor cells achieving this complete process [162]. PCa predominantly forms bone metastases [163], which are known to cause severe symptoms such as vertebral fractures and/or spinal cord compression. The PCa bone tropism is probably due to the SDF-1/CXCR4 pathway. In fact, an experimental mouse model demonstrated that endothelial cells and osteoblasts in the bone marrow release CXCL12, which attracts PCa cells expressing the CXCR4 receptor [164]. The fact that PCa cells, by expressing α2β1 integrin, show preferential adhesion to collagen is also relevant [165]. Consequently, high collagen levels may also contribute to bone tropism toward the bone matrix [166]. In this context, the CAFs involved in deposition of the ECM components, such as collagen, fibronectin and tenascin, may contribute to critical protein interactions within the metastatic niche [167,168]. Interestingly, tenascin, which is absent in adult bones, may be re-expressed during PCa bone metastasis, and metastatic PCa cells interact with tenascin through α9β1 integrin [168]. In addition, it has been reported that tenascin detected in high levels in the circulation from PCa patients previously to a radical prostatectomy could contribute efficiently to predicting BCR-free survival [169].

5. Emergent Role of the Extracellular Vesicles in the Intercellular Signaling from Tumor Microenvironment

Extracellular vesicles (EVs) are responsible for a concrete nano-communication system among the different cell types of the tumor (Figure 4). They can be sorted into three different categories based on their size: apoptotic bodies (1000–5000 nm), microvesicles (500–1000 nm in diameter) and exosomes (30–150 nm) [170]. Exosomes, which originate in the endocytic compartment, withhold, at least partially, the content of the parent cell [171], such as cytokines; growth factors and nucleic acids (mRNA, miRNA and DNA), among others [172].
EVs acquired special interest from the clinical use of liquid biopsies to explore circulating tumor cell (CTC)-derived products [173]. In addition, the presence of two PCa cancer RNA biomarkers in EVs isolated from urine was demonstrated: TMPRSS2:ERG and PCA3 [174]. A more recent study supported the interest of urine EVs for the diagnosis of PCa, especially high-grade cancer [175]. Plasma and serum EVs have also been found as potential biomarkers for a PCa diagnosis [176]. In addition, tumor-derived EVs were found significantly higher in plasma from patients with CRPC and associated with a dimmer chance of survival [177]. On the other hand, it was reported that the presence of EVs containing specific miRNAs predict radiation therapy efficacy [178] or biochemical recurrence after radical prostatectomy [179].
PCa EVs also promote a tumor-supportive environment by inducing reprogramming of the stroma [180,181]. It has been proven that tumor-derived exosomes (T-D-EXs) induce changes in MSCs, both phenotypic and functional, which might wield profound effects on tumor growth [182] and epigenetic changes that can be promoted by the genetic cargo of T-D-EXs [183]. The mechanism of which T-D-EXs impact MSCs is not known, and it has not been elucidated yet if a protein transfer is enough or if nucleic acids and transcription factors are required [184]. It has been described that T-D-EXs from chronic lymphocytic leukemia, breast cancer or PCa can stimulate MSC migration to the tumor site [185] and MSC differentiation into myofibroblasts, which causes the overexpression of αSMA [186]. Dai J et al. reported a prime example of said interactions, witnessing that PCa-derived EVs promote bone metastasis through the EV-mediated transfer of pyruvate kinase M2 from PCa cancer cells into bone marrow stromal cells [187].
EVs have also been found to play a key role in the paracrine communication between PCa cancer cells and CAFs [188]. Atypically large EVs released by PCa cells further enhance the migration of CAFs by the intercellular transmission of functional miRNA such as miR-1227 [189]. It was also shown that PCa EVs induce a pro-tumorigenic phenotype in fibroblasts via TGF-β, which promotes angiogenesis and tumor growth [190,191]. Furthermore, CAFs produce exosomes containing microRNA-409, which is known to inhibit the translation of tumor-suppressor genes, hence promoting EMT and tumor invasiveness [192]. They have also been shown to induce the migration and invasion of PCa cells via the CX3CL1-CX3CR1 pathway [193]. CAF-derived EVs contain amino acids and lipids that may be utilized by cancer cells under nutrient deprivation conditions [194].
It was also reported that EVs are responsible for reciprocal interactions between both PCa and immune cells. Thus, PCa-derived EVs facilitate immune evasion by downregulating natural killer and CD8+ T cells [195]. In addition, the interaction between TAMs and the EV-mediated transfer of miR-95 is known to promote PCa progression [196]. On the other hand, MSC-derived exosomes arise special interest in the context of intercellular communication. Under physiological conditions, MSCs behave as a munificent source of exosomes [151], seemingly responsible for numerous functions that are broadly attributed to MSCs, such as their influence on adjacent stromal cells [197,198]. First and foremost, MSC-derived exosomes are able to interact with a wide variety of cell types in order to assure they appropriately uphold the tumor growth (Figure 4). MSC-derived exosomes transport a variety of molecules and genes comprising more than 850 gene products and 150 miRNAs [199,200], which allow them to impact on different cellular responses in several cells [201]. Remarkably, MSCs are receptors of signals generated by the tumor and, in turn, accomplished producers of their own exosomes. Therefore, there is a horizontal transfer of information carried out by exosomes to neighboring cells that molds the physiological environment to one supporting tumor survival [182].

6. Tumor Stroma and Therapeutic Opportunities

Several studies have shown that the tumor stroma, although being morphologically abnormal, is genetically intact and stable [202,203,204]. This suggests that stromal cells may be more susceptible to therapeutic intervention than the genetically unstable tumor epithelium.
The concept that targeting the stroma is a viable therapeutic option has been widely consolidated by the available strategies targeting angiogenic cells in clinical trials on patients with advanced breast cancer [205]. Cancer therapies should focus on progressively disrupting the dynamic interaction between neoplasm cells and the tumor milieu by aiming at metabolic deregulation and inflammation so the tissue homeostasis will be partially restored and the immune cancer kill switch turned on. However, this therapeutic approach would require a deeper understanding of the interactions among the cancer cells, the TME and the immune system, given the adaptive complexity of said communications. For instance, based on the knowledge that the interaction between HGF secreted by the stroma cells with its c-Met receptor located in the epithelium must occur for PCa cells to become migratory, it was shown that resveratrol inhibits HGF-mediated interactions between the stroma and the epithelium and suppresses epithelial PCa cell migration by attenuating EMT [206].

6.1. Inhibing CAFs

Considering the protumor functions exerted by CAFs, we could devise therapeutic strategies, such as reprogramming CAFs into normal fibroblasts or by blocking signaling pathways involved in the crosstalk between CAFs and cancer cells [64,207]. In addition, compared to cancer cells, CAFs are genetically more stable and have fewer chances of developing drug resistance, thus representing a therapeutic target less likely to develop chemoresistance [208,209]. Consequently, diverse strategies could be developed associated with said CAFs, such as targeting their capacity to use mechanical forces on the basal membrane [210] or induce lactate reduction in order to drive the TME towards a less inflamed state so the immune system can perform an effective intervention. This happens, in part, because of the possible dysregulation of the RTK, PI3K and MAPK signaling pathways, which can be the first promoters of upregulated glycolysis in neoplasm cells. The subsequent increase of lactate production into the TME will lead to its acidification and the ensuing activation of TGF-β [211], which prompts the recruitment and transformation of CAFs. Far from being purely hypothetical, new agents blocking CAF protumor activity have already undergone preclinical and even clinical evaluations [212,213]. Regarding PCa, it has been shown that YAP1 can convert normal fibroblasts into CAFs in this carcinoma microenvironment. Therefore, silencing YAP1 in tumor stromal cells can effectively inhibit tumor growth [53]. It has been also demonstrated that endo-, phyto- and synthetic cannabinoid treatments are able to simultaneously strike PCa cells and CAFs [214]. In addition, it was suggested that, considering that CAF-secreted exosomal miR-423-5p promoted chemotherapy resistance in PCa cells by targeting GREM2 through the TGF-β pathway, the inhibition of miR-423-5p might enhance the drug sensitivity of PCa [82].

6.2. Immunotherapy

Several clinical trials on the effectiveness of inhibitors of cytokine receptors and/or neutralizing antibodies to avoid the exposure to inflammatory factors that contribute to tumor progression have been conducted [215,216]. Among the most considered immune inhibitors were those ones against programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) [217,218]. The immunotherapies showed durable clinical responses in tumors such as renal cell cancer and melanoma [219,220]. However, these therapeutic potentialities have not yet been confirmed in PCa [218].
The TME of PCa is highly immunosuppressive due the actions of the immune cells (regulatory T cells, TAMs and MDSCs) [218]. This immunosuppressive effect mediated by cytokines (TGF-β, adenosine, IL-6, IL-8, IL-10 and VEGF); prostaglandin E2 and programmed death-ligand 1 (PD-L1) with programmed cell death protein 1 (PD-1) [221], as well as the secretion of adenosine via prostatic acid phosphatase. However, most of the trials in PCa have targeted a single immunosuppressive mechanism, so the clinical efficacy is likely to be limited. The use of combination therapies to avoid multiple mechanisms of resistance should be considered [218]. Furthermore, there are data indicating a relationship between ADT and the immunological antitumor response by inducing immune cell infiltration and increasing the sensitivity of tumor cells to immune-mediated lysis. In addition, mice receiving a combination of enzalutamide treatment with a cancer vaccine had a significantly increased overall survival [222,223,224]. In this sense, many clinical trials have shown an increase of the antitumor effectiveness of immunotherapies when combined with ADT [225,226,227]. In fact, it was reported that immune-related genes (JUNB, SOCS3 and ZFP36) may have a key role in the ADT immune remodeling process in PCa, which impact the prognosis [228]. Consequently, it is essential to comprehensively describe the PCa immune microenvironment in order to facilitate identifying suitable patients to undergo immunotherapy. In this sense, certain alterations such as dysfunctional DDR, CDK12 alterations or microsatellite instability have been identified as advantageously responsive to immunotherapy in PCa [229,230,231].

6.3. MSC as New Therapeutic Strategy

Non-associated tumor MSCs are widely distributed among tissues, and they display a key role in homeostasis [232,233]. It is possible to conceive an antitumor alternative based on MSCs if we were to take into consideration the protumor or antitumor effects dependent from their tissular origin and tumor lineage [234,235]. For example, MSCs of reproductive sources seem to have an antitumor effect on specific carcinomas [234,236]. It was even reported that MSCs from uterine cervix origin display not only anticancer effects against triple-negative breast cancer cells but also against protumor stromal cells, such CAFs and cancer-associated macrophages [237,238].
Based on the mentioned precedents, and the known tropism for tumors MSCs exhibit, the idea of tracking down a specific type of MSC with antitumor effects against PCa is neither utopian or far-fetched [239]. MSCs may be developed as vehicles for drug delivery. For example, MSCs may deliver oncolytic viral loads into tumors [240,241]. MSCs have also been genetically manipulated to express immunomodulatory cytokines, which can promote cancer cell killing effects. MSCs genetically modified to produce IFN-β induce significant antiproliferative effects in metastatic PCa preclinical models [242]. In addition, MSCs have been genetically manipulated to express specific enzymes, as aforementioned, such as herpes simplex virus-thymidine kinase (HSV-TK) or cytosine deaminase, which can convert administrated prodrugs, such as fluorouracil and ganciclovir, into active cytotoxic agents. Therefore, this strategy may increase the antitumor activity of chemotherapy and minimize the systemic toxicity, as demonstrated in experimental models of PCa [243,244].
However, cell-based therapies have brought to the forefront several safety issues related to the transplantation of breeding living cells, including, but not limited to, immunological mismatch, the formation of emboli, the possible chance of MSC entering into senescence and even tumorigenicity. Nonetheless, scientific data show that the beneficial effects of MSC endure through the secretion of paracrine factors (cytokines and growth factors) and EVs. Due to the anti-inflammatory, antioxidative stress, regenerative, angiogenic and antiapoptotic capabilities from these components, MSC secretome should be studied as a promising candidate for new medical biotechnology [245]. Furthermore, the usage of EVs of the MSC secretome, unlike cellular therapies, can be better assessed in terms of the safety, efficiency and dosage and in a very dissimilar way to conventional therapeutic agents. Secretome endures storage without cryopreservative agents and their potential toxicity. The use of secretome-derived products has proven to be cheaper and more feasible for clinical use, since the employment of the secretome is nowhere near as expensive, in both time and capital, as expanding and maintaining clonal cell lines. Needless to say, secretomes for therapies, such as the conditioned medium of exosomes, could be prepared in advance and be available for treatments when required [246].
Interestingly, it is estimated that the coalition of paracrine factors, summarized as secretomes, are responsible for up to 80% of the therapeutic impact of MSCs. It has been conveyed that MSCs secrete high amounts of tumor growth-inhibiting cytokines, such as CXCL10, IL-12, IFN-α, IFN-β, IFN-γ, DKK-1/3, latency-associated peptide (LAP), TNF superfamily member 14 (TNFSF14), also known as LIGHT, TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand) and the Fms-related tyrosine kinase 3 (FLT-3) ligand. The antitumor effect of MSCs has also been reported as being partly subservient to TIMP-1 and TIMP-2 activity, both abundant in the secretome. This may be due to MMP inhibition, these enzymes being related to the migration and invasion of cancer cells [234]. Commonly, it is assumed that MSC-derived EVs render akin functions to their parent cells [247], some of which may also be antitumor effects [234]. This is the case, for example, of the AD-MSC-EVs, which evinced PCa growth-inhibiting behavior [248]. MSC-EVs arise further interest for oncological therapy due to their tumor tropism. It is also known that cancer cells internalize a higher amount of exosomes compared with normal cells [249,250]. On the other hand, exosomes can be loaded with anticancer particles (for example, cytotoxic chemotherapy agents, small interfering RNA (siRNAs) or miRNAs) using different techniques, such as incubation, by the transfection of exosome-producing cells or by chemical transfection electroporation [251].
In summary, using MSCs as anticancer therapy might turn out to be an interesting strategy, provided we conduct the appropriate experimental models to explore the mechanisms. However, we need to resolve several aspects, such as obtaining an optimal MSC secretome product for PCa treatment, ensuring their standardization and mass in vitro production in bioreactors and the use of functional assays to test the obtained biological products.

7. Conclusions and Future Perspectives

The two main unresolved concerns about PCa are the absence of more precise prognostic factors to identify patients at risk of metastasis and the need of more effective treatments for them. Most researchers have focused on the characteristics of PCa cells rather than on the stromal components. Due to this, the stromal component in PCa has not been studied as much as in breast cancer.
The stroma of PCa offers many possibilities for future research. The dynamic aspects of this structure may reflect the complex cellular inter-signaling of PCa and may even be interconnected with mechanisms through which lifestyles can considerably influence prostate carcinogenesis. In this sense, for example, it has been described that obesity was affiliated with shorter telomeres in PCa-associated stromal cells, which was correlated with an increased risk of PCa fatal outcome [252,253]. In this line, more recently, it was reported that, among men with the aggressive disease (Gleason ≥ 4 + 3 and stage > T2), these ones with obesity had three-fold increased odds of shorted telomeres in prostate stromal cells when compared to normal weight men. Therefore, it was suggested that telomere shortening in prostate stromal cells may be one mechanism through which someone’s lifestyle influences a dire prostate carcinogenesis [254].
Recent studies also showed interest in integrating panels of PCa tumor stromal markers that, as with the expression of CD31 (vascular marker), alpha smooth muscle actin (αSMA) and PR expression ratio between the PCa stroma and prostate normal tissue stroma, play a crucial role in the onset and progression of PCa [255]. In addition, new studies are demonstrating the importance of considering mathematical computational models that integrate the classic clinicopathological factors derived from a PCa epithelium tumor with recently gathered data from the functional biology of the stroma, such as single-cell RNA-Seq, whole-exosome sequencing, proteomic and metabolomic methods [256,257,258]. Thus, the stroma could be a contributing factor in discriminating against PCa that differ widely in their prognoses. Nevertheless, further research on the molecular mechanisms of tumor–stroma interactions is still needed to develop novel therapeutics based on targeting stromal-derived protumor activities in PCa [207].

Author Contributions

L.O.G., N.E., M.F., N.B., A.R.E., S.E. and J.M.F.-G. analyzed the bibliography and prepared the figures. F.J.V., L.O.G. and N.E. designed the project and wrote the manuscript. All authors reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.


This research was supported by “Fundación para la Investigación en Urología (FIU)” grant: Beca Leonardo de la Peña 2021.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [PubMed]
  2. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  3. Grönberg, H. Prostate cancer epidemiology. Lancet 2003, 361, 859–864. [Google Scholar] [CrossRef]
  4. Gandaglia, G.; Leni, R.; Bray, F.; Fleshner, N.; Freedland, S.J.; Kibel, A.; Stattin, P.; Van Poppel, H.; La Vecchia, C. Epidemiology and Prevention of Prostate Cancer. Eur. Urol. Oncol. 2021, 4, 877–892. [Google Scholar] [CrossRef]
  5. Huggins, C.; Hodges, C.V. Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate 1941. J. Urol. 2002, 168, 9–12. [Google Scholar] [CrossRef]
  6. Fizazi, K.; Higano, C.S.; Nelson, J.B.; Gleave, M.; Miller, K.; Morris, T.; Nathan, F.E.; McIntosh, S.; Pemberton, K.; Moul, J.W. Phase III, Randomized, Placebo-Controlled Study of Docetaxel in Combination with Zibotentan in Patients with Metastatic Castration-Resistant Prostate Cancer. J. Clin. Oncol. 2013, 31, 1740–1747. [Google Scholar] [CrossRef] [PubMed]
  7. Sartor, O.; Lewis, B. Beyond Just Androgen Deprivation Therapy: Novel Therapies Combined with Radiation. Semin. Radiat. Oncol. 2017, 27, 87–93. [Google Scholar] [CrossRef]
  8. Gamat-Huber, M.; McNeel, D.G. Androgen deprivation and immunotherapy for the treatment of prostate cancer. Endocr.-Relat. Cancer 2017, 24, T297–T310. [Google Scholar] [CrossRef]
  9. Wong, Y.N.S.; Ferraldeschi, R.; Attard, G.; de Bono, J. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat. Rev. Clin. Oncol. 2014, 11, 365–376. [Google Scholar] [CrossRef]
  10. Rycaj, K.; Li, H.; Zhou, J.; Chen, X.; Tang, D.G. Cellular determinants and microenvironmental regulation of prostate cancer metastasis. Semin. Cancer Biol. 2017, 44, 83–97. [Google Scholar] [CrossRef]
  11. Hughes, C.; Murphy, A.; Martin, C.; Sheils, O.; O’Leary, J. Molecular pathology of prostate cancer. J. Clin. Pathol. 2005, 58, 673–684. [Google Scholar] [CrossRef] [PubMed]
  12. Coffey, D.S. Similarities of prostate and breast cancer: Evolution, diet, and estrogens. Urology 2001, 57, 31–38. [Google Scholar] [CrossRef]
  13. López-Abente, G.; Mispireta, S.; Pollán, M. Breast and prostate cancer: An analysis of common epidemiological features in mortality trends in Spain. BMC Cancer 2014, 14, 874. [Google Scholar] [CrossRef] [PubMed]
  14. Bonnans, C.; Chou, J.; Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 2014, 15, 786–801. [Google Scholar] [CrossRef]
  15. Scott, L.E.; Weinberg, S.H.; Lemmon, C.A. Mechanochemical Signaling of the Extracellular Matrix in Epithelial-Mesenchymal Transition. Front. Cell Dev. Biol. 2019, 7, 135. [Google Scholar] [CrossRef]
  16. Corn, P.G. The tumor microenvironment in prostate cancer: Elucidating molecular pathways for therapy development. Cancer Manag. Res. 2012, 4, 183–193. [Google Scholar] [CrossRef]
  17. Cunha, G.R.; Hayward, S.W.; Dahiya, R.; Foster, B.A. Smooth Muscle-Epithelial Interactions in Normal and Neoplastic Prostatic Development. Cells Tissues Organs 1996, 155, 63–72. [Google Scholar] [CrossRef]
  18. Begley, L.A.; Kasina, S.; MacDonald, J.; Macoska, J.A. The inflammatory microenvironment of the aging prostate facilitates cellular proliferation and hypertrophy. Cytokine 2008, 43, 194–199. [Google Scholar] [CrossRef]
  19. Orr, B.; Riddick, A.C.P.; Stewart, G.D.; Anderson, R.A.; Franco, O.E.; Hayward, S.W.; Thomson, A.A. Identification of stromally expressed molecules in the prostate by tag-profiling of cancer-associated fibroblasts, normal fibroblasts and fetal prostate. Oncogene 2012, 31, 1130–1142. [Google Scholar] [CrossRef]
  20. Sun, Y.; Campisi, J.; Higano, C.; Beer, T.M.; Porter, P.; Coleman, I.; True, L.; Nelson, P.S. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 2012, 18, 1359–1368. [Google Scholar] [CrossRef]
  21. Ziada, A.; Rosenblum, M.; Crawford, E.D. Benign prostatic hyperplasia: An overview. Urology 1999, 53, 1–6. [Google Scholar] [CrossRef]
  22. Schauer, I.G.; Rowley, D.R. The functional role of reactive stroma in benign prostatic hyperplasia. Differentiation 2011, 82, 200–210. [Google Scholar] [CrossRef] [PubMed]
  23. Midwood, K.S.; Chiquet, M.; Tucker, R.P.; Orend, G. Tenascin-C at a glance. J. Cell Sci. 2016, 129, 4321–4327. [Google Scholar] [CrossRef] [PubMed]
  24. De Marzo, A.M.; Platz, E.A.; Sutcliffe, S.; Xu, J.; Grönberg, H.; Drake, C.G.; Nakai, Y.; Isaacs, W.B.; Nelson, W.G. Inflammation in prostate carcinogenesis. Nat. Rev. Cancer 2007, 7, 256–269. [Google Scholar] [CrossRef]
  25. Ruska, K.M.; Sauvageot, J.; Epstein, J.I. Histology and Cellular Kinetics of Prostatic Atrophy. Am. J. Surg. Pathol. 1998, 22, 1073–1077. [Google Scholar] [CrossRef]
  26. Josson, S.; Matsuoka, Y.; Chung, L.W.K.; Zhau, H.E.; Wang, R. Tumor–stroma co-evolution in prostate cancer progression and metastasis. Semin. Cell Dev. Biol. 2010, 21, 26–32. [Google Scholar] [CrossRef]
  27. Zhou, M. High-grade prostatic intraepithelial neoplasia, PIN-like carcinoma, ductal carcinoma, and intraductal carcinoma of the prostate. Mod. Pathol. 2018, 31, S71–S79. [Google Scholar] [CrossRef]
  28. Kryza, T.; Silva, L.M.; Bock, N.; Fuhrman-Luck, R.A.; Stephens, C.R.; Gao, J.; Samaratunga, H.; Lawrence, M.G.; Hooper, J.; Dong, Y.; et al. Kallikrein-related peptidase 4 induces cancer-associated fibroblast features in prostate-derived stromal cells. Mol. Oncol. 2017, 11, 1307–1329. [Google Scholar] [CrossRef]
  29. Bissell, M.J.; Radisky, D. Putting tumours in context. Nat. Rev. Cancer 2001, 1, 46–54. [Google Scholar] [CrossRef]
  30. Dvorak, H.F. Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 1986, 315, 1650–1659. [Google Scholar] [CrossRef]
  31. Sappino, A.-P.; Skalli, O.; Jackson, B.; Schürch, W.; Gabbiani, G. Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int. J. Cancer 1988, 41, 707–712. [Google Scholar] [CrossRef] [PubMed]
  32. Cox, T.R.; Bird, D.; Baker, A.-M.; Barker, H.; Ho, M.W.-Y.; Lang, G.; Erler, J.T. LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis. Cancer Res. 2013, 73, 1721–1732. [Google Scholar] [CrossRef] [PubMed]
  33. Hanahan, D.; Coussens, L.M. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 2012, 21, 309–322. [Google Scholar] [CrossRef] [PubMed]
  34. Quail, D.F.; Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 2013, 19, 1423–1437. [Google Scholar] [CrossRef]
  35. Sala, M.; Ros, M.; Saltel, F. A Complex and Evolutive Character: Two Face Aspects of ECM in Tumor Progression. Front. Oncol. 2020, 10, 1620. [Google Scholar] [CrossRef]
  36. Wu, T.-H.; Yu, M.-C.; Chen, T.-C.; Lee, C.-F.; Chan, K.-M.; Wu, T.-J.; Chou, H.-S.; Lee, W.-C.; Chen, M.-F. Encapsulation is a significant prognostic factor for better outcome in large hepatocellular carcinoma. J. Surg. Oncol. 2012, 105, 85–90. [Google Scholar] [CrossRef]
  37. Pickup, M.W.; Mouw, J.K.; Weaver, V.M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014, 15, 1243–1253. [Google Scholar] [CrossRef]
  38. Xiao, Q.; Ge, G. Lysyl Oxidase, Extracellular Matrix Remodeling and Cancer Metastasis. Cancer Microenviron. 2012, 5, 261–273. [Google Scholar] [CrossRef]
  39. Erler, J.T.; Bennewith, K.L.; Cox, T.R.; Lang, G.; Bird, D.; Koong, A.; Le, Q.-T.; Giaccia, A.J. Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche. Cancer Cell 2009, 15, 35–44. [Google Scholar] [CrossRef]
  40. Khamis, Z.I.; Sahab, Z.J.; Sang, Q.-X.A. Active Roles of Tumor Stroma in Breast Cancer Metastasis. Int. J. Breast Cancer 2012, 2012, 574025. [Google Scholar] [CrossRef] [Green Version]
  41. Soysal, S.D.; Tzankov, A.; Muenst, S.E. Role of the Tumor Microenvironment in Breast Cancer. Pathobiology 2015, 82, 142–152. [Google Scholar] [CrossRef] [PubMed]
  42. Pandey, P.R.; Saidou, J.; Watabe, K. Role of myoepithelial cells in breast tumor progression. Front. Biosci. 2010, 15, 226–236. [Google Scholar] [CrossRef] [PubMed]
  43. Jones, J.; Shaw, J.; Pringle, J.; Walker, R. Primary breast myoepithelial cells exert an invasion-suppressor effect on breast cancer cells via paracrine down-regulation of MMP expression in fibroblasts and tumour cells. J. Pathol. 2003, 201, 562–572. [Google Scholar] [CrossRef] [PubMed]
  44. Barsky, S.H. Myoepithelial mRNA expression profiling reveals a common tumor-suppressor phenotype. Exp. Mol. Pathol. 2003, 74, 113–122. [Google Scholar] [CrossRef]
  45. Nguyen, M.; Lee, M.C.; Wang, J.L.; Tomlinson, J.S.; Shao, Z.-M.; Alpaugh, M.L.; Barsky, S.H. The human myoepithelial cell displays a multifaceted anti-angiogenic phenotype. Oncogene 2000, 19, 3449–3459. [Google Scholar] [CrossRef]
  46. Gudjonsson, T.; Rønnov-Jessen, L.; Villadsen, R.; Rank, F.; Bissell, M.J.; Petersen, O.W. Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. J. Cell Sci. 2002, 115, 39–50. [Google Scholar] [CrossRef]
  47. Sternlicht, M.D.; Safarians, S.; Rivera, S.P.; Barsky, S.H. Characterizations of the extracellular matrix and proteinase inhibitor content of human myoepithelial tumors. Lab. Investig. 1996, 74, 781–796. [Google Scholar]
  48. Folgueira, M.A.A.K.; Maistro, S.; Katayama, M.L.H.; Roela, R.A.; Mundim, F.G.L.; Nanogaki, S.; de Bock, G.H.; Brentani, M.M. Markers of breast cancer stromal fibroblasts in the primary tumour site associated with lymph node metastasis: A systematic review including our case series. Biosci. Rep. 2013, 33, e00085. [Google Scholar] [CrossRef]
  49. Santi, A.; Kugeratski, F.G.; Zanivan, S. Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics 2018, 18, e1700167. [Google Scholar] [CrossRef]
  50. Yuan, Y.; Jiang, Y.-C.; Sun, C.-K.; Chen, Q.-M. Role of the tumor microenvironment in tumor progression and the clinical applications (Review). Oncol. Rep. 2016, 35, 2499–2515. [Google Scholar] [CrossRef]
  51. Gandellini, P.; Andriani, F.; Merlino, G.; D’Aiuto, F.; Roz, L.; Callari, M. Complexity in the tumour microenvironment: Cancer associated fibroblast gene expression patterns identify both common and unique features of tumour-stroma crosstalk across cancer types. Semin. Cancer Biol. 2015, 35, 96–106. [Google Scholar] [CrossRef] [PubMed]
  52. Öhlund, D.; Elyada, E.; Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 2014, 211, 1503–1523. [Google Scholar] [CrossRef] [PubMed]
  53. Shen, T.; Li, Y.; Zhu, S.; Yu, J.; Zhang, B.; Chen, X.; Zhang, Z.; Ma, Y.; Niu, Y.; Shang, Z. YAP1 plays a key role of the conversion of normal fibroblasts into cancer-associated fibroblasts that contribute to prostate cancer progression. J. Exp. Clin. Cancer Res. 2020, 39, 36. [Google Scholar] [CrossRef] [PubMed]
  54. Anderberg, C.; Pietras, K. On the origin of cancer-associated fibroblasts. Cell Cycle 2009, 8, 1461–1465. [Google Scholar] [CrossRef] [PubMed]
  55. Franco, O.E.; Jiang, M.; Strand, D.W.; Peacock, J.; Fernandez, S.; Jackson, R.S., 2nd; Revelo, M.P.; Bhowmick, N.A.; Hayward, S.W. Altered TGF-β Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis. Cancer Res. 2011, 71, 1272–1281. [Google Scholar] [CrossRef]
  56. Kiskowski, M.A.; Jackson, R.S., 2nd; Banerjee, J.; Li, X.; Kang, M.; Iturregui, J.M.; Franco, O.E.; Hayward, S.W.; Bhowmick, N.A. Role for Stromal Heterogeneity in Prostate Tumorigenesis. Cancer Res. 2011, 71, 3459–3470. [Google Scholar] [CrossRef]
  57. Astin, J.W.; Batson, J.; Kadir, S.; Charlet, J.; Persad, R.A.; Gillatt, D.; Oxley, J.D.; Nobes, C.D. Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells. Nat. Cell Biol. 2010, 12, 1194–1204. [Google Scholar] [CrossRef]
  58. Su, Q.; Zhang, B.; Zhang, L.; Dang, T.; Rowley, D.; Ittmann, M.; Xin, L. Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer. Oncogene 2017, 36, 618–627. [Google Scholar] [CrossRef]
  59. Tuxhorn, J.A.; Ayala, G.E.; Smith, M.J.; Smith, V.C.; Dang, T.D.; Rowley, D.R. Reactive stroma in human prostate cancer: Induction of myofibroblast phenotype and extracellular matrix remodeling. Clin. Cancer Res. 2002, 8, 2912–2923. [Google Scholar]
  60. Josefsson, A.; Adamo, H.; Hammarsten, P.; Granfors, T.; Stattin, P.; Egevad, L.; Laurent, A.E.; Wikström, P.; Bergh, A. Prostate Cancer Increases Hyaluronan in Surrounding Nonmalignant Stroma, and This Response Is Associated with Tumor Growth and an Unfavorable Outcome. Am. J. Pathol. 2011, 179, 1961–1968. [Google Scholar] [CrossRef]
  61. Erdogan, B.; Ao, M.; White, L.M.; Means, A.L.; Brewer, B.M.; Yang, L.; Washington, M.K.; Shi, C.; Franco, O.E.; Weaver, A.M.; et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 2017, 216, 3799–3816. [Google Scholar] [CrossRef] [PubMed]
  62. Nissen, N.I.; Karsdal, M.; Willumsen, N. Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology. J. Exp. Clin. Cancer Res. 2019, 38, 115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Jaeschke, A.; Jacobi, A.; Lawrence, M.G.; Risbridger, G.P.; Frydenberg, M.; Williams, E.D.; Vela, I.; Hutmacher, D.W.; Bray, L.J.; Taubenberger, A. Cancer-associated fibroblasts of the prostate promote a compliant and more invasive phenotype in benign prostate epithelial cells. Mater. Today Bio 2020, 8, 100073. [Google Scholar] [CrossRef] [PubMed]
  64. Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 2020, 20, 174–186. [Google Scholar] [CrossRef]
  65. Kessenbrock, K.; Plaks, V.; Werb, Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell 2010, 141, 52–67. [Google Scholar] [CrossRef]
  66. Gong, Y.; Chippada-Venkata, U.D.; Oh, W.K. Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Prostate Cancer Progression. Cancers 2014, 6, 1298–1327. [Google Scholar] [CrossRef]
  67. Escaff, S.; Fernández, J.M.; González, L.O.; Suárez, A.; González-Reyes, S.; González, J.M.; Vizoso, F.J. Study of matrix metalloproteinases and their inhibitors in prostate cancer. Br. J. Cancer 2010, 102, 922–929. [Google Scholar] [CrossRef]
  68. Fernandez-Gomez, J.; Escaf, S.; Gonzalez, L.-O.; Suarez, A.; Gonzalez-Reyes, S.; González, J.; Miranda, O.; Vizoso, F. Relationship between metalloprotease expression in tumour and stromal cells and aggressive behaviour in prostate carcinoma: Simultaneous high-throughput study of multiple metalloproteases and their inhibitors using tissue array analysis of radical prostatectomy samples. Scand. J. Urol. Nephrol. 2011, 45, 171–176. [Google Scholar] [CrossRef]
  69. Wood, M.; Fudge, K.; Mohler, J.L.; Frost, A.R.; Garcia, F.; Wang, M.; Stearns, M.E. In situ hybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer. Clin. Exp. Metastasis 1997, 15, 246–258. [Google Scholar] [CrossRef]
  70. Romero, D.; Al-Shareef, Z.; Gorroño-Etxebarria, I.; Atkins, S.; Turrell, F.; Chhetri, J.; Bengoa-Vergniory, N.; Zenzmaier, C.; Berger, P.; Waxman, J.; et al. Dickkopf-3 regulates prostate epithelial cell acinar morphogenesis and prostate cancer cell invasion by limiting TGF-β-dependent activation of matrix metalloproteases. Carcinogenesis 2016, 37, 18–29. [Google Scholar] [CrossRef]
  71. Al Shareef, Z.; Kardooni, H.; Murillo-Garzón, V.; Domenici, G.; Stylianakis, E.; Steel, J.H.; Rabano, M.; Gorroño-Etxebarria, I.; Zabalza, I.; Vivanco, M.D.; et al. Protective effect of stromal Dickkopf-3 in prostate cancer: Opposing roles for TGFBI and ECM-1. Oncogene 2018, 37, 5305–5324. [Google Scholar] [CrossRef] [PubMed]
  72. Levesque, C.; Nelson, P.S. Cellular Constituents of the Prostate Stroma: Key Contributors to Prostate Cancer Progression and Therapy Resistance. Cold Spring Harb. Perspect. Med. 2018, 8, a030510. [Google Scholar] [CrossRef]
  73. Giannoni, E.; Bianchini, F.; Masieri, L.; Serni, S.; Torre, E.; Calorini, L.; Chiarugi, P. Reciprocal Activation of Prostate Cancer Cells and Cancer-Associated Fibroblasts Stimulates Epithelial-Mesenchymal Transition and Cancer Stemness. Cancer Res. 2010, 70, 6945–6956. [Google Scholar] [CrossRef] [PubMed]
  74. Ippolito, L.; Morandi, A.; Taddei, M.L.; Parri, M.; Comito, G.; Iscaro, A.; Raspollini, M.R.; Magherini, F.; Rapizzi, E.; Masquelier, J.; et al. Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene 2019, 38, 5339–5355. [Google Scholar] [CrossRef] [PubMed]
  75. Wilde, L.; Roche, M.; Domingo-Vidal, M.; Tanson, K.; Philp, N.; Curry, J.; Martinez-Outschoorn, U. Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development. Semin. Oncol. 2017, 44, 198–203. [Google Scholar] [CrossRef]
  76. Duda, D.G.; Duyverman, A.M.M.J.; Kohno, M.; Snuderl, M.; Steller, E.J.A.; Fukumura, D.; Jain, R.K. Malignant cells facilitate lung metastasis by bringing their own soil. Proc. Natl. Acad. Sci. USA 2010, 107, 21677–21682. [Google Scholar] [CrossRef]
  77. Ortiz-Otero, N.; Clinch, A.B.; Hope, J.; Wang, W.; Reinhart-King, C.A.; King, M.R. Cancer associated fibroblasts confer shear resistance to circulating tumor cells during prostate cancer metastatic progression. Oncotarget 2020, 11, 1037–1050. [Google Scholar] [CrossRef]
  78. Rivello, F.; Matuła, K.; Piruska, A.; Smits, M.; Mehra, N.; Huck, W.T.S. Probing single-cell metabolism reveals prognostic value of highly metabolically active circulating stromal cells in prostate cancer. Sci. Adv. 2020, 6, eaaz3849. [Google Scholar] [CrossRef]
  79. Eder, T.; Weber, A.; Neuwirt, H.; Grünbacher, G.; Ploner, C.; Klocker, H.; Sampson, N.; Eder, I.E. Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture. Int. J. Mol. Sci. 2016, 17, 1458. [Google Scholar] [CrossRef]
  80. Cheteh, E.H.; Sarne, V.; Ceder, S.; Bianchi, J.; Augsten, M.; Rundqvist, H.; Egevad, L.; Östman, A.; Wiman, K.G. Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells. Cell Death Discov. 2020, 6, 42. [Google Scholar] [CrossRef]
  81. Cheteh, E.H.; Augsten, M.; Rundqvist, H.; Bianchi, J.; Sarne, V.; Egevad, L.; Bykov, V.J.; Östman, A.; Wiman, K.G. Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death. Cell Death Dis. 2017, 8, e2848. [Google Scholar] [CrossRef] [PubMed]
  82. Shan, G.; Gu, J.; Zhou, D.; Li, L.; Cheng, W.; Wang, Y.; Tang, T.; Wang, X. Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-β signaling pathway. Exp. Mol. Med. 2020, 52, 1809–1822. [Google Scholar] [CrossRef] [PubMed]
  83. Yang, L.; Wang, L.; Lin, H.-K.; Kan, P.-Y.; Xie, S.; Tsai, M.-Y.; Wang, P.-H.; Chen, Y.-T.; Chang, C. Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem. Biophys. Res. Commun. 2003, 305, 462–469. [Google Scholar] [CrossRef]
  84. Ishii, K.; Sasaki, T.; Iguchi, K.; Kajiwara, S.; Kato, M.; Kanda, H.; Hirokawa, Y.; Arima, K.; Mizokami, A.; Sugimura, Y. Interleukin-6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation. Prostate 2018, 78, 849–856. [Google Scholar] [CrossRef]
  85. Blom, S.; Erickson, A.; Östman, A.; Rannikko, A.; Mirtti, T.; Kallioniemi, O.; Pellinen, T. Fibroblast as a critical stromal cell type determining prognosis in prostate cancer. Prostate 2019, 79, 1505–1513. [Google Scholar] [CrossRef] [PubMed]
  86. Kato, M.; Placencio-Hickok, V.R.; Madhav, A.; Haldar, S.; Tripathi, M.; Billet, S.; Mishra, R.; Smith, B.; Rohena-Rivera, K.; Agarwal, P.; et al. Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner. Oncogene 2019, 38, 716–730. [Google Scholar] [CrossRef]
  87. Mishra, R.; Haldar, S.; Placencio, V.; Madhav, A.; Rohena-Rivera, K.; Agarwal, P.; Duong, F.; Angara, B.; Tripathi, M.; Liu, Z.; et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J. Clin. Investig. 2018, 128, 4472–4484. [Google Scholar] [CrossRef]
  88. Eiro, N.; Fernandez-Gomez, J.; Sacristán, R.; Fernandez-Garcia, B.; Lobo, B.; Gonzalez-Suarez, J.; Quintas, A.; Escaf, S.; Vizoso, F.J. Stromal factors involved in human prostate cancer development, progression and castration resistance. J. Cancer Res. Clin. Oncol. 2017, 143, 351–359. [Google Scholar] [CrossRef]
  89. González, L.; Eiro, N.; Fernandez-Garcia, B.; González, L.O.; Dominguez, F.; Vizoso, F.J. Gene expression profile of normal and cancer-associated fibroblasts according to intratumoral inflammatory cells phenotype from breast cancer tissue. Mol. Carcinog. 2016, 55, 1489–1502. [Google Scholar] [CrossRef]
  90. Dennis, L.K.; Lynch, C.F.; Torner, J.C. Epidemiologic association between prostatitis and prostate cancer. Urology 2002, 60, 78–83. [Google Scholar] [CrossRef]
  91. Bilani, N.; Bahmad, H.; Abou-Kheir, W. Prostate Cancer and Aspirin Use: Synopsis of the Proposed Molecular Mechanisms. Front. Pharmacol. 2017, 8, 145. [Google Scholar] [CrossRef]
  92. Kirby, R.S.; Lowe, D.; Bultitude, M.I.; Shuttleworth, K.E.D. Intra-prostatic Urinary Reflux: An Aetiological Factor in Abacterial Prostatitis. Br. J. Urol. 1982, 54, 729–731. [Google Scholar] [CrossRef] [PubMed]
  93. Gurel, B.; Lucia, M.S.; Thompson, I.M., Jr.; Goodman, P.J.; Tangen, C.M.; Kristal, A.R.; Parnes, H.L.; Hoque, A.; Lippman, S.M.; Sutcliffe, S.; et al. Chronic Inflammation in Benign Prostate Tissue Is Associated with High-Grade Prostate Cancer in the Placebo Arm of the Prostate Cancer Prevention Trial. Cancer Epidemiol. Biomarkers Prev. 2014, 23, 847–856. [Google Scholar] [CrossRef] [PubMed]
  94. Steiner, M.S.; Gingrich, J.; Chauhan, R.D. Prostate cancer gene therapy. Surg. Oncol. Clin. North Am. 2002, 11, 607–620. [Google Scholar] [CrossRef]
  95. Harper, J.; Sainson, R.C. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin. Cancer Biol. 2014, 25, 69–77. [Google Scholar] [CrossRef] [PubMed]
  96. Popivanova, B.K.; Kostadinova, F.I.; Furuichi, K.; Shamekh, M.M.; Kondo, T.; Wada, T.; Egashira, K.; Mukaida, N. Blockade of a Chemokine, CCL2, Reduces Chronic Colitis-Associated Carcinogenesis in Mice. Cancer Res. 2009, 69, 7884–7892. [Google Scholar] [CrossRef]
  97. Roca, H.; Varsos, Z.S.; Sud, S.; Craig, M.J.; Ying, C.; Pienta, K.J. CCL2 and Interleukin-6 Promote Survival of Human CD11b+ Peripheral Blood Mononuclear Cells and Induce M2-type Macrophage Polarization. J. Biol. Chem. 2009, 284, 34342–34354. [Google Scholar] [CrossRef]
  98. Lin, E.Y.; Pollard, J.W. Role of infiltrated leucocytes in tumour growth and spread. Br. J. Cancer 2004, 90, 2053–2058. [Google Scholar] [CrossRef]
  99. Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867. [Google Scholar] [CrossRef]
  100. Daniel, D.; Chiu, C.; Giraudo, E.; Inoue, M.; Mizzen, L.A.; Chu, N.R.; Hanahan, D. CD4+ T Cell-Mediated Antigen-Specific Immunotherapy in a Mouse Model of Cervical Cancer. Cancer Res. 2005, 65, 2018–2025. [Google Scholar] [CrossRef]
  101. Sica, A.; Bronte, V. Altered macrophage differentiation and immune dysfunction in tumor development. J. Clin. Investig. 2007, 117, 1155–1166. [Google Scholar] [CrossRef] [PubMed]
  102. Le Bitoux, M.-A.; Stamenkovic, I. Tumor-host interactions: The role of inflammation. Histochem. Cell Biol. 2008, 130, 1079–1090. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Bingle, L.; Brown, N.; Lewis, C.E. The role of tumour-associated macrophages in tumour progression: Implications for new anticancer therapies. J. Pathol. 2002, 196, 254–265. [Google Scholar] [CrossRef]
  104. Lewis, C.E.; Pollard, J.W. Distinct Role of Macrophages in Different Tumor Microenvironments. Cancer Res. 2006, 66, 605–612. [Google Scholar] [CrossRef]
  105. Lundholm, M.; Hägglöf, C.; Wikberg, M.L.; Stattin, P.; Egevad, L.; Bergh, A.; Wikström, P.; Palmqvist, R.; Edin, S. Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions. Sci. Rep. 2015, 5, 15651. [Google Scholar] [CrossRef]
  106. Lanciotti, M.; Masieri, L.; Raspollini, M.R.; Minervini, A.; Mari, A.; Comito, G.; Giannoni, E.; Carini, M.; Chiarugi, P.; Serni, S. The Role of M1 and M2 Macrophages in Prostate Cancer in relation to Extracapsular Tumor Extension and Biochemical Recurrence after Radical Prostatectomy. BioMed Res. Int. 2014, 2014, 486798. [Google Scholar] [CrossRef] [PubMed]
  107. Wen, J.; Huang, G.; Liu, S.; Wan, J.; Wang, X.; Zhu, Y.; Kaliney, W.; Zhang, C.; Cheng, L.; Wen, X.; et al. Polymorphonuclear MDSCs are enriched in the stroma and expanded in metastases of prostate cancer. J. Pathol. Clin. Res. 2020, 6, 171–177. [Google Scholar] [CrossRef] [PubMed]
  108. Alexe, G.; Dalgin, G.S.; Scanfeld, D.; Tamayo, P.; Mesirov, J.P.; DeLisi, C.; Harris, L.; Barnard, N.; Martel, M.; Levine, A.J.; et al. High Expression of Lymphocyte-Associated Genes in Node-Negative HER2+ Breast Cancers Correlates with Lower Recurrence Rates. Cancer Res. 2007, 67, 10669–10676. [Google Scholar] [CrossRef]
  109. Arnould, L.; Gelly, M.; Penault-Llorca, F.; Benoit, L.; Bonnetain, F.; Migeon, C.; Cabaret, V.; Fermeaux, V.; Bertheau, P.; Garnier, J.; et al. Trastuzumab-based treatment of HER2-positive breast cancer: An antibody-dependent cellular cytotoxicity mechanism? Br. J. Cancer 2006, 94, 259–267. [Google Scholar] [CrossRef]
  110. Bates, G.J.; Fox, S.B.; Han, C.; Leek, R.D.; Garcia, J.F.; Harris, A.L.; Banham, A.H. Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse. J. Clin. Oncol. 2006, 24, 5373–5380. [Google Scholar] [CrossRef]
  111. Desmedt, C.; Haibe-Kains, B.; Wirapati, P.; Buyse, M.; Larsimont, D.; Bontempi, G.; Delorenzi, M.; Piccart, M.; Sotiriou, C. Biological Processes Associated with Breast Cancer Clinical Outcome Depend on the Molecular Subtypes. Clin. Cancer Res. 2008, 14, 5158–5165. [Google Scholar] [CrossRef] [PubMed]
  112. Rody, A.; Holtrich, U.; Pusztai, L.; Liedtke, C.; Gaetje, R.; Ruckhaeberle, E.; Solbach, C.; Hanker, L.; Ahr, A.; Metzler, D.; et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 2009, 11, R15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Denkert, C.; Loibl, S.; Noske, A.; Roller, M.; Müller, B.M.; Komor, M.; Budczies, J.; Darb-Esfahani, S.; Kronenwett, R.; Hanusch, C.; et al. Tumor-Associated Lymphocytes As an Independent Predictor of Response to Neoadjuvant Chemotherapy in Breast Cancer. J. Clin. Oncol. 2010, 28, 105–113. [Google Scholar] [CrossRef] [PubMed]
  114. Löfdahl, B.; Ahlin, C.; Holmqvist, M.; Holmberg, L.; Zhou, W.; Fjällskog, M.-L.; Amini, R.-M. Inflammatory cells in node-negative breast cancer. Acta Oncol. 2012, 51, 680–686. [Google Scholar] [CrossRef] [PubMed]
  115. Mahmoud, S.; Paish, E.C.; Powe, D.G.; Macmillan, R.D.; Lee, A.H.S.; Ellis, I.; Green, A. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res. Treat. 2011, 127, 99–108. [Google Scholar] [CrossRef]
  116. Mahmoud, S.; Lee, A.H.S.; Paish, E.C.; Macmillan, R.D.; Ellis, I.; Green, A.R. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res. Treat. 2012, 132, 545–553. [Google Scholar] [CrossRef]
  117. Saltz, J.; Gupta, R.; Hou, L.; Kurc, T.; Singh, P.; Nguyen, V.; Samaras, D.; Shroyer, K.R.; Zhao, T.; Batiste, R.; et al. Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images. Cell Rep. 2018, 23, 181–193.e7. [Google Scholar] [CrossRef]
  118. Rooney, M.S.; Shukla, S.A.; Wu, C.J.; Getz, G.; Hacohen, N. Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity. Cell 2015, 160, 48–61. [Google Scholar] [CrossRef]
  119. Meng, J.; Zhou, Y.; Lu, X.; Bian, Z.; Chen, Y.; Zhou, J.; Zhang, L.; Hao, Z.; Zhang, M.; Liang, C. Immune response drives outcomes in prostate cancer: Implications for immunotherapy. Mol. Oncol. 2021, 15, 1358–1375. [Google Scholar] [CrossRef]
  120. Zhao, X.; Hu, D.; Li, J.; Zhao, G.; Tang, W.; Cheng, H. Database Mining of Genes of Prognostic Value for the Prostate Adenocarcinoma Microenvironment Using the Cancer Gene Atlas. BioMed Res. Int. 2020, 2020, 5019793. [Google Scholar] [CrossRef]
  121. Zamarron, B.F.; Chen, W. Dual Roles of Immune Cells and Their Factors in Cancer Development and Progression. Int. J. Biol. Sci. 2011, 7, 651–658. [Google Scholar] [CrossRef] [PubMed]
  122. Landskron, G.; De La Fuente, M.; Thuwajit, P.; Thuwajit, C.; Hermoso, M.A. Chronic Inflammation and Cytokines in the Tumor Microenvironment. J. Immunol. Res. 2014, 2014, 149185. [Google Scholar] [CrossRef] [Green Version]
  123. Eiró, N.; Bermudez-Fernandez, S.; Fernandez-Garcia, B.; Atienza, S.; Beridze, N.; Escaf, S.; Vizoso, F.J. Analysis of the Expression of Interleukins, Interferon β, and Nuclear Factor-κ B in Prostate Cancer and their Relationship with Biochemical Recurrence. J. Immunother. 2014, 37, 366–373. [Google Scholar] [CrossRef] [PubMed]
  124. Suh, J.; Rabson, A.B. NF-kappaB activation in human prostate cancer: Important mediator or epiphenomenon? J. Cell. Biochem. 2004, 91, 100–117. [Google Scholar] [CrossRef] [PubMed]
  125. Lee, K.C.; Bradley, D.A.; Hussain, M.; Meyer, C.R.; Chenevert, T.L.; Jacobson, J.A.; Johnson, T.D.; Galban, C.J.; Rehemtulla, A.; Pienta, K.J.; et al. A Feasibility Study Evaluating the Functional Diffusion Map as a Predictive Imaging Biomarker for Detection of Treatment Response in a Patient with Metastatic Prostate Cancer to the Bone. Neoplasia 2007, 9, 1003–1011. [Google Scholar] [CrossRef]
  126. Yu, S.-H.; Maynard, J.P.; Vaghasia, A.M.; De Marzo, A.M.; Drake, C.G.; Sfanos, K.S. A role for paracrine interleukin-6 signaling in the tumor microenvironment in prostate tumor growth. Prostate 2019, 79, 215–222. [Google Scholar] [CrossRef]
  127. Adler, H.L.; McCurdy, M.A.; Kattan, M.W.; Timme, T.L.; Scardino, P.T.; Thompson, T.C. Elevated levels of circulating inter-leukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J. Urol. 1999, 161, 182–187. [Google Scholar] [CrossRef]
  128. Drachenberg, D.E.; Elgamal, A.-A.A.; Rowbotham, R.; Peterson, M.; Murphy, G.P. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999, 41, 127–133. [Google Scholar] [CrossRef]
  129. Fizazi, K.; De Bono, J.S.; Flechon, A.; Heidenreich, A.; Voog, E.; Davis, N.B.; Qi, M.; Bandekar, R.; Vermeulen, J.T.; Cornfeld, M.; et al. Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur. J. Cancer 2012, 48, 85–93. [Google Scholar] [CrossRef]
  130. Inoue, K.; Slaton, J.W.; Eve, B.Y.; Kim, S.J.; Perrotte, P.; Balbay, M.D.; Yano, S.; Bar-Eli, M.; Radinsky, R.; Pettaway, C.A.; et al. Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin. Cancer Res. 2000, 6, 2104–2119. [Google Scholar]
  131. Mijatovic, T.; Mahieu, T.; Bruyère, C.; De Nève, N.; Dewelle, J.; Simon, G.; Dehoux, M.J.; van der Aar, E.; Haibe-Kains, B.; Bontempi, G.; et al. UNBS5162, a Novel Naphthalimide That Decreases CXCL Chemokine Expression in Experimental Prostate Cancers. Neoplasia 2008, 10, 573–586. [Google Scholar] [CrossRef] [PubMed]
  132. Butler, J.M.; Kobayashi, H.; Rafii, S. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat. Rev. Cancer 2010, 10, 138–146. [Google Scholar] [CrossRef] [PubMed]
  133. Butler, J.M.; Rafii, S. Generation of a Vascular Niche for Studying Stem Cell Homeostasis. Methods Mol. Biol. 2012, 904, 221–233. [Google Scholar] [CrossRef] [PubMed]
  134. Ghajar, C.M.; Peinado, H.; Mori, H.; Matei, I.R.; Evason, K.J.; Brazier, H.; Almeida, D.; Koller, A.; Hajjar, K.A.; Stainier, D.Y.; et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 2013, 15, 807–817. [Google Scholar] [CrossRef] [PubMed]
  135. Ghiabi, P.; Jiang, J.; Pasquier, J.; Maleki, M.; Abu-Kaoud, N.; Rafii, S.; Rafii, A. Endothelial Cells Provide a Notch-Dependent Pro-Tumoral Niche for Enhancing Breast Cancer Survival, Stemness and Pro-Metastatic Properties. PLoS ONE 2014, 9, e112424. [Google Scholar] [CrossRef]
  136. Folkman, J.; Watson, K.; Ingber, D.; Hanahan, D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 1989, 339, 58–61. [Google Scholar] [CrossRef] [PubMed]
  137. Hida, K.; Ohga, N.; Akiyama, K.; Maishi, N.; Hida, Y. Heterogeneity of tumor endothelial cells. Cancer Sci. 2013, 104, 1391–1395. [Google Scholar] [CrossRef]
  138. Bergers, G.; Benjamin, L.E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 2003, 3, 401–410. [Google Scholar] [CrossRef]
  139. Cid, S.; Eiro, N.; González, L.O.; Beridze, N.; Vazquez, J.; Vizoso, F.J. Expression and Clinical Significance of Metalloproteases and Their Inhibitors by Endothelial Cells from Invasive Breast Carcinomas. Clin. Breast Cancer 2016, 16, e83–e91. [Google Scholar] [CrossRef]
  140. Tsai, Y.-C.; Chen, W.-Y.; Abou-Kheir, W.; Zeng, T.; Yin, J.J.; Bahmad, H.; Lee, Y.-C.; Liu, Y.-N. Androgen deprivation therapy-induced epithelial-mesenchymal transition of prostate cancer through downregulating SPDEF and activating CCL2. Biochim. Biophys. Acta-Mol. Basis Dis. 2018, 1864, 1717–1727. [Google Scholar] [CrossRef]
  141. Tsao, T.; Beretov, J.; Ni, J.; Bai, X.; Bucci, J.; Graham, P.; Li, Y. Cancer stem cells in prostate cancer radioresistance. Cancer Lett. 2019, 465, 94–104. [Google Scholar] [CrossRef] [PubMed]
  142. Lazennec, G.; Jorgensen, C. Concise Review: Adult Multipotent Stromal Cells and Cancer: Risk or Benefit? Stem Cells 2008, 26, 1387–1394. [Google Scholar] [CrossRef]
  143. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.C.; Krause, D.S.; Deans, R.J.; Keating, A.; Prockop, D.J.; Horwitz, E.M. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef]
  144. Ridge, S.M.; Sullivan, F.J.; Glynn, S.A. Mesenchymal stem cells: Key players in cancer progression. Mol. Cancer 2017, 16, 31. [Google Scholar] [CrossRef] [PubMed]
  145. Lazennec, G.; Lam, P.Y. Recent discoveries concerning the tumor—Mesenchymal stem cell interactions. Biochim. Biophys. Acta 2016, 1866, 290–299. [Google Scholar] [CrossRef]
  146. El-Haibi, C.P.; Karnoub, A.E. Mesenchymal Stem Cells in the Pathogenesis and Therapy of Breast Cancer. J. Mammary Gland Biol. Neoplasia 2010, 15, 399–409. [Google Scholar] [CrossRef]
  147. Zhu, W.; Huang, L.; Li, Y.; Zhang, X.; Gu, J.; Yan, Y.; Xu, X.; Wang, M.; Qian, H.; Xu, W. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett. 2012, 315, 28–37. [Google Scholar] [CrossRef] [PubMed]
  148. Melzer, C.; Yang, Y.; Hass, R. Interaction of MSC with tumor cells. Cell Commun. Signal. 2016, 14, 20. [Google Scholar] [CrossRef] [PubMed]
  149. Syn, N.; Wang, L.; Sethi, G.; Thiery, J.-P.; Goh, B.-C. Exosome-Mediated Metastasis: From Epithelial–Mesenchymal Transition to Escape from Immunosurveillance. Trends Pharmacol. Sci. 2016, 37, 606–617. [Google Scholar] [CrossRef]
  150. Provenzano, P.P.; Inman, D.R.; Eliceiri, K.W.; Keely, P.J. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK–ERK linkage. Oncogene 2009, 28, 4326–4343. [Google Scholar] [CrossRef]
  151. Narayanan, R.; Huang, C.-C.; Ravindran, S. Hijacking the Cellular Mail: Exosome Mediated Differentiation of Mesenchymal Stem Cells. Stem Cells Int. 2016, 2016, 3808674. [Google Scholar] [CrossRef] [PubMed]
  152. Phinney, D.G.; Di Giuseppe, M.; Njah, J.; Sala, E.; Shiva, S.; St Croix, C.M.; Stolz, D.B.; Watkins, S.C.; Di, Y.P.; Leikauf, G.D.; et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat. Commun. 2015, 6, 8472. [Google Scholar] [CrossRef] [PubMed]
  153. Conforti, A.; Scarsella, M.; Starc, N.; Giorda, E.; Biagini, S.; Proia, A.; Carsetti, R.; Locatelli, F.; Bernardo, M.E. Microvescicles Derived from Mesenchymal Stromal Cells Are Not as Effective as Their Cellular Counterpart in the Ability to Modulate Immune Responses In Vitro. Stem Cells Dev. 2014, 23, 2591–2599. [Google Scholar] [CrossRef] [Green Version]
  154. Amarnath, S.; Foley, J.E.; Farthing, D.E.; Gress, R.E.; Laurence, A.; Eckhaus, M.A.; Métais, J.-Y.; Rose, J.J.; Hakim, F.T.; Felizardo, T.C.; et al. Bone Marrow-Derived Mesenchymal Stromal Cells Harness Purinergenic Signaling to Tolerize Human Th1 Cells In Vivo. Stem Cells 2015, 33, 1200–1212. [Google Scholar] [CrossRef] [PubMed]
  155. Ono, M.; Kosaka, N.; Tominaga, N.; Yoshioka, Y.; Takeshita, F.; Takahashi, R.-U.; Yoshida, M.; Tsuda, H.; Tamura, K.; Ochiya, T. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci. Signal. 2014, 7, ra63. [Google Scholar] [CrossRef]
  156. Ohyashiki, J.H.; Umezu, T.; Ohyashiki, K. Exosomes promote bone marrow angiogenesis in hematologic neoplasia: The role of hypoxia. Curr. Opin. Hematol. 2016, 23, 268–273. [Google Scholar] [CrossRef]
  157. Chen, H.-W.; Wang, L.-T.; Wang, F.-H.; Fang, L.-W.; Lai, H.-Y.; Chen, H.-H.; Lu, J.; Hung, M.-S.; Cheng, Y.; Chen, M.-Y.; et al. Mesenchymal Stem Cells Tune the Development of Monocyte-Derived Dendritic Cells Toward a Myeloid-Derived Suppressive Phenotype through Growth-Regulated Oncogene Chemokines. J. Immunol. 2013, 190, 5065–5077. [Google Scholar] [CrossRef]
  158. Contreras, H.R.; López-Moncada, F.; Castellón, E.A. Cancer stem cell and mesenchymal cell cooperative actions in metastasis progression and hormone resistance in prostate cancer: Potential role of androgen and gonadotropin-releasing hormone receptors (Review). Int. J. Oncol. 2020, 56, 1075–1082. [Google Scholar] [CrossRef]
  159. Cheng, J.-W.; Duan, L.-X.; Yu, Y.; Wang, P.; Feng, J.-L.; Feng, G.-Z.; Liu, Y. Bone marrow mesenchymal stem cells promote prostate cancer cell stemness via cell–cell contact to activate the Jagged1/Notch1 pathway. Cell Biosci. 2021, 11, 87. [Google Scholar] [CrossRef]
  160. Yu, Y.; Yang, F.-H.; Zhang, W.-T.; Guo, Y.-D.; Ye, L.; Yao, X.-D. Mesenchymal stem cells desensitize castration-resistant prostate cancer to docetaxel chemotherapy via inducing TGF-β1-mediated cell autophagy. Cell Biosci. 2021, 11, 7. [Google Scholar] [CrossRef]
  161. Chambers, A.F.; Groom, A.C.; MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2002, 2, 563–572. [Google Scholar] [CrossRef] [PubMed]
  162. Rucci, N.; Teti, A. Osteomimicry: How the Seed Grows in the Soil. Calcif. Tissue Int. 2018, 102, 131–140. [Google Scholar] [CrossRef] [PubMed]
  163. Turpin, A.; Duterque-Coquillaud, M.; Vieillard, M.-H. Bone Metastasis: Current State of Play. Transl. Oncol. 2020, 13, 308–320. [Google Scholar] [CrossRef] [PubMed]
  164. Engl, T.; Relja, B.; Marian, D.; Blumenberg, C.; Müller, I.; Beecken, W.-D.; Jones, J.; Ringel, E.M.; Bereiter-Hahn, J.; Jonas, D.; et al. CXCR4 Chemokine Receptor Mediates Prostate Tumor Cell Adhesion through α5 and β3 Integrins. Neoplasia 2006, 8, 290–301. [Google Scholar] [CrossRef]
  165. Liu, A.Y.; True, L.D. Characterization of Prostate Cell Types by CD Cell Surface Molecules. Am. J. Pathol. 2002, 160, 37–43. [Google Scholar] [CrossRef]
  166. Kostenuik, P.J.; Sanchez-Sweatman, O.; Orr, F.W.; Singh, G. Bone cell matrix promotes the adhesion of human prostatic carcinoma cells via the α2β1 integrin. Clin. Exp. Metastasis 1996, 14, 19–26. [Google Scholar] [CrossRef]
  167. Özdemir, B.C.; Hensel, J.; Secondini, C.; Wetterwald, A.; Schwaninger, R.; Fleischmann, A.; Raffelsberger, W.; Poch, O.; Delorenzi, M.; Temanni, R.; et al. The Molecular Signature of the Stroma Response in Prostate Cancer-Induced Osteoblastic Bone Metastasis Highlights Expansion of Hematopoietic and Prostate Epithelial Stem Cell Niches. PLoS ONE 2014, 9, e114530. [Google Scholar] [CrossRef]
  168. San Martin, R.; Pathak, R.; Jain, A.; Jung, S.Y.; Hilsenbeck, S.G.; Piña-Barba, M.C.; Sikora, A.G.; Pienta, K.J.; Rowley, D.R. Tenascin-C and Integrin α9 Mediate Interactions of Prostate Cancer with the Bone Microenvironment. Cancer Res. 2017, 77, 5977–5988. [Google Scholar] [CrossRef]
  169. Kiebish, M.A.; Cullen, J.; Mishra, P.; Ali, A.; Milliman, E.; Rodrigues, L.O.; Chen, E.Y.; Tolstikov, V.; Zhang, L.; Panagopoulos, K.; et al. Multi-omic serum biomarkers for prognosis of disease progression in prostate cancer. J. Transl. Med. 2020, 18, 10. [Google Scholar] [CrossRef]
  170. Cocucci, E.; Meldolesi, J. Ectosomes and exosomes: Shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015, 25, 364–372. [Google Scholar] [CrossRef]
  171. Abels, E.R.; Breakefield, X.O. Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake. Cell. Mol. Neurobiol. 2016, 36, 301–312. [Google Scholar] [CrossRef] [PubMed]
  172. Boyiadzis, M.; Whiteside, T.L. The emerging roles of tumor-derived exosomes in hematological malignancies. Leukemia 2017, 31, 1259–1268. [Google Scholar] [CrossRef] [PubMed]
  173. Parikh, A.R.; Leshchiner, I.; Elagina, L.; Goyal, L.; Levovitz, C.; Siravegna, G.; Livitz, D.; Rhrissorrakrai, K.; Martin, E.E.; Van Seventer, E.E.; et al. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat. Med. 2019, 25, 1415–1421. [Google Scholar] [CrossRef]
  174. Nilsson, J.; Skog, J.; Nordstrand, A.; Baranov, V.; Minchevanilsson, L.; Breakefield, X.O.; Widmark, A. Prostate cancer-derived urine exosomes: A novel approach to biomarkers for prostate cancer. Br. J. Cancer 2009, 100, 1603–1607. [Google Scholar] [CrossRef] [PubMed]
  175. Işın, M.; Uysaler, E.; Özgür, E.; Köseoğlu, H.; Şanlı, Ö.; Yücel, Ö.B.; Gezer, U.; Dalay, N. Exosomal lncRNA-p21 levels may help to distinguish prostate cancer from benign disease. Front. Genet. 2015, 6, 168. [Google Scholar] [CrossRef]
  176. Hatano, K.; Fujita, K. Extracellular vesicles in prostate cancer: A narrative review. Transl. Androl. Urol. 2021, 10, 1890–1907. [Google Scholar] [CrossRef]
  177. Nanou, A.; Coumans, F.A.; van Dalum, G.; Zeune, L.L.; Dolling, D.; Onstenk, W.; Crespo, M.; Fontes, M.S.; Rescigno, P.; Fowler, G.; et al. Circulating tumor cells, tumor-derived extracellular vesicles and plasma cytokeratins in castration-resistant prostate cancer patients. Oncotarget 2018, 9, 19283–19293. [Google Scholar] [CrossRef]
  178. Yu, Q.; Li, P.; Weng, M.; Wu, S.; Zhang, Y.; Chen, X.; Zhang, Q.; Shen, G.; Ding, X.; Fu, S. Nano-Vesicles are a Potential Tool to Monitor Therapeutic Efficacy of Carbon Ion Radiotherapy in Prostate Cancer. J. Biomed. Nanotechnol. 2018, 14, 168–178. [Google Scholar] [CrossRef]
  179. Fredsøe, J.; Rasmussen, A.K.I.; Mouritzen, P.; Borre, M.; Ørntoft, T.; Sørensen, K.D. A five-microRNA model (pCaP) for predicting prostate cancer aggressiveness using cell-free urine. Int. J. Cancer 2019, 145, 2558–2567. [Google Scholar] [CrossRef]
  180. Elmageed, Z.Y.A.; Yang, Y.; Thomas, R.; Ranjan, M.; Mondal, D.; Moroz, K.; Fang, Z.; Rezk, B.M.; Moparty, K.; Sikka, S.C.; et al. Neoplastic Reprogramming of Patient-Derived Adipose Stem Cells by Prostate Cancer Cell-Associated Exosomes. Stem Cells 2014, 32, 983–997. [Google Scholar] [CrossRef]
  181. Minciacchi, V.R.; Spinelli, C.; Reis-Sobreiro, M.; Cavallini, L.; You, S.; Zandian, M.; Li, X.; Mishra, R.; Chiarugi, P.; Adam, R.M.; et al. MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer. Cancer Res. 2017, 77, 2306–2317. [Google Scholar] [CrossRef] [PubMed]
  182. Dostert, G.; Mesure, B.; Menu, P.; Velot, E. How Do Mesenchymal Stem Cells Influence or Are Influenced by Microenvironment through Extracellular Vesicles Communication? Front. Cell Dev. Biol. 2017, 5, 6. [Google Scholar] [CrossRef] [PubMed]
  183. Sharma, A. Bioinformatic analysis revealing association of exosomal mRNAs and proteins in epigenetic inheritance. J. Theor. Biol. 2014, 357, 143–149. [Google Scholar] [CrossRef] [PubMed]
  184. Lindoso, R.S.; Collino, F.; Camussi, G. Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells. Oncotarget 2015, 6, 7959–7969. [Google Scholar] [CrossRef] [PubMed]
  185. Sánchez, C.A.; Andahur, E.I.; Valenzuela, R.; Castellón, E.A.; Fullá, J.A.; Ramos, C.G.; Triviño, J.C. Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche. Oncotarget 2016, 7, 3993–4008. [Google Scholar] [CrossRef]
  186. Lee, K.W.; Cho, J.A.; Park, H.; Lim, E.H. Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int. J. Oncol. 2012, 40, 130–138. [Google Scholar] [CrossRef]
  187. Dai, J.; Escara-Wilke, J.; Keller, J.M.; Jung, Y.; Taichman, R.S.; Pienta, K.J.; Keller, E.T. Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis. J. Exp. Med. 2019, 216, 2883–2899. [Google Scholar] [CrossRef]
  188. Vlaeminck-Guillem, V. Extracellular Vesicles in Prostate Cancer Carcinogenesis, Diagnosis, and Management. Front. Oncol. 2018, 8, 222. [Google Scholar] [CrossRef]
  189. Morello, M.; Minciacchi, V.; de Candia, P.; Yang, J.; Posadas, E.; Kim, H.; Griffiths, D.; Bhowmick, N.; Chung, L.; Gandellini, P.; et al. Large oncosomes mediate intercellular transfer of functional microRNA. Cell Cycle 2013, 12, 3526–3536. [Google Scholar] [CrossRef]
  190. Webber, J.P.; Spary, L.K.; Sanders, A.J.; Chowdhury, R.; Jiang, W.G.; Steadman, R.; Wymant, J.; Jones, A.T.; Kynaston, H.; Mason, M.D.; et al. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 2015, 34, 290–302. [Google Scholar] [CrossRef]
  191. Chowdhury, R.; Webber, J.P.; Gurney, M.; Mason, M.D.; Tabi, Z.; Clayton, A. Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts. Oncotarget 2015, 6, 715–731. [Google Scholar] [CrossRef] [PubMed]
  192. Josson, S.; Gururajan, M.; Sung, S.Y.; Hu, P.; Shao, C.; Zhau, H.E.; Liu, C.; Lichterman, J.; Duan, P.; Li, Q.; et al. Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. Oncogene 2015, 34, 2690–2699. [Google Scholar] [CrossRef] [PubMed]
  193. Castellana, D.; Zobairi, F.; Martinez, M.C.; Panaro, M.A.; Mitolo, V.; Freyssinet, J.-M.; Kunzelmann, C. Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis. Cancer Res. 2009, 69, 785–793. [Google Scholar] [CrossRef] [Green Version]
  194. Zhao, H.; Yang, L.; Baddour, J.; Achreja, A.; Bernard, V.; Moss, T.; Marini, J.C.; Tudawe, T.; Seviour, E.G.; San Lucas, F.A.; et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 2016, 5, e10250. [Google Scholar] [CrossRef]
  195. Lundholm, M.; Schröder, M.; Nagaeva, O.; Baranov, V.; Widmark, A.; Mincheva-Nilsson, L.; Wikström, P. Prostate Tumor-Derived Exosomes Down-Regulate NKG2D Expression on Natural Killer Cells and CD8+ T Cells: Mechanism of Immune Evasion. PLoS ONE 2014, 9, e108925. [Google Scholar] [CrossRef]
  196. Guan, H.; Peng, R.; Fang, F.; Mao, L.; Chen, Z.; Yang, S.; Dai, C.; Wu, H.; Wang, C.; Feng, N.; et al. Tumor-associated macrophages promote prostate cancer progression via exosome-mediated miR-95 transfer. J. Cell. Physiol. 2020, 235, 9729–9742. [Google Scholar] [CrossRef]
  197. Di Trapani, M.; Bassi, G.; Midolo, M.; Gatti, A.; Kamga, P.T.; Cassaro, A.; Carusone, R.; Adamo, A.; Krampera, M. Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Sci. Rep. 2016, 6, 24120. [Google Scholar] [CrossRef] [PubMed]
  198. Marote, A.; Teixeira, F.G.; Mendes-Pinheiro, B.; Salgado, A.J. MSCs-Derived Exosomes: Cell-Secreted Nanovesicles with Regenerative Potential. Front. Pharmacol. 2016, 7, 231. [Google Scholar] [CrossRef] [PubMed]
  199. Lai, R.C.; Tan, S.S.; Teh, B.J.; Sze, S.K.; Arslan, F.; De Kleijn, D.P.; Choo, A.; Lim, S.K. Proteolytic Potential of the MSC Exosome Proteome: Implications for an Exosome-Mediated Delivery of Therapeutic Proteasome. Int. J. Proteom. 2012, 2012, 971907. [Google Scholar] [CrossRef]
  200. Chen, T.S.; Lai, R.C.; Lee, M.M.; Choo, A.B.H.; Lee, C.N.; Lim, S.K. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010, 38, 215–224. [Google Scholar] [CrossRef]
  201. Whiteside, T.L. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin. Immunol. 2018, 35, 69–79. [Google Scholar] [CrossRef] [PubMed]
  202. Weinberg, R.A. Coevolution in the tumor microenvironment. Nat. Genet. 2008, 40, 494–495. [Google Scholar] [CrossRef] [PubMed]
  203. Bianchi-Frias, D.; Basom, R.; Delrow, J.J.; Coleman, I.M.; Dakhova, O.; Qu, X.; Fang, M.; Franco, O.E.; Ericson, N.G.; Bielas, J.H.; et al. Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations. Mol. Cancer Res. 2016, 14, 374–384. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  204. Qiu, W.; Hu, M.; Sridhar, A.; Opeskin, K.; Fox, S.; Shipitsin, M.; Trivett, M.; Thompson, E.R.; Ramakrishna, M.; Gorringe, K.; et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat. Genet. 2008, 40, 650–655. [Google Scholar] [CrossRef] [PubMed]
  205. Kristensen, T.B.; Knutsson, M.L.T.; Wehland, M.; Laursen, B.E.; Grimm, D.; Warnke, E.; Magnusson, N.E. Anti-Vascular Endothelial Growth Factor Therapy in Breast Cancer. Int. J. Mol. Sci. 2014, 15, 23024–23041. [Google Scholar] [CrossRef] [PubMed]
  206. Hsieh, T.-C.; Wu, J.M. Resveratrol Suppresses Prostate Cancer Epithelial Cell Scatter/Invasion by Targeting Inhibition of Hepatocyte Growth Factor (HGF) Secretion by Prostate Stromal Cells and Upregulation of E-cadherin by Prostate Cancer Epithelial Cells. Int. J. Mol. Sci. 2020, 21, 1760. [Google Scholar] [CrossRef]
  207. Bonollo, F.; Thalmann, G.N.; Kruithof-de Julio, M.; Karkampouna, S. The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis. Cancers 2020, 12, 1887. [Google Scholar] [CrossRef]
  208. Correia, A.L.; Bissell, M.J. The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist. Updat. 2012, 15, 39–49. [Google Scholar] [CrossRef]
  209. Kerbel, R.S. A cancer therapy resistant to resistance. Nature 1997, 390, 335–336. [Google Scholar] [CrossRef]
  210. Glentis, A.; Oertle, P.; Mariani, P.; Chikina, A.; El Marjou, F.; Attieh, Y.; Zaccarini, F.; Lae, M.; Loew, D.; Dingli, F.; et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 2017, 8, 924. [Google Scholar] [CrossRef]
  211. Tuder, R.M.; Lara, A.R.; Thannickal, V.J. Lactate, a Novel Trigger of Transforming Growth Factor-β Activation in Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 2012, 186, 701–703. [Google Scholar] [CrossRef] [PubMed]
  212. Zhang, X.H.-F.; Jin, X.; Malladi, S.; Zou, Y.; Wen, Y.H.; Brogi, E.; Smid, M.; Foekens, J.A.; Massagué, J. Selection of Bone Metastasis Seeds by Mesenchymal Signals in the Primary Tumor Stroma. Cell 2013, 154, 1060–1073. [Google Scholar] [CrossRef]
  213. Khan, G.J.; Sun, L.; Khan, S.; Yuan, S.; Nongyue, H. Versatility of Cancer Associated Fibroblasts: Commendable Targets for Anti-tumor Therapy. Curr. Drug Targets 2018, 19, 1573–1588. [Google Scholar] [CrossRef] [PubMed]
  214. Pietrovito, L.; Iozzo, M.; Bacci, M.; Giannoni, E.; Chiarugi, P. Treatment with Cannabinoids as a Promising Approach for Impairing Fibroblast Activation and Prostate Cancer Progression. Int. J. Mol. Sci. 2020, 21, 787. [Google Scholar] [CrossRef] [PubMed]
  215. Dorff, T.B.; Goldman, B.; Pinski, J.K.; Mack, P.C.; Lara, P.N., Jr.; Van Veldhuizen, P.J., Jr.; Quinn, D.I.; Vogelzang, N.J.; Thompson, I.M., Jr.; Hussain, M.H. Clinical and Correlative Results of SWOG S0354: A Phase II Trial of CNTO328 (Siltuximab), a Monoclonal Antibody against Interleukin-6, in Chemotherapy-Pretreated Patients with Castration-Resistant Prostate Cancer. Clin. Cancer Res. 2010, 16, 3028–3034. [Google Scholar] [CrossRef] [PubMed]
  216. Alas, S.; Emmanouilides, C.; Bonavida, B. Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin’s lymphoma to apoptosis. Clin. Cancer Res. 2001, 7, 709–723. [Google Scholar]
  217. Webb, E.S.; Liu, P.; Baleeiro, R.; Lemoine, N.R.; Yuan, M.; Wang, Y.-H. Immune checkpoint inhibitors in cancer therapy. J. Biomed. Res. 2018, 32, 317–326. [Google Scholar] [CrossRef]
  218. Stultz, J.; Fong, L. How to turn up the heat on the cold immune microenvironment of metastatic prostate cancer. Prostate Cancer Prostatic Dis. 2021, 24, 697–717. [Google Scholar] [CrossRef]
  219. Redman, J.M.; Gibney, G.T.; Atkins, M.B. Advances in immunotherapy for melanoma. BMC Med. 2016, 14, 20. [Google Scholar] [CrossRef]
  220. Rolfo, C.; Caglevic, C.; Santarpia, M.; Araujo, A.; Giovannetti, E.; Gallardo, C.D.; Pauwels, P.; Mahave, M. Immunotherapy in NSCLC: A Promising and Revolutionary Weapon. Adv. Exp. Med. Biol. 2017, 995, 97–125. [Google Scholar] [CrossRef]
  221. Fukumura, D.; Kloepper, J.; Amoozgar, Z.; Duda, D.G.; Jain, R.K. Enhancing cancer immunotherapy using antiangiogenics: Opportunities and challenges. Nat. Rev. Clin. Oncol. 2018, 15, 325–340. [Google Scholar] [CrossRef] [PubMed]
  222. Ardiani, A.; Farsaci, B.; Rogers, C.J.; Protter, A.; Guo, Z.; King, T.H.; Apelian, D.; Hodge, J.W. Combination Therapy with a Second-Generation Androgen Receptor Antagonist and a Metastasis Vaccine Improves Survival in a Spontaneous Prostate Cancer Model. Clin. Cancer Res. 2013, 19, 6205–6218. [Google Scholar] [CrossRef] [PubMed]
  223. Ardiani, A.; Gameiro, S.R.; Kwilas, A.R.; Donahue, R.N.; Hodge, J.W. Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway. Oncotarget 2014, 5, 9335–9348. [Google Scholar] [CrossRef] [PubMed]
  224. Chiu, H.H.; Yong, T.M.; Wang, J.; Wang, Y.; Vessella, R.L.; Ueda, T.; Wang, Y.-Z.; Sadar, M.D. Induction of neuronal apoptosis inhibitory protein expression in response to androgen deprivation in prostate cancer. Cancer Lett. 2010, 292, 176–185. [Google Scholar] [CrossRef] [Green Version]
  225. Kantoff, P.; Schuetz, T.J.; Blumenstein, B.A.; Glode, L.M.; Bilhartz, D.L.; Wyand, M.; Manson, K.; Panicali, D.L.; Laus, R.; Schlom, J.; et al. Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer. J. Clin. Oncol. 2010, 28, 1099–1105. [Google Scholar] [CrossRef]
  226. Antonarakis, E.S.; Kibel, A.S.; Yu, E.Y.; Karsh, L.I.; Elfiky, A.; Shore, N.D.; Vogelzang, N.J.; Corman, J.M.; Millard, F.E.; Maher, J.C.; et al. Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial. Clin. Cancer Res. 2017, 23, 2451–2459. [Google Scholar] [CrossRef]
  227. McNeel, D.G.; Smith, H.A.; Eickhoff, J.C.; Lang, J.M.; Staab, M.J.; Wilding, G.; Liu, G. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol. Immunother. 2012, 61, 1137–1147. [Google Scholar] [CrossRef]
  228. Long, X.; Hou, H.; Wang, X.; Liu, S.; Diao, T.; Lai, S.; Hu, M.; Zhang, S.; Liu, M.; Zhang, H. Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration. Cell Death Dis. 2020, 11, 779. [Google Scholar] [CrossRef]
  229. Abida, W.; Cheng, M.L.; Armenia, J.; Middha, S.; Autio, K.A.; Vargas, H.A.; Rathkopf, D.; Morris, M.J.; Danila, D.C.; Slovin, S.F.; et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2019, 5, 471–478. [Google Scholar] [CrossRef] [PubMed]
  230. Wu, Y.-M.; Cieślik, M.; Lonigro, R.J.; Vats, P.; Reimers, M.A.; Cao, X.; Ning, Y.; Wang, L.; Kunju, L.P.; de Sarkar, N.; et al. Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 2018, 173, 1770–1782.e14. [Google Scholar] [CrossRef]
  231. Lang, S.H.; Swift, S.L.; White, H.; Misso, K.; Kleijnen, J.; Quek, R.G. A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer. Int. J. Oncol. 2019, 55, 597–616. [Google Scholar] [CrossRef] [PubMed]
  232. Vizoso, F.J.; Eiro, N.; Costa, L.; Esparza, P.; Landin, M.; Diaz-Rodriguez, P.; Schneider, J.; Perez-Fernandez, R. Mesenchymal Stem Cells in Homeostasis and Systemic Diseases: Hypothesis, Evidences, and Therapeutic Opportunities. Int. J. Mol. Sci. 2019, 20, 3738. [Google Scholar] [CrossRef]
  233. Fernández-Francos, S.; Eiro, N.; Costa, L.; Escudero-Cernuda, S.; Fernández-Sánchez, M.; Vizoso, F. Mesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine. Int. J. Mol. Sci. 2021, 22, 3576. [Google Scholar] [CrossRef] [PubMed]
  234. Eiro, N.; Fraile, M.; Fernández-Francos, S.; Sánchez, R.; Costa, L.A.; Vizoso, F.J. Importance of the origin of mesenchymal (stem) stromal cells in cancer biology: “alliance” or “war” in intercellular signals. Cell Biosci. 2021, 11, 109. [Google Scholar] [CrossRef] [PubMed]
  235. Costa, L.A.; Eiro, N.; Fraile, M.; Gonzalez, L.O.; Saá, J.; Garcia-Portabella, P.; Vega, B.; Schneider, J.; Vizoso, F.J. Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: Implications for further clinical uses. Cell. Mol. Life Sci. 2021, 78, 447–467. [Google Scholar] [CrossRef] [PubMed]
  236. Eiro, N.; Fraile, M.; Schneider, J.; Vizoso, F. Non Pregnant Human Uterus as Source of Mesenchymal Stem Cells. Curr. Stem Cell Res. Ther. 2018, 13, 423–431. [Google Scholar] [CrossRef] [PubMed]
  237. Eiró, N.; Sendon-Lago, J.; Seoane, S.; Bermúdez, M.A.; Lamelas, M.L.; Garcia-Caballero, T.; Schneider, J.; Perez-Fernandez, R.; Vizoso, F.J. Potential therapeutic effect of the secretome from human uterine cervical stem cells against both cancer and stromal cells compared with adipose tissue stem cells. Oncotarget 2014, 5, 10692–10708. [Google Scholar] [CrossRef]
  238. Schneider, J.; Eiró, N.; Pérez-Fernández, R.; Martínez-Ordóñez, A.; Vizoso, F. Human Uterine Cervical Stromal Stem Cells (hUCESCs): Why and How they Exert their Antitumor Activity. Cancer Genom. Proteom. 2016, 13, 331–337. [Google Scholar]
  239. Maffey, A.; Storini, C.; Diceglie, C.; Martelli, C.; Sironi, L.; Calzarossa, C.; Tonna, N.; Lovchik, R.; Delamarche, E.; Ottobrini, L.; et al. Mesenchymal stem cells from tumor microenvironment favour breast cancer stem cell proliferation, cancerogenic and metastatic potential, via ionotropic purinergic signalling. Sci. Rep. 2017, 7, 13162. [Google Scholar] [CrossRef]
  240. Mader, E.K.; Maeyama, Y.; Lin, Y.; Butler, G.W.; Russell, H.M.; Galanis, E.; Russell, S.J.; Dietz, A.B.; Peng, K.-W. Mesenchymal Stem Cell Carriers Protect Oncolytic Measles Viruses from Antibody Neutralization in an Orthotopic Ovarian Cancer Therapy Model. Clin. Cancer Res. 2009, 15, 7246–7255. [Google Scholar] [CrossRef]
  241. Kim, J.; Hall, R.R.; Lesniak, M.S.; Ahmed, A.U. Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions. Viruses 2015, 7, 6200–6217. [Google Scholar] [CrossRef] [PubMed]
  242. Ren, C.; Kumar, S.; Chanda, D.D.; Kallman, L.; Chen, J.; Mountz, J.D.; Ponnazhagan, S. Cancer gene therapy using mesenchymal stem cells expressing interferon-β in a mouse prostate cancer lung metastasis model. Gene Ther. 2008, 15, 1446–1453. [Google Scholar] [CrossRef] [PubMed]
  243. Cavarretta, I.; Altanerova, V.; Matuskova, M.; Kucerova, L.; Culig, Z.; Altaner, C. Adipose Tissue–derived Mesenchymal Stem Cells Expressing Prodrug-converting Enzyme Inhibit Human Prostate Tumor Growth. Mol. Ther. 2010, 18, 223–231. [Google Scholar] [CrossRef] [PubMed]
  244. Levy, O.; Brennen, W.N.; Han, E.; Rosen, D.M.; Musabeyezu, J.; Safaee, H.; Ranganath, S.; Ngai, J.; Heinelt, M.; Milton, Y.; et al. A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials 2016, 91, 140–150. [Google Scholar] [CrossRef]
  245. Teixeira, F.G.; Salgado, A.J. Mesenchymal stem cells secretome: Current trends and future challenges. Neural Regen. Res. 2020, 15, 75–77. [Google Scholar] [CrossRef]
  246. Osugi, M.; Katagiri, W.; Yoshimi, R.; Inukai, T.; Hibi, H.; Ueda, M. Conditioned Media from Mesenchymal Stem Cells Enhanced Bone Regeneration in Rat Calvarial Bone Defects. Tissue Eng. Part A 2012, 18, 1479–1489. [Google Scholar] [CrossRef]
  247. Wei, W.; Ao, Q.; Wang, X.; Cao, Y.; Liu, Y.; Zheng, S.G.; Tian, X. Mesenchymal Stem Cell–Derived Exosomes: A Promising Biological Tool in Nanomedicine. Front. Pharmacol. 2020, 11, 590470. [Google Scholar] [CrossRef]
  248. Takahara, K.; Ii, M.; Inamoto, T.; Nakagawa, T.; Ibuki, N.; Yoshikawa, Y.; Tsujino, T.; Uchimoto, T.; Saito, K.; Takai, T.; et al. microRNA-145 Mediates the Inhibitory Effect of Adipose Tissue-Derived Stromal Cells on Prostate Cancer. Stem Cells Dev. 2016, 25, 1290–1298. [Google Scholar] [CrossRef]
  249. Smyth, T.J.; Redzic, J.S.; Graner, M.W.; Anchordoquy, T.J. Examination of the specificity of tumor cell derived exosomes with tumor cells in vitro. Biochim. Biophys. Acta-Biomembr. 2014, 1838, 2954–2965. [Google Scholar] [CrossRef]
  250. Kidd, S.; Spaeth, E.; Dembinski, J.L.; Dietrich, M.; Watson, K.; Klopp, A.; Battula, V.L.; Weil, M.; Andreeff, M.; Marini, F.C. Direct Evidence of Mesenchymal Stem Cell Tropism for Tumor and Wounding Microenvironments Using In Vivo Bioluminescent Imaging. Stem Cells 2009, 27, 2614–2623. [Google Scholar] [CrossRef]
  251. Spugnini, E.P.; Logozzi, M.; Di Raimo, R.; Mizzoni, D.; Fais, S. A Role of Tumor-Released Exosomes in Paracrine Dissemination and Metastasis. Int. J. Mol. Sci. 2018, 19, 3968. [Google Scholar] [CrossRef] [PubMed]
  252. Heaphy, C.M.; Yoon, G.S.; Peskoe, S.B.; Joshu, C.E.; Lee, T.K.; Giovannucci, E.; Mucci, L.A.; Kenfield, S.A.; Stampfer, M.J.; Hicks, J.L.; et al. Prostate Cancer Cell Telomere Length Variability and Stromal Cell Telomere Length as Prognostic Markers for Metastasis and Death. Cancer Discov. 2013, 3, 1130–1141. [Google Scholar] [CrossRef] [PubMed]
  253. Joshu, C.E.; Peskoe, S.B.; Heaphy, C.M.; Kenfield, S.A.; Van Blarigan, E.L.; Mucci, L.A.; Giovannucci, E.L.; Stampfer, M.J.; Yoon, G.; Lee, T.K.; et al. Prediagnostic Obesity and Physical Inactivity Are Associated with Shorter Telomere Length in Prostate Stromal Cells. Cancer Prev. Res. 2015, 8, 737–742. [Google Scholar] [CrossRef] [PubMed]
  254. Joshu, C.E.; Heaphy, C.M.; Barber, J.R.; Lu, J.; Zarinshenas, R.; Davis, C.; Han, M.; Lotan, T.L.; Sfanos, K.S.; De Marzo, A.M.; et al. Obesity is Associated with Shorter Telomere Length in Prostate Stromal Cells in Men with Aggressive Prostate Cancer. Cancer Prev. Res. 2020, 14, 463–470. [Google Scholar] [CrossRef] [PubMed]
  255. Gevaert, T.; Van Eycke, Y.-R.; Vanden Broeck, T.; Van Poppel, H.; Salmon, I.; Rorive, S.; Muilwijk, T.; Claessens, F.; De Ridder, D.; Joniau, S.; et al. The potential of tumour microenvironment markers to stratify the risk of recurrence in prostate cancer patients. PLoS ONE 2020, 15, e0244663. [Google Scholar] [CrossRef]
  256. Frankenstein, Z.; Basanta, D.; Franco, O.E.; Gao, Y.; Javier, R.A.; Strand, D.W.; Lee, M.; Hayward, S.W.; Ayala, G.; Anderson, A.R.A. Stromal reactivity differentially drives tumour cell evolution and prostate cancer progression. Nat. Ecol. Evol. 2020, 4, 870–884. [Google Scholar] [CrossRef]
  257. Mahal, B.A.; Alshalalfa, M.; Zhao, S.G.; Beltran, H.; Chen, W.S.; Chipidza, F.; Davicioni, E.; Karnes, R.J.; Ku, S.; Lotan, T.L.; et al. Genomic and clinical characterization of stromal infiltration markers in prostate cancer. Cancer 2020, 126, 1407–1412. [Google Scholar] [CrossRef]
  258. Bhargava, H.K.; Leo, P.; Elliott, R.; Janowczyk, A.; Whitney, J.; Gupta, S.; Fu, P.; Yamoah, K.; Khani, F.; Robinson, B.D.; et al. Computationally Derived Image Signature of Stromal Morphology Is Prognostic of Prostate Cancer Recurrence Following Prostatectomy in African American Patients. Clin. Cancer Res. 2020, 26, 1915–1923. [Google Scholar] [CrossRef] [Green Version]
Figure 1. Evolution of the number of published studies based on the tumoral stroma in breast and prostate carcinomas. Source: PubMed.
Figure 1. Evolution of the number of published studies based on the tumoral stroma in breast and prostate carcinomas. Source: PubMed.
Cancers 14 04412 g001
Figure 2. Representative tissue section. (A) Normal prostate tissue with epithelial luminal and basal layers and the surrounding stroma tissue (200×). (B) Benign prostate hypertrophy (BPH) tissue showing cell proliferation and migration (200×). (C) Proliferative inflammatory atrophy (PIA) tissue (100×). (D) High-grade prostatic intraepithelial neoplasia (HGPIN) in the peripheral zone of the prostate (200×). (E) Prostate cancer tissue (100×).
Figure 2. Representative tissue section. (A) Normal prostate tissue with epithelial luminal and basal layers and the surrounding stroma tissue (200×). (B) Benign prostate hypertrophy (BPH) tissue showing cell proliferation and migration (200×). (C) Proliferative inflammatory atrophy (PIA) tissue (100×). (D) High-grade prostatic intraepithelial neoplasia (HGPIN) in the peripheral zone of the prostate (200×). (E) Prostate cancer tissue (100×).
Cancers 14 04412 g002
Figure 3. Schematic representation of the cellular components from a prostate tumor.
Figure 3. Schematic representation of the cellular components from a prostate tumor.
Cancers 14 04412 g003
Figure 4. Schematic representation of paracrine interactions through exosomes among different cell types from prostate carcinomas. T-D-EXs: tumor-derived exosomes; MSC-D-EXs: mesenchymal stem cell-derived exosomes; CAFs: cancer-associated fibroblasts; MICs: mononuclear inflammatory cells.
Figure 4. Schematic representation of paracrine interactions through exosomes among different cell types from prostate carcinomas. T-D-EXs: tumor-derived exosomes; MSC-D-EXs: mesenchymal stem cell-derived exosomes; CAFs: cancer-associated fibroblasts; MICs: mononuclear inflammatory cells.
Cancers 14 04412 g004
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

González, L.O.; Eiro, N.; Fraile, M.; Beridze, N.; Escaf, A.R.; Escaf, S.; Fernández-Gómez, J.M.; Vizoso, F.J. Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment. Cancers 2022, 14, 4412.

AMA Style

González LO, Eiro N, Fraile M, Beridze N, Escaf AR, Escaf S, Fernández-Gómez JM, Vizoso FJ. Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment. Cancers. 2022; 14(18):4412.

Chicago/Turabian Style

González, Luis O., Noemi Eiro, Maria Fraile, Nana Beridze, Andres R. Escaf, Safwan Escaf, Jesús M. Fernández-Gómez, and Francisco J. Vizoso. 2022. "Prostate Cancer Tumor Stroma: Responsibility in Tumor Biology, Diagnosis and Treatment" Cancers 14, no. 18: 4412.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop