Next Article in Journal
Delay of Aortic Arterial Input Function Time Improves Detection of Malignant Vertebral Body Lesions on Dynamic Contrast-Enhanced MRI Perfusion
Next Article in Special Issue
Mutational Signatures in Gastric Cancer and Their Clinical Implications
Previous Article in Journal
Gene Targets of CAR-T Cell Therapy for Glioblastoma
Previous Article in Special Issue
Rising Incidence of Non-Cardia Gastric Cancer among Young Women in the United States, 2000–2018: A Time-Trend Analysis Using the USCS Database
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 15
Issue 8
10.3390/cancers15082354
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities

by
Kay K. Myo Min
1,†,
Charlie B. Ffrench
1,†,
Claire F. Jessup
2,3,
Mia Shepherdson
2,4,
Savio George Barreto
2,4 and
Claudine S. Bonder
1,3,*
1
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia
2
College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia
3
Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia
4
Hepatopancreatobiliary & Liver Transplant Unit, Division of Surgery & Perioperative Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2023, 15(8), 2354; https://doi.org/10.3390/cancers15082354
Submission received: 17 March 2023 / Revised: 6 April 2023 / Accepted: 14 April 2023 / Published: 18 April 2023
(This article belongs to the Special Issue Clinical and Translational Research in Gastrointestinal Cancers)
Browse Figures
Review Reports Versions Notes

Abstract

:

Simple Summary

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic tumours, representing greater than 90% of all diagnosed cases of pancreatic cancer. PDAC has the lowest 5-year survival rate of all tumour malignancies with less than 9% patient survival. A unique feature of PDAC tumours is the presence of a dense fibrotic fortress that creates a physical barrier around the cancer cells, thus resulting in a reduced penetrability of drugs and a ‘sanctuary’ in which cancer cells thrive, termed desmoplasia. Extensive desmoplasia in the PDAC tumour microenvironment (TME) is a crucial factor that influences PDAC development, progression, metastasis, and resistance to treatment. This review will focus on the role of the TME in PDAC, current treatments for PDAC, and a reflection on past and current clinical trials targeting components of the TME in PDAC.

Abstract

An overabundance of desmoplasia in the tumour microenvironment (TME) is one of the defining features that influences pancreatic ductal adenocarcinoma (PDAC) development, progression, metastasis, and treatment resistance. Desmoplasia is characterised by the recruitment and activation of fibroblasts, heightened extracellular matrix deposition (ECM) and reduced blood supply, as well as increased inflammation through an influx of inflammatory cells and cytokines, creating an intrinsically immunosuppressive TME with low immunogenic potential. Herein, we review the development of PDAC, the drivers that initiate and/or sustain the progression of the disease and the complex and interwoven nature of the cellular and acellular components that come together to make PDAC one of the most aggressive and difficult to treat cancers. We review the challenges in delivering drugs into the fortress of PDAC tumours in concentrations that are therapeutic due to the presence of a highly fibrotic and immunosuppressive TME. Taken together, we present further support for continued/renewed efforts focusing on aspects of the extremely dense and complex TME of PDAC to improve the efficacy of therapy for better patient outcomes.

Graphical Abstract

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic neoplasms, representing greater than 90% of all diagnosed cases of pancreatic cancer with neuroendocrine tumours accounting for the remaining 10% [1]. PDAC has the lowest 5-year survival rate of all tumour malignancies with less than 9% patient survival [2]. Poor survival of patients with PDAC is largely attributed to the cancer developing with few symptoms and as a result, most PDAC patients are diagnosed with an advanced stage of disease, often including metastases to the liver, lungs, and peritoneum [3,4,5]. Unfortunately, the incidence of PDAC is on the rise. In the United States, the incidence of pancreatic cancer is projected to reach the second leading cause of cancer-related death (behind lung cancer) by 2040 and will surpass breast, prostate, and colorectal cancers [2,6].

2. Disease Development

PDAC originates from the exocrine portion of the pancreas which constitutes 90% of the organ and consists of acinar cells and a ductal network. Acinar cells exhibit a degree of plasticity which allows them to contribute to both homeostasis and regeneration of pancreatic exocrine tissue. Under environmental stimuli (e.g., tissue damage, inflammation, stress) acinar cells transdifferentiate to a more epithelial phenotype, a process known as acinar to ductal metaplasia (ADM) [7,8]. During ADM, acinar cells are more susceptible to mutational hits, which can accumulate and lead to the development of precursor neoplasms and invasive adenocarcinoma (Figure 1). Pancreatic intraepithelial neoplasms (PanINs) are the most common form of pancreatic precursor lesions. The three grades of PanINs, namely, PanIN-1A (flat) and PanIN-1B (papillary), PanIN-2 and PanIN-3 consist of increasing amounts of cell atypia [9]. Additionally, intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are cystic pancreatic lesions that can also lead to invasive PDAC [7,9]. The accumulation of genetic changes (in several oncogenic and tumour suppressor genes) within these cells leads to an invasive PDAC [7].

3. Drivers

A unique feature of PDAC tumours is an abundance of dense fibrotic stroma that constitutes up to 90% of the tumour volume [10,11]. The dense desmoplastic stroma creates a physical barrier around the cancer cells, fortifying the epithelium and hindering vascularisation, thus resulting in reduced penetrability of drugs and a ‘sanctuary’ in which cancer cells thrive [12]. Extensive desmoplasia in the tumour microenvironment (TME) is a crucial factor that influences PDAC development, progression, metastasis, and resistance to treatment [13] and is arguably the most important pathophysiological feature of this cancer.
PDAC is documented to have a complex genomic landscape and mutation profile of cancer associated genes [14,15]. During tumour development, key oncogenic alterations occur where the genes KRAS (Kirsten rat sarcoma viral oncogene homolog), CDKN2A (cyclin dependent kinase inhibitor 2A), SMAD4 (Mothers against decapentaplegic homolog 4), and TP53 (Tumour protein 53) are most frequently mutated [4,16].
Key signalling pathways have been implicated in the development of PDAC and the development of desmoplasia. In particular, the tumour growth factor (TGF)-β signalling pathway plays an important role in pancreatic carcinogenesis [17]. TGF-β also regulates the development of the desmoplastic TME by inducing a fibroblast response which causes dense build-up of stromal cells and extracellular matrix (ECM) [18]. Cancer associated fibroblasts (CAFs) are the primary producer of the ECM protein collagen which is one of the main contributors of tumour desmoplasia in PDAC [19,20].
Integrin signalling is also an important cornerstone of PDAC TME homeostasis as it mediates adhesion of cells to ECM components such as collagen (types I and IV), fibronectin, and laminin [21]. As the main receptors for ECM molecules, integrins engage with the actin cytoskeleton via the linker protein talin and initiate bidirectional signals from both sides of the plasma membrane. Integrins can function collectively as mechanoreceptors in response to extracellular mechanical signals such as sheer stress and transduce the signal into the cell (outside-in signalling) [22]. Integrins are also known to regulate cancer cell activation and recruitment of CAFs in the stroma through TGF-β and participate in ECM remodelling (via the platelet derived growth factor receptor (PDGFR)), to provide a pre-metastatic niche for invading cancer cells (inside-out signalling) [23,24]. The bi-directional signalling of integrins is critical for promoting and regulating cell proliferation, adhesion, and migration, as well as chemotherapy resistance [21,25].
Signalling through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is initiated upon binding of cytokines such as interleukin (IL)-1 and IL-6 to their receptor, and is reported to enhance PDAC fibrosis, and ECM remodelling for increased stiffness of PDAC tumours [26,27,28]. In PDAC, IL-1α-induced signalling leads to activation of JAK1/2 and STAT1/3 in ECM producing pancreatic stellate cells which then promotes an inflammatory state of CAFs favouring further tumour growth [29].
Sonic hedgehog (SHH) is also overexpressed by neoplastic PDAC cells, and this pathway is important for the formation of a fibroblast-rich desmoplastic stroma [30]. The increased expression of SHH has been observed during pancreatic tumourigenesis, where the expression becomes elevated as the tumour progresses towards an advanced stage of PDAC, and aberrant activation of the Hedgehog signalling pathway is reported to be associated with metastatic potential of the tumour [3,27,31].

4. Tumour Microenvironment

The TME of PDAC tumours is characterised by the recruitment and activation of CAFs, heightened ECM deposition (e.g., collagen), reduced blood supply, as well as increased inflammation via the influx of inflammatory cells and cytokines into the tumour (Figure 2) [32].

4.1. Fibroblasts

The PDAC TME consists of an abundance of stromal cells such as pancreatic stellate cells and CAFs, which are major contributors to the dense desmoplastic reaction seen in PDAC through the production of acellular components that make up the ECM [33,34]. Stellate cells are myofibroblast-like cells that produce large amounts of ECM components, growth factors, and cytokines/chemokines in support of PDAC growth [35,36,37]. Bachem, Schünemann [38] and colleagues documented that when stellate cells were grown in the conditioned media of PDAC cancer cell lines, there was an increase in cell proliferation and synthesis of collagen type I and fibronectin. When the opposite occurred (i.e., PDAC cells were grown in the conditioned media of stellate cells), PDAC cells demosnstrated increased proliferation, invasion and migration [39]. Furthermore, mice injected with CAFs and PDAC cells produced larger tumours with increased desmoplasia and fibrosis when compared to PDAC cells injected alone [13,38,40].
CAFs are major orchestrators of the pancreatic TME due to their dominant production of acellular components of the ECM, e.g., collagen [33,34]. In the stroma, CAFs interact with other cells as well as the ECM to mediate cancer cell proliferation, migration, invasion, and metastasis, in part through reorganisation of the ECM. Within the PDAC tumour, there exists a tumour-stroma crosstalk between cancer cells and CAFs through paracrine signalling which influences tumour progression and desmoplasia through the production of growth factors, cytokines, and chemokines [32]. For instance, factors such as IL-6 and IL-1 (both of which induce JAK/STAT signalling) are secreted by cancer cells to promote CAF activation [29,41]. In response, CAFs then secrete chemokines, cytokines (e.g., IL-6), growth factors (e.g., vascular endothelial growth factor, VEGF), exosomes, and metabolites to instruct cancer cells and other TME components that promote angiogenesis and recruit immunosuppressive cells for immune cell evasion; thus further promoting PDAC progression [32,42,43]. The release of the growth factor TGF-β by cancer cells also induces the formation of a desmoplastic ECM produced by CAFs, and up-regulation of integrins on CAFs. Integrin α3β1 binds laminin-332 to mediate CAF activation and promote PDAC growth and invasion. Integrins also assist in the assembly of fibronectin at CAF cell protrusions to further enable integrin-mediated cancer cell migration [34,44,45]. Taken together, there exists a complex relationship between PDAC cells, CAFs, stellate cells, the TME, the immune cell response and cancer progression.

4.2. Extracellular Matrix

The ECM is a non-cellular component of the TME which provides essential physical scaffolding as well as biochemical and biomechanical cues to the cells [46]. ECM components include collagen, fibronectin, proteoglycans, and hyaluronic acid, as well as catalytically active enzymes and proteinases [47]. The connective tissue of PDAC can make up 60–90% of the total tumour area [48], and its presence correlates with poor survival for PDAC patients [49].
In PDAC progression and in pancreatitis, collagens are the most prominent component of ECM proteins, comprising more than 90% of the ECM matrisome at all stages of disease. Proteoglycans and glyco-proteins such as fibronectin make up the rest of the matrix and these ECM proteins are all overexpressed in PDAC [20]. An analysis of tumour extracts also reveal that of the 28 different collagen subtypes (categorised into four subfamilies), PDAC tumours contain an overabundance of fibril-forming collagen subfamily types I, III, and V, and network-forming collagen subfamily type IV [50,51]. High collagen content in PDAC is reported to correlate with reduced patient survival [52]. Collagens I, IV, and V promote the pro-tumourigenic features of PDAC cell survival, proliferation, migration, invasion and EMT [53,54,55]. In PDAC tumours, collagen I is the most abundant ECM protein in the TME and has a high affinity for signalling via integrin β1 that is expressed on the surface of PDAC cells. More specifically, integrins β1 and β6 are reported to promote PDAC cell growth, survival, migration, and invasion [46,56,57]. Type IV collagen exerts its pro-tumorigenic effects on the pancreatic cancer cells via an autocrine loop, where it interacts with integrin receptors on the surface of the cancer cells to enhance their survival [53]. Similarly, type V collagen influences cancer cells in a paracrine fashion via activation of the β1-integrin/focal adhesion kinase (FAK) signalling pathway [58]. Indicating that the cellular and acellular components in the TME work in tandem to maintain and regulate cancer cell growth.
Tumour stiffness caused by collagen cross-linking can also enhance cancer cell proliferation and promote cancer cell invasion via integrin signalling. Briefly, collagen cross-linking occurs via a family of enzymes, lysyl oxidases (LOX), which activate signalling factors such as yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) for cancer cell proliferation [59,60]. An increase in collagen thickness and tissue tension is also linked to PDAC prognosis [28,61]. Notably, increased collagen content, accompanied by an increase in another ECM protein hyaluronan (HA), both contribute to drug resistance (e.g., doxorubicin) in pancreatic cancer [62]. Notably, the desmoplastic collagen in PDAC is not all tumour promoting but can also be a barrier to cancer development. By way of example, a study by Rhim, Oberstein [30] showed that reducing stromal desmoplasia in the TME of PDAC tumours (by inhibiting the SHH pathway component Smoothened) accelerated tumour growth and metastasis.

4.3. Vasculature

As tumours increase in size, the TME becomes increasingly hypoxic, and cancer cells adapt by upregulating tissue processes that enhance access to the blood supply [4,63]. One such process, and another hallmark of cancer progression, is the induction of neo-angiogenesis (the formation of new blood vessels from existing endothelial cell lined vessels). Angiogenesis is a process largely driven by the signalling protein VEGF [64] which is upregulated in response to hypoxia [7,65].
Interestingly, some tumours, including PDAC, are considered ‘hypo-vascular’ and are populated with avascular stromal ‘deserts’ with substantially lower microvessel densities when compared to healthy areas of the pancreas [66]. Vascular dysfunction presents as a major obstacle to pharmaco-delivery and drug efficacy in the fight against PDAC; Komar, Kauhanen [67] and colleagues documented that compared to adjacent normal pancreatic tissue, the blood flow in pancreatic tumours is decreased by ~60% which consequently infers poor blood perfusion and impaired drug delivery to the tumour site [67].
Despite the dysfunctional vasculature and poor blood perfusion, PDAC tumours are still able to thrive by adapting and using alternate metabolic and scavenging pathways (e.g., autophagy and micropinocytosis) [68,69]. To this end, studies have shown that some solid tumours, including PDAC, are able to gain access to the blood circulatory system via a method independent of endothelial cell lined vasculature, by forming their own vessel-like structures in a process known as vasculogenic mimicry (VM) [70,71]. Studies have shown that a VM phenotype has been associated with poor prognosis and that PDAC cancer cells have the ability to form functional VM vessels in vitro and in vivo [71,72]. While much is still to be uncovered about the VM potential of PDAC cells, Yang, Zhu [73] demonstrated that hypoxia-inducible factor 2 alpha (HIF-2α) promotes VM formation in vitro and in vivo through twist family basic helix-loop-helix (bHLH) transcription 1 (Twist1) binding to vascular endothelial-cadherin (VE-cadherin) in pancreatic cancer cells. Our own work has also highlighted the expression of adhesion molecules by VM-competent cancer cells allowing for the active recruitment of circulating leukocyte subsets [74].

4.4. Immune Cell Presence

PDAC tumours are often considered immunologically ‘cold’; however, the role of the immune TME in PDAC is emerging as an important prognostic feature [75]. The PDAC TME is characterised by a highly heterogeneous immune cell infiltration profile: in the early stages of PDAC development, the TME is largely pro-inflammatory, but following the infiltration of immunosuppressive cells, the TME shifts to an anti-inflammatory state [76]. When this occurs, the PDAC TME has a high content of regulatory T cells (Tregs), tumour associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), as well as a relatively low prevalence of anti-tumour CD4+ and CD8+ T cells, natural kill (NK cells), and dendritic cells (DCs) [34].

4.4.1. Conventional T Lymphocytes

T lymphocytes are central to tumour immunology, being able to specifically recognise tumour-associated antigens. Circulating effector, memory and effector memory T cells are all able to migrate from the blood to tumour sites. Conventional cytotoxic CD8+ T cells are powerful effectors of the antitumour immune response, capable of directly killing cancer cells by secreting granules containing enzymes including granzymes and perforin. The infiltration of tumours by CD8+ T cells is associated with an improved prognosis in multiple cancer types including PDAC [77,78]. While many studies have focussed on CD8+ T cells, the importance of CD4+ T cells for tumour control and response to immunotherapy approaches is becoming apparent [79]. CD4+ helper T cells license antigen-presenting cells (APC) to engage in effective priming of CD8 T cells, as well as activating NK cells, myeloid cells, and other cell types via secreted factors. There is growing evidence for a cytotoxic subset of CD4+ T cells capable of directly killing cancer cells. Conventional subsets of CD4+ T cells including T helper type 1 (TH1), TH2, TH17, TH9, T follicular helper (TFH) and Tregs are found within tumours and numbers of CD4+ T cells with TH1 phenotype are associated with beneficial outcomes. In addition to recruited populations of T cells, tissue resident memory T cells (TRM) are a tissue-specific component of the TME. TRM are CD4 or CD8 positive T lymphocytes that persist in tissues long-term following primary T cell responses, and their proportion within the T cell infiltrate is related to a good prognosis [80]. A recent PDAC study of tumour infiltrating lymphocytes identified significant populations of CD8+ TRM with an exhausted (PD1 high, TIGIT high) phenotype, Tregs and TH17 cells in line with an immunosuppressed microenvironment [81]. Furthermore, it has been shown that both the infiltration of CD4+ T cells and CD8+ T cells is associated with improved overall survival (OS) and disease-free survival (DFS) in PDAC; however, the TME of PDAC tumours have poor infiltration of CD4+ and CD8+ lymphocytes [82,83].

4.4.2. Regulatory T Lymphocytes

Tregs are a subpopulation of CD3 + CD4 + CD25+ T cells that express the transcription factor forkhead box P3 (FOXP3) and have a role in maintaining homeostasis and self-tolerance. In PDAC, Tregs are considered pro-tumorigenic due to their ability to promote the TME development, promote cancer cell invasion and facilitate anti-tumour immune escape [84]. The number of tumour infiltrating Tregs gradually increases throughout the progression of PDAC and is strongly associated with poor prognosis due to their ability to suppress tumour specific CD4+ and CD8+ T cells and NK cells [85]. Tregs have been documented to directly modulate the TME through the production of IL-10, TGF-β, IL-35 and granzyme B, and indirectly through the expression of cytotoxic lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) [84]. IL-10 and IL-35 are immunosuppressive cytokines produced by Tregs that inhibit effector immune cells (i.e., CD4+ and CD8+ T cells), therefore protecting the cancer cells from immune surveillance [84,86]. Tregs can also modulate immunosuppression through the CTLA-4 and PD-1 pathways. CTLA-4 can bind at higher affinity to CD80 and CD86 ligands expressed on APCs than CD28 which is the co-factor essential for activation of naïve T cells. Bengsch, Knoblock [87] demonstrated that targeting CD25, using an anti-CD25 antibody in PDAC, reduced the number of Treg cells within the tumour and increased the number of CD4+ T helper cells, reaffirming that depleting Tregs revitalises the immune system for an anti-tumour immune response.

4.4.3. B Lymphocytes

B cells are the key component of the adaptive humoral immune system and function by producing antigen-specific antibodies against non-self [76]. Relevant to tumour immunology, they are also able to present antigen to T cells within the TME [88]. The role of B cells within the PDAC TME remains to be fully elucidated, with some studies suggesting a pro-tumourigenic role and others suggesting an anti-tumourigenic role. For example, an in vivo study by Spear, Candido [89] observed that B cells have an immunosuppressive role when in secondary lymphoid organs, however, are more immunostimulatory when found in the PDAC TME and therefore support the anti-tumour immune response [89]. Castino, Cortese [90] also demonstrated that within PDAC tumours B cells are found in two histologically different structures, either as infiltrating lymphocytes or in organised tertiary lymphoid tissue (TLTs). An increase in OS for PDAC patients was only associated with B cells found in TLTs, and this was correlated with a higher number of infiltrating CD8+ T cells; however, infiltrating B cells within the TME was associated with a poorer OS [90]. Clearly, there is a need for further studies to better elucidate the function of B cells in PDAC development.

4.4.4. Natural Killer Cells

NK cells are innate cytolytic immune cells that recognise and directly kill cancer cells through receptor activation. NK cells are also able to elicit an anti-tumour response through interactions with other immune cell types (e.g., DCs, macrophages and T cells) [91]. There are two main subtypes of NK cells: CD56dim which exert potent cytotoxicity and secrete low levels of cytokines (e.g., interferon gamma (IFNγ), tumour necrosis factor alpha (TNFα)), and CD56 bright which are poorly cytotoxic and secrete high levels of cytokines [85]. In PDAC, NK cells are characterised by impaired anti-tumour activity as well as reduced expression of cytotoxicity receptors [91]. Peng, Zhang [92] demonstrated that the percentage of surface receptors and cytotoxic granules (e.g., perforin and granzyme B) were significantly downregulated in NK cells following exposure to PDAC cancer cells. It is thought that the impaired NK activity is due to secreted factors such as TGF-β and IL-10, as well as indoleamine 2,3-dioxygenase (IDO) and matrix metalloproteinases (MMPs) [91,92]. Furthermore, a study by Lim, Kim [93] and colleagues demonstrated that NK cells isolated from PDAC patient tumours had reduced expression of C-X-C motif chemokine receptor 2 (CXCR-2) when compared to healthy donor NKs, which is suggested to be responsible for the low numbers of NK cells seen within the PDAC TME [93].

4.4.5. Tumour Associated Macrophages

TAMs are a type of myeloid cell that are found in high proportions within the PDAC TME [94]. TAMs are known to exert both pro-tumourigenic and anti-tumourigenic roles depending on the polarised phenotype of the macrophage [95]. In the early stages of PDAC the TME is characterised by macrophages that have a M1 phenotype (i.e., pro-inflammatory) [95,96]. M1 TAMs are attracted to the TME by cytokines such as IFNγ and TNFα where they secrete proinflammatory cytokines, chemokines and effector molecules to intensify the tumouricidal activity [97]. As PDAC disease progresses, TAMs are influenced by the release of cytokines such as IL-4, IL-10, IL-13 and TGF-β and as a result polarise to a M2 phenotype (i.e., anti-inflammatory) [98]. The M2 phenotype is documented to promote immunosuppression, angiogenesis, ECM remodelling and desmoplasia, accelerate metastasis, and overall progression of disease [99]. M2 macrophages produce IL-10, TGF-β, chemokine (C-C motif) ligand (CCL) 2, CCL17 and other cytokines/chemokines that inhibit the activity of CD8+ cytotoxic T cells and NK cells whilst promoting the migration of Tregs into the tumour [97]. Interestingly, Liou, Döppler [100] showed that the depletion of macrophages or the neutralisation of macrophage attracting intercellular adhesion molecule 1 (ICAM-1) delayed the development of PanIN lesions, therefore revealing a role for TAMs within the PDAC TME and a potential therapeutic avenue.

4.4.6. Myeloid-Derived Suppressor Cells

MDSCs are a heterogenous population of activated myeloid progenitor cells that are formed in the process of myelopoiesis within the bone marrow [101]. During homeostasis, immature myeloid cells (IMCs) differentiate into lineage-specific cell populations. However, in a cancer setting, the overproduction of soluble factors such as granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), IL-6, VEGF and TNFα promotes the formation of MDSCs that are recruited to the tumour site via the CXC family of chemokines such as CCL2, CXCL-12, CXCL-15 [102]. MDSCs can be characterised into two distinct populations; monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs) [96]. MDSCs are known to contribute to the immunosuppressive TME within PDAC through the direct and indirect inhibition of T cells and NK cells, and the cross-talk and stimulation of Treg cells [91,96]. It has also been demonstrated that compared to healthy controls PDAC patients have elevated levels of MDSCs within the bone marrow and blood circulation which are rapidly recruited to the PDAC TME [103]. Furthermore, it has been shown that targeting G-MDSCs in PDAC increased the numbers of activated cytotoxic T cells within the PDAC TME, whilst also inducing apoptosis of cancer cells and remodelling of the TME (particularly the stroma) [104].

4.4.7. Dendritic Cells

DCs are professional APCs that form a critical link between the innate and adaptive immune systems [85]. Tumour-specific immunity is mediated by DCs as they recognise, process, and then present tumour associated antigens to adaptive cells [76]. DCs are rarely found within the PDAC TME, but rather in the stroma surrounding the tumour. DCs in the TME are often dysfunctional due to cancer cell secreted factors (e.g., IL-6, VEGF, TGF-β, and reactive oxygen species (ROSs)) [105]. These dysfunctional DCs are compromised in their ability to engulf, process, and present tumour-specific antigens, thereby inhibiting an anti-tumour response [85]. When DCs are present in high numbers within the peripheral circulation and the PDAC TME, there is improved OS of the patients [106]. Furthermore, Fukunaga, Miyamoto [107] demonstrated that the number of DCs within the PDAC TME was significantly increased when CD4+ and CD8+ TILs were also present.

5. Current Treatments and Hurdles

Currently, PDAC treatment outcomes are determined by the disease stage at presentation. The treatment associated with the best OS is a margin-negative surgical resection including chemo- and/or radiotherapy. However, this is only achieved in ~10–20% of patients who are diagnosed at a relatively early stage. The remaining 80–90% of patients present with advanced, non-resectable disease and a majority possessing distant metastasis [7,108]. Advanced PDAC tumours are currently treated with chemotherapeutics such as gemcitabine, capecitabine and 5-fluorouracil [109]. FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and fluorouracil) or a combination therapy of gemcitabine and a nanoparticle albumin-bound paclitaxel (nab-paclitaxel) have been employed and have demonstrated an improved survival in a higher proportion of patients when compared to gemcitabine alone [110]. Unfortunately, these treatments are associated with increased toxicity and hence, can only be prescribed in patients with a good performance index [111]. In addition to the late diagnosis of PDAC patients, there are also intrinsic and extrinsic factors that can impede upon therapy success. Such examples include acquired chemotherapy resistance, high mutational burden and pro-oncogenic signalling potential by the cancer cells, high metastatic burden, and the presence of an immunosuppressive TME. Furthermore, the dense stromal and connective tissue in PDAC tumours contributes to elevated tissue pressure through eliciting solid stress by compressing on the blood vessels, further inhibiting effective penetration of anti-cancer drugs, and thus contributing to a lack of efficiency for PDAC treatments [12,112,113,114]. Thus, the OS for PDAC patients has not improved in decades highlighting the need for more potent therapies and earlier detection methods.

Clinical Trials

Erlotinib (epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor), and Olaparib (a poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor) are the only two approved targeted therapies used for the treatment of PDAC (Table 1, Figure 2) [115]. However, most patients have, or inevitably develop, intrinsic resistance to EGFR inhibitors, leading to disease progression [116]. In fact, as a survival mechanism, tumours have reportedly developed resistance through the activation of EGFR-independent signalling pathways, which are downstream of the erythroblastic leukaemia viral oncogene homologue (ErbB) family members that promote persistent cancer cell survival [116]. Olarparib is also approved for PDAC patients with breast cancer gene 1 (BRCA1) or BRCA2 germline mutations in their cancer cells, which reportedly only reflects a small subset of patients diagnosed with metastatic pancreatic cancer [117,118].
Historically, clinical trials with targeted treatments for PDAC have been underwhelming. Multiple clinical trials of anti-angiogenic agents that target the tumour vasculature without interfering with the normal vasculature yielded disappointing results (Table 2, Figure 2) [112,119]. Even anti-cancer therapies proven to be successful in the treatment of other cancers such as Trametinib, a MEK (mitogen-activated protein kinase kinase) inhibitor were found to be ineffective in PDAC [27]. Additionally, given that the hedgehog signalling pathway is key in PDAC development, SHH inhibition was also tested, but without success. Further investigation in murine studies revealed that complete inhibition of SHH led to an increase in vascularity and proliferation, showing that Hedgehog driven tumours also supress tumour growth by restraining tumour angiogenesis [30]. Due to the immunosuppressive nature of the PDAC TME, several clinical trials have investigated immune checkpoint inhibitors (ICIs), anti-PD-1 or anti-programmed death ligand-1 (PD-L1) (that block the inhibition of T cell activation by cancer cells) as both a monotherapy and in combination with other therapies, i.e., gemcitabine); however, results have thus far been disappointing (Table 2) [120,121,122,123,124].
The dense stromal reaction leading to the compression of blood vessels and inadequate drug penetration has also emerged as a potential target for therapeutic intervention. A preclinical study demonstrated that excessive HA present in PDAC tumours (which elevates interstitial pressure and impairs perfusion) is degraded by pegvorhyaluronidase alfa (PEGPH20), and that this degradation of HA by PEGPH20 led to an increase in drug delivery. Another clinical trial targeted ECM producing pancreatic stellate cells via all-trans-retinoic acid (ATRA) to reprogram pancreatic stroma and suppress PDAC growth. ATRA in combination with gemcitabine-nab-paclitaxel chemotherapy delivered to patients with advanced, unresectable PDAC is currently in a phase II randomised trial [125]. Another approach utilised Losartan, a clinically approved angiotensin II receptor antagonist with antifibrotic activity (i.e., reduce the amount of collagen and HA in the tumour) [126], which led to decompression of tumour vessels and significantly improved perfusion [127]. Losartan has also been reported to enhance immune activation, and currently a randomized phase II study on combining chemoradiotherapy and losartan with ICI immunotherapy nivolumab (anti-PD-1 blocking antibody) is in progress [128]. A clinical trial is also underway testing the efficacy of targeting connective tissue growth factor (CTGF). In preclinical mouse models, treatment with pamrevlumab (or FG-3019), a humanized monoclonal antibody targeting CTGF, shows that pamrevlumab attenuates tumour growth, metastasis, and angiogenesis [129]. The clinical trial testing pamrevlumab in combination with gemcitabine-nab-paclitaxel or FOLFIRINOX in patients with locally advanced PDAC is currently ongoing.
Given that PDAC tumours are intrinsically immunosuppressive and have lower immunogenic potential [34], targeting the tumour promoting immune cells is an attractive approach to inhibit PDAC progression. To this end, current clinical trials are investigating novel immune-modulating agents such as those targeting CAF-mediated immunosuppression, checkpoint inhibitors, myeloid cells, Tregs, stromal depletion (by targeting CAF, FAK, PDGFRα, IL-1, IL-6), and chimeric antigen receptor (CAR)-T cells (e.g., carcinoembryonic antigen (CEA), mesothelin (MSLN) and mucin 1 (MUC1)) (Figure 2). These agents are being considered as a monotherapy as well as in combination with standard of care chemotherapeutic drugs [130,131]. Immunotherapy aims to improve the anti-tumour immune response and has proven successful in other solid cancers (e.g., melanoma); however, this has not been the case in PDAC [132]. Several immunotherapies of different categories including immunomodulators (e.g., ICIs), immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, monoclonal antibodies (mAbs), adoptive cell therapies and cancer vaccines have and are being assessed in PDAC [132].
Table
Table 1. Non-chemotherapy targeted drug clinical trials that progressed to approval.
Table 1. Non-chemotherapy targeted drug clinical trials that progressed to approval.
Trial [Reference]YearTargetTrial DesignComparator GroupsOverall SurvivalInference
NCT00026338
(NCIC CTG PA.3) [115]		2001–2004HER1/EGFRPhase III Randomised Triple blinded
Parallel assignment		Erlotinib and gem (n = 285)
vs.
Placebo and gem (n = 284)		OS was significantly longer in the erlotinib and gem group with an estimated HR of 0.82 (95% CI, 0.69 to 0.99; p = 0.038)
PFS was significantly longer in the erlotinib and gem group with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; p = 0.004)		Erlotinib improves OS and PFS when used concurrently with gem
NCT02184195
[118]		2014–2019PARPPhase III
Randomised
Quadruple blinded
Parallel assignment		Olaparib (n = 92)
vs.
Placebo (n = 62)		No significant difference in OS
PFS was significantly longer in the olaparib group than in the placebo group HR of 0.53 (95% CI, 0.35 to 0.82; p = 0.004)		Olaparib improves PFS to patients with germline BRCA mutated PDAC
Abbreviations: CI–confidence interval, HER1/EGFR–human epidermal growth factor receptor type 1, HR–hazard ratio, OS–overall survival, PFS–progression free survival.
Table
Table 2. Failed clinical trials targeting the PDAC tumour microenvironment.
Table 2. Failed clinical trials targeting the PDAC tumour microenvironment.
Trial [Reference]YearTargetTrial DesignComparator GroupsOverall SurvivalInference
Anti-angiogenic agents
NCT00088894
(CALGB 80303)
[133]		2004–2006VEGFAPhase III
Randomised
Double blinded
Parallel assignment		Bevacizumab and gem (n = 302)
vs.
Placebo and gem (n = 300)		No significant difference in OS and PFSThe combination of bevacizumab and gem does not improve survival in PDAC
NCT0095966
(BAY 43-9006)
[134]		2004–2006Raf serine/threonine kinase isoforms, VEGFR2, receptor tyrosine kinasesPhase III
Not blinded
Single group assignment		Sorafenib and gem (n = 17)Trial terminated–lack of efficacyThe combination of sorafenib and gem does not improve survival in PDAC
VMIN 000005133 (PEGASUS-PC study)
[135]		2009–2014VEGFR2Phase II/III
Randomised
Double blinded Parallel assignment		Elpamotide and gem (n = 100)
vs.
Placebo and gem (n = 53)		No significant difference in OS
No significant difference in PFS		The combination of elpamotide and gem does not improve survival in PDAC
Anti-fibrotic/ECM agents
NCT01231581
[136]		2010–2012MEK1/2Phase II
Randomised
Double-blinded
Parallel assignment		Trametinib and gem (n = 80)
vs.
Placebo and gem (n = 80)		No significant difference in OS and PFSThe combination of trametinib and gem does not improve survival in PDAC
NCT01130142
[137]		2010–2012Hedgehog pathwayPhase I/II
Randomised
Double-blinded
Parallel assignment		Saridegib (IPI-926) and gem
vs.
Placebo and gem
Total n = 122		Trial terminated–patient survival diminished (increase in vascularisation and proliferation)The combination of saridegib and gem diminishes patient survival
NCT01064622
[138] 		2009–2012Hedgehog pathway
(smoothened)		Phase II
Randomised
Double-blinded Parallel assignment		Vismodegib and gem (n = 53)
vs.
Placebo and gem (n = 53)		No significant difference in OS and PFSThe combination of vismodegib and gem does not improve survival in PDAC
NCT02715804
(HALO-301)
[139]		2016–2019HyaluronanPhase III
Randomised
Double-blinded
Parallel assignment		PEGPH20 and AG (n = 327)
vs.
Placebo and AG (n = 165)		No significant difference in OS and PFSThe combination of PEGPH20 and AG does not improve survival in PDAC
NCT01821729
[140]		2013–2018Renin-angiotensin systemPhase II
Not blinded
Single group assignment		FOLFIRINOX, losartan and proton beam RT (n = 49)69% of participants became eligible for tumour resectionFOLFIRINOX, losartan and proton beam RT was well tolerated, further studies required
Immunological agents
NCT02558894
[121]		2015–2017PD-L1
CTLA-4		Phase II
Randomised
Not blinded
Parallel assignment		Durvalumab alone (n = 33)
vs.
Durvalumab and tremelimumab (n = 32)		No significant difference in OS and PFSThe combination of durvalumab and tremelimumab does not improve survival in PDAC
Brahmer, 2013
NCT00729664
[122]		2009–2015PD-L1Phase I
Non-randomised
Not blinded
Parallel assignment		MDX1105-01 at increasing concentrations (n = 14 PDAC patients)No objective response to treatmentMDX1105-01 does not improve survival in PDAC
NCT00112580
[141] 		2005–2009CTLA-4Phase II
Not blinded
Single group assignment		Ipilimumab (n = 27) No or minor objective response to treatmentIpilimumab does not improve survival in PDAC
NCT00084383
[142]		2002–2005GM-CSFPhase II
Not blinded
Single group assignment		GVAX
and adjuvant chemoradiotherapy (n = 60)		Median OS of 24.8 months (95% CI, 21.2–31.6)GVAX and adjuvant chemotherapy was well tolerated, further studies required
NCT02562898
[143]		2015–2019B cells (reprogramming)Phase I/II
Non-randomised
Not blinded
Parallel assignment		Ibrutinib, paclitaxel and gem (n = 18)No objective response to treatmentIbrutinib, paclitaxel and gem does not improve survival in PDAC
Abbreviations: CI–confidence interval, FOLFIRINOX–oxaliplatin, irinotecan, leucovorin and fluorouracil, Gem–Gemcitabine, HER1/EGFR–human epidermal growth factor receptor type 1, HR–hazard ratio, MEK1/2–Mitogen-activated protein kinase 1/2, OS–overall survival, PFS–progression free survival, RAF–rapidly accelerated fibrosarcoma.

6. Conclusions

While the survival rates of most cancers have dramatically improved in the last few decades, this is not the case for PDAC where the 5-year survival rate has remained below 9% [144]. At the present time, achieving an improved survival rate for patients with PDAC is fraught with barriers including the lack of a specific biomarker to detect PDAC at an early stage (when meaningful attempts at treatment are feasible), and the inability to identify patients who will benefit from aggressive treatments (surgery and chemo-/radio-therapy) [145]. Unfortunately, even the most exciting advances in cancer treatments have been disappointing in PDAC. For example, while immunotherapy (e.g., ICIs such as anti-PD-1 antibodies) has transformed the treatment landscape for many cancer patients (e.g., lung, melanoma), for PDAC patients, <2% show improved outcomes.
As detailed above, the main challenge is the difficulty in delivering drugs to the tumour, with the presence of a densely packed ‘desmoplastic’ TME preventing most anti-PDAC drugs and immune cells from reaching the ‘heart’ of the tumour in therapeutic/effective concentration. Given that the prognosis of PDAC patients is largely determined by stage of diagnosis and tumour biology [146], renewed efforts focusing on aspects of the extremely dense and complex TME provide hope for improved efficacy of PDAC therapy.

Author Contributions

Conceptualisation K.K.M.M., C.B.F., S.G.B. and C.S.B.; writing—original draft preparation, K.K.M.M., C.B.F. and C.S.B.; writing—review and editing K.K.M.M., C.B.F., C.F.J., M.S., S.G.B. and C.S.B.; supervision, S.G.B. and C.S.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by grants awarded to S.G.B. and C.S.B. [Pankind 21.R7.INV.CB.UOSA.6.2 and NHMRC Ideas grant GNT2021009], Flinders Foundation grant to S.G.B. [49358025], as well as RTP post-graduate awards to K.K.M.M. and C.B.F.

Acknowledgments

Figures created using BioRender.com.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Nikšić, M.; Matz, M.; Valkov, M.; Marcos-Gragera, R.; Stiller, C.; Rosso, S.; Coleman, M.P.; Allemani, C.; Group, C.W. World-wide trends in net survival from pancreatic cancer by morphological sub-type: An analysis of 1,258,329 adults diagnosed in 58 countries during 2000–2014 (CONCORD-3). Cancer Epidemiol. 2022, 80, 102196. [Google Scholar] [CrossRef] [PubMed]
  2. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2021. CA Cancer J. Clin. 2021, 71, 7–33. [Google Scholar] [CrossRef] [PubMed]
  3. Yachida, S.; Iacobuzio-Donahue, C.A. The pathology and genetics of metastatic pancreatic cancer. Arch. Pathol. Lab. Med. 2009, 133, 413–422. [Google Scholar] [CrossRef] [PubMed]
  4. Kamisawa, T.; Wood, L.D.; Itoi, T.; Takaori, K. Pancreatic cancer. Lancet 2016, 388, 73–85. [Google Scholar] [CrossRef]
  5. Le Large, T.Y.S.; Bijlsma, M.F.; Kazemier, G.; van Laarhoven, H.W.M.; Giovannetti, E.; Jimenez, C.R. Key biological processes driving metastatic spread of pancreatic cancer as identified by multi-omics studies. Semin. Cancer Biol. 2017, 44, 153–169. [Google Scholar] [CrossRef]
  6. Rahib, L.; Wehner, M.R.; Matrisian, L.M.; Nead, K.T. Estimated projection of US cancer incidence and death to 2040. JAMA Netw. Open 2021, 4, e214708. [Google Scholar] [CrossRef]
  7. Orth, M.; Metzger, P.; Gerum, S.; Mayerle, J.; Schneider, G.; Belka, C.; Schnurr, M.; Lauber, K. Pancreatic ductal adenocarcinoma: Biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat. Oncol. 2019, 14, 141. [Google Scholar] [CrossRef]
  8. Kopp, J.L.; von Figura, G.; Mayes, E.; Liu, F.-F.; Dubois, C.L.; Morris, J.P., IV; Pan, F.C.; Akiyama, H.; Wright, C.V.; Jensen, K. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 22, 737–750. [Google Scholar] [CrossRef]
  9. Distler, M.; Aust, D.; Weitz, J.; Pilarsky, C.; Grützmann, R. Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. BioMed Res. Int. 2014, 2014, 474905. [Google Scholar] [CrossRef]
  10. Özdemir, B.C.; Pentcheva-Hoang, T.; Carstens, J.L.; Zheng, X.; Wu, C.C.; Simpson, T.R.; Laklai, H.; Sugimoto, H.; Kahlert, C.; Novitskiy, S.V.; et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014, 25, 719–734. [Google Scholar] [CrossRef]
  11. Polireddy, K.; Chen, Q. Cancer of the Pancreas: Molecular Pathways and Current Advancement in Treatment. J. Cancer 2016, 7, 1497–1514. [Google Scholar] [CrossRef] [PubMed]
  12. Provenzano, P.P.; Cuevas, C.; Chang, A.E.; Goel, V.K.; Von Hoff, D.D.; Hingorani, S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21, 418–429. [Google Scholar] [CrossRef] [PubMed]
  13. Cannon, A.; Thompson, C.; Hall, B.R.; Jain, M.; Kumar, S.; Batra, S.K. Desmoplasia in pancreatic ductal adenocarcinoma: Insight into pathological function and therapeutic potential. Genes Cancer 2018, 9, 78. [Google Scholar] [CrossRef] [PubMed]
  14. Campbell, P.J.; Yachida, S.; Mudie, L.J.; Stephens, P.J.; Pleasance, E.D.; Stebbings, L.A.; Morsberger, L.A.; Latimer, C.; McLaren, S.; Lin, M.-L.; et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 2010, 467, 1109–1113. [Google Scholar] [CrossRef]
  15. Raphael, B.J.; Hruban, R.H.; Aguirre, A.J.; Moffitt, R.A.; Yeh, J.J.; Stewart, C.; Robertson, A.G.; Cherniack, A.D.; Gupta, M.; Getz, G. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 2017, 32, 185–203.e13. [Google Scholar] [CrossRef]
  16. Oshima, M.; Okano, K.; Muraki, S.; Haba, R.; Maeba, T.; Suzuki, Y.; Yachida, S. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann. Surg. 2013, 258, 336–346. [Google Scholar] [CrossRef]
  17. Ahmed, S.; Bradshaw, A.D.; Gera, S.; Dewan, M.Z.; Xu, R. The TGF-β/Smad4 Signaling Pathway in Pancreatic Carcinogenesis and Its Clinical Significance. J. Clin. Med. 2017, 6, 5. [Google Scholar] [CrossRef]
  18. Löhr, M.; Schmidt, C.; Ringel, J.; Kluth, M.; Müller, P.; Nizze, H.; Jesnowski, R. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 2001, 61, 550–555. [Google Scholar]
  19. 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]
  20. Tian, C.; Clauser, K.R.; Öhlund, D.; Rickelt, S.; Huang, Y.; Gupta, M.; Mani, D.R.; Carr, S.A.; Tuveson, D.A.; Hynes, R.O. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc. Natl. Acad. Sci. USA 2019, 116, 19609–19618. [Google Scholar] [CrossRef]
  21. Cooper, J.; Giancotti, F.G. Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell 2019, 35, 347–367. [Google Scholar] [CrossRef] [PubMed]
  22. Jang, I.; Beningo, K.A. Integrins, CAFs and Mechanical Forces in the Progression of Cancer. Cancers 2019, 11, 721. [Google Scholar] [CrossRef] [PubMed]
  23. Su, C.-y.; Li, J.-q.; Zhang, L.-l.; Wang, H.; Wang, F.-h.; Tao, Y.-w.; Wang, Y.-q.; Guo, Q.-r.; Li, J.-j.; Liu, Y.; et al. The Biological Functions and Clinical Applications of Integrins in Cancers. Front. Pharmacol. 2020, 11, 579068. [Google Scholar] [CrossRef]
  24. Peng, C.; Zou, X.; Xia, W.; Gao, H.; Li, Z.; Liu, N.; Xu, Z.; Gao, C.; He, Z.; Niu, W.; et al. Integrin αvβ6 plays a bi-directional regulation role between colon cancer cells and cancer-associated fibroblasts. Biosci. Rep. 2018, 38, BSR20180243. [Google Scholar] [CrossRef]
  25. Geiger, B.; Bershadsky, A.; Pankov, R.; Yamada, K.M. Transmembrane crosstalk between the extracellular matrix and the cytoskeleton. Nat. Rev. Mol. Cell Biol. 2001, 2, 793–805. [Google Scholar] [CrossRef]
  26. Seidel, H.M.; Lamb, P.; Rosen, J. Pharmaceutical intervention in the JAK/STAT signaling pathway. Oncogene 2000, 19, 2645–2656. [Google Scholar] [CrossRef] [PubMed]
  27. Matsuoka, T.; Yashiro, M. Molecular targets for the treatment of pancreatic cancer: Clinical and experimental studies. World J. Gastroenterol. 2016, 22, 776–789. [Google Scholar] [CrossRef] [PubMed]
  28. Laklai, H.; Miroshnikova, Y.A.; Pickup, M.W.; Collisson, E.A.; Kim, G.E.; Barrett, A.S.; Hill, R.C.; Lakins, J.N.; Schlaepfer, D.D.; Mouw, J.K.; et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 2016, 22, 497–505. [Google Scholar] [CrossRef]
  29. Biffi, G.; Oni, T.E.; Spielman, B.; Hao, Y.; Elyada, E.; Park, Y.; Preall, J.; Tuveson, D.A. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2019, 9, 282–301. [Google Scholar] [CrossRef]
  30. Rhim, A.D.; Oberstein, P.E.; Thomas, D.H.; Mirek, E.T.; Palermo, C.F.; Sastra, S.A.; Dekleva, E.N.; Saunders, T.; Becerra, C.P.; Tattersall, I.W.; et al. Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma. Cancer Cell 2014, 25, 735–747. [Google Scholar] [CrossRef]
  31. Pasca di Magliano, M.; Sekine, S.; Ermilov, A.; Ferris, J.; Dlugosz, A.A.; Hebrok, M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 2006, 20, 3161–3173. [Google Scholar] [CrossRef] [PubMed]
  32. Pereira, B.A.; Vennin, C.; Papanicolaou, M.; Chambers, C.R.; Herrmann, D.; Morton, J.P.; Cox, T.R.; Timpson, P. CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer. Trends Cancer 2019, 5, 724–741. [Google Scholar] [CrossRef] [PubMed]
  33. Apte, M.V.; Haber, P.S.; Darby, S.J.; Rodgers, S.C.; McCaughan, G.W.; Korsten, M.A.; Pirola, R.C.; Wilson, J.S. Pancreatic stellate cells are activated by proinflammatory cytokines: Implications for pancreatic fibrogenesis. Gut 1999, 44, 534–541. [Google Scholar] [CrossRef] [PubMed]
  34. Liot, S.; Balas, J.; Aubert, A.; Prigent, L.; Mercier-Gouy, P.; Verrier, B.; Bertolino, P.; Hennino, A.; Valcourt, U.; Lambert, E. Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins. Front. Immunol. 2021, 12, 612271. [Google Scholar] [CrossRef]
  35. Hwang, R.F.; Moore, T.; Arumugam, T.; Ramachandran, V.; Amos, K.D.; Rivera, A.; Ji, B.; Evans, D.B.; Logsdon, C.D. Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression. Cancer Res. 2008, 68, 918–926. [Google Scholar] [CrossRef]
  36. Thomas, D.; Radhakrishnan, P. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol. Cancer 2019, 18, 14. [Google Scholar] [CrossRef]
  37. Pandol, S.; Edderkaoui, M.; Gukovsky, I.; Lugea, A.; Gukovskaya, A. Desmoplasia of pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 2009, 7, S44–S47. [Google Scholar] [CrossRef]
  38. Bachem, M.G.; Schünemann, M.; Ramadani, M.; Siech, M.; Beger, H.; Buck, A.; Zhou, S.; Schmid-Kotsas, A.; Adler, G. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005, 128, 907–921. [Google Scholar] [CrossRef]
  39. Hamada, S.; Masamune, A.; Takikawa, T.; Suzuki, N.; Kikuta, K.; Hirota, M.; Hamada, H.; Kobune, M.; Satoh, K.; Shimosegawa, T. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 2012, 421, 349–354. [Google Scholar] [CrossRef]
  40. Boyle, S.T.; Poltavets, V.; Kular, J.; Pyne, N.T.; Sandow, J.J.; Lewis, A.C.; Murphy, K.J.; Kolesnikoff, N.; Moretti, P.A.B.; Tea, M.N.; et al. ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism. Nat. Cell Biol. 2020, 22, 882–895. [Google Scholar] [CrossRef]
  41. Johnson, D.E.; O’Keefe, R.A.; Grandis, J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 2018, 15, 234–248. [Google Scholar] [CrossRef] [PubMed]
  42. Liu, T.; Han, C.; Wang, S.; Fang, P.; Ma, Z.; Xu, L.; Yin, R. Cancer-associated fibroblasts: An emerging target of anti-cancer immunotherapy. J. Hematol. Oncol. 2019, 12, 86. [Google Scholar] [CrossRef] [PubMed]
  43. Feig, C.; Jones, J.O.; Kraman, M.; Wells, R.J.; Deonarine, A.; Chan, D.S.; Connell, C.M.; Roberts, E.W.; Zhao, Q.; Caballero, O.L.; et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 20212–20217. [Google Scholar] [CrossRef] [PubMed]
  44. Gaggioli, C.; Hooper, S.; Hidalgo-Carcedo, C.; Grosse, R.; Marshall, J.F.; Harrington, K.; Sahai, E. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 2007, 9, 1392–1400. [Google Scholar] [CrossRef] [PubMed]
  45. Zeltz, C.; Primac, I.; Erusappan, P.; Alam, J.; Noel, A.; Gullberg, D. Cancer-associated fibroblasts in desmoplastic tumors: Emerging role of integrins. Semin. Cancer Biol. 2020, 62, 166–181. [Google Scholar] [CrossRef]
  46. Perez, V.M.; Kearney, J.F.; Yeh, J.J. The PDAC Extracellular Matrix: A Review of the ECM Protein Composition, Tumor Cell Interaction, and Therapeutic Strategies. Front. Oncol. 2021, 11, 751311. [Google Scholar] [CrossRef]
  47. Feig, C.; Gopinathan, A.; Neesse, A.; Chan, D.S.; Cook, N.; Tuveson, D.A. The Pancreas Cancer Microenvironment. Clin. Cancer Res. 2012, 18, 4266–4276. [Google Scholar] [CrossRef]
  48. Leppänen, J.; Lindholm, V.; Isohookana, J.; Haapasaari, K.M.; Karihtala, P.; Lehenkari, P.P.; Saarnio, J.; Kauppila, J.H.; Karttunen, T.J.; Helminen, O.; et al. Tenascin C, Fibronectin, and Tumor-Stroma Ratio in Pancreatic Ductal Adenocarcinoma. Pancreas 2019, 48, 43–48. [Google Scholar] [CrossRef]
  49. Whatcott, C.J.; Diep, C.H.; Jiang, P.; Watanabe, A.; LoBello, J.; Sima, C.; Hostetter, G.; Shepard, H.M.; Von Hoff, D.D.; Han, H. Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer. Clin. Cancer Res. 2015, 21, 3561–3568. [Google Scholar] [CrossRef]
  50. Mollenhauer, J.; Roether, I.; Kern, H.F. Distribution of extracellular matrix proteins in pancreatic ductal adenocarcinoma and its influence on tumor cell proliferation in vitro. Pancreas 1987, 2, 14–24. [Google Scholar] [CrossRef]
  51. Xu, S.; Xu, H.; Wang, W.; Li, S.; Li, H.; Li, T.; Zhang, W.; Yu, X.; Liu, L. The role of collagen in cancer: From bench to bedside. J. Transl. Med. 2019, 17, 309. [Google Scholar] [CrossRef] [PubMed]
  52. Imamura, T.; Iguchi, H.; Manabe, T.; Ohshio, G.; Yoshimura, T.; Wang, Z.H.; Suwa, H.; Ishigami, S.; Imamura, M. Quantitative analysis of collagen and collagen subtypes I, III, and V in human pancreatic cancer, tumor-associated chronic pancreatitis, and alcoholic chronic pancreatitis. Pancreas 1995, 11, 357–364. [Google Scholar] [CrossRef]
  53. Öhlund, D.; Franklin, O.; Lundberg, E.; Lundin, C.; Sund, M. Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop. BMC Cancer 2013, 13, 154. [Google Scholar] [CrossRef] [PubMed]
  54. Weniger, M.; Honselmann, K.C.; Liss, A.S. The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship. Cancers 2018, 10, 316. [Google Scholar] [CrossRef] [PubMed]
  55. Armstrong, T.; Packham, G.; Murphy, L.B.; Bateman, A.C.; Conti, J.A.; Fine, D.R.; Johnson, C.D.; Benyon, R.C.; Iredale, J.P. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2004, 10, 7427–7437. [Google Scholar] [CrossRef] [PubMed]
  56. Grzesiak, J.J.; Tran Cao, H.S.; Burton, D.W.; Kaushal, S.; Vargas, F.; Clopton, P.; Snyder, C.S.; Deftos, L.J.; Hoffman, R.M.; Bouvet, M. Knockdown of the β(1) integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis. Int. J. Cancer 2011, 129, 2905–2915. [Google Scholar] [CrossRef] [PubMed]
  57. Reader, C.S.; Vallath, S.; Steele, C.W.; Haider, S.; Brentnall, A.; Desai, A.; Moore, K.M.; Jamieson, N.B.; Chang, D.; Bailey, P.; et al. The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. J. Pathol. 2019, 249, 332–342. [Google Scholar] [CrossRef]
  58. Berchtold, S.; Grünwald, B.; Krüger, A.; Reithmeier, A.; Hähl, T.; Cheng, T.; Feuchtinger, A.; Born, D.; Erkan, M.; Kleeff, J.; et al. Collagen type V promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Cancer Lett. 2015, 356, 721–732. [Google Scholar] [CrossRef]
  59. Rice, A.J.; Cortes, E.; Lachowski, D.; Cheung, B.C.H.; Karim, S.A.; Morton, J.P.; del Río Hernández, A. Matrix stiffness induces epithelial–mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogenesis 2017, 6, e352. [Google Scholar] [CrossRef]
  60. Levental, K.R.; Yu, H.; Kass, L.; Lakins, J.N.; Egeblad, M.; Erler, J.T.; Fong, S.F.T.; Csiszar, K.; Giaccia, A.; Weninger, W.; et al. Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling. Cell 2009, 139, 891–906. [Google Scholar] [CrossRef]
  61. Zhou, Z.H.; Ji, C.D.; Xiao, H.L.; Zhao, H.B.; Cui, Y.H.; Bian, X.W. Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis. J. Cancer 2017, 8, 1466–1476. [Google Scholar] [CrossRef] [PubMed]
  62. Li, X.; Shepard, H.M.; Cowell, J.A.; Zhao, C.; Osgood, R.J.; Rosengren, S.; Blouw, B.; Garrovillo, S.A.; Pagel, M.D.; Whatcott, C.J.; et al. Parallel Accumulation of Tumor Hyaluronan, Collagen, and Other Drivers of Tumor Progression. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2018, 24, 4798–4807. [Google Scholar] [CrossRef] [PubMed]
  63. Folkman, J. Tumor angiogenesis: Therapeutic implications. N. Engl. J. Med. 1971, 285, 1182–1186. [Google Scholar] [PubMed]
  64. Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed]
  65. Du, J.; Sun, B.; Zhao, X.; Gu, Q.; Dong, X.; Mo, J.; Sun, T.; Wang, J.; Sun, R.; Liu, Y. Hypoxia promotes vasculogenic mimicry formation by inducing epithelial–mesenchymal transition in ovarian carcinoma. Gynecol. Oncol. 2014, 133, 575–583. [Google Scholar] [CrossRef]
  66. Olive, K.P.; Jacobetz, M.A.; Davidson, C.J.; Gopinathan, A.; McIntyre, D.; Honess, D.; Madhu, B.; Goldgraben, M.A.; Caldwell, M.E.; Allard, D.; et al. Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer. Science 2009, 324, 1457–1461. [Google Scholar] [CrossRef] [PubMed]
  67. Komar, G.; Kauhanen, S.; Liukko, K.; Seppänen, M.; Kajander, S.; Ovaska, J.; Nuutila, P.; Minn, H. Decreased Blood Flow with Increased Metabolic Activity: A Novel Sign of Pancreatic Tumor Aggressiveness. Clin. Cancer Res. 2009, 15, 5511–5517. [Google Scholar] [CrossRef] [PubMed]
  68. Encarnación-Rosado, J.; Kimmelman, A.C. Harnessing metabolic dependencies in pancreatic cancers. Nat. Rev. Gastroenterol. Hepatol. 2021, 18, 482–492. [Google Scholar] [CrossRef]
  69. Jiang, B.; Zhou, L.; Lu, J.; Wang, Y.; Liu, C.; You, L.; Guo, J. Stroma-targeting therapy in pancreatic cancer: One coin with two sides? Front. Oncol. 2020, 10, 576399. [Google Scholar] [CrossRef]
  70. Delgado-Bellido, D.; Serrano-Saenz, S.; Fernández-Cortés, M.; Oliver, F.J. Vasculogenic mimicry signaling revisited: Focus on non-vascular VE-cadherin. Mol. Cancer 2017, 16, 65. [Google Scholar] [CrossRef]
  71. Fouladzadeh, A.; Dorraki, M.; Min, K.K.M.; Cockshell, M.P.; Thompson, E.J.; Verjans, J.W.; Allison, A.; Bonder, C.S.; Abbott, D. The development of tumour vascular networks. Commun. Biol. 2021, 4, 1111. [Google Scholar] [CrossRef]
  72. Han, H.; Du, L.; Cao, Z.; Zhang, B.; Zhou, Q. Triptonide potently suppresses pancreatic cancer cell-mediated vasculogenic mimicry by inhibiting expression of VE-cadherin and chemokine ligand 2 genes. Eur. J. Pharmacol. 2018, 818, 593–603. [Google Scholar] [CrossRef] [PubMed]
  73. Yang, J.; Zhu, D.-M.; Zhou, X.-G.; Yin, N.; Zhang, Y.; Zhang, Z.-X.; Li, D.-C.; Zhou, J. HIF-2α promotes the formation of vasculogenic mimicry in pancreatic cancer by regulating the binding of Twist1 to the VE-cadherin promoter. Oncotarget 2017, 8, 47801. [Google Scholar] [CrossRef]
  74. Tan, L.Y.; Cockshell, M.P.; Moore, E.; Myo Min, K.K.; Ortiz, M.; Johan, M.Z.; Ebert, B.; Ruszkiewicz, A.; Brown, M.P.; Ebert, L.M.; et al. Vasculogenic mimicry structures in melanoma support the recruitment of monocytes. Oncoimmunology 2022, 11, 2043673. [Google Scholar] [CrossRef]
  75. Karamitopoulou, E. Tumour microenvironment of pancreatic cancer: Immune landscape is dictated by molecular and histopathological features. Br. J. Cancer 2019, 121, 5–14. [Google Scholar] [CrossRef] [PubMed]
  76. Muller, M.; Haghnejad, V.; Schaefer, M.; Gauchotte, G.; Caron, B.; Peyrin-Biroulet, L.; Bronowicki, J.-P.; Neuzillet, C.; Lopez, A. The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges. Cancers 2022, 14, 995. [Google Scholar] [CrossRef]
  77. Raskov, H.; Orhan, A.; Christensen, J.P.; Gögenur, I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br. J. Cancer 2021, 124, 359–367. [Google Scholar] [CrossRef] [PubMed]
  78. Carstens, J.L.; Correa de Sampaio, P.; Yang, D.; Barua, S.; Wang, H.; Rao, A.; Allison, J.P.; LeBleu, V.S.; Kalluri, R. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat. Commun. 2017, 8, 15095. [Google Scholar] [CrossRef] [PubMed]
  79. Speiser, D.E.; Chijioke, O.; Schaeuble, K.; Münz, C. CD4(+) T cells in cancer. Nat. Cancer 2023, 4, 317–329. [Google Scholar] [CrossRef]
  80. Amsen, D.; van Gisbergen, K.P.J.M.; Hombrink, P.; van Lier, R.A.W. Tissue-resident memory T cells at the center of immunity to solid tumors. Nat. Immunol. 2018, 19, 538–546. [Google Scholar] [CrossRef]
  81. Pearce, H.; Croft, W.; Nicol, S.M.; Margielewska-Davies, S.; Powell, R.; Cornall, R.; Davis, S.J.; Marcon, F.; Pugh, M.R.; Fennell, É.; et al. Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade. Cancer Immunol. Res. 2023, 11, 435–449. [Google Scholar] [CrossRef]
  82. Orhan, A.; Vogelsang, R.P.; Andersen, M.B.; Madsen, M.T.; Hölmich, E.R.; Raskov, H.; Gögenur, I. The prognostic value of tumour-infiltrating lymphocytes in pancreatic cancer: A systematic review and meta-analysis. Eur. J. Cancer 2020, 132, 71–84. [Google Scholar] [CrossRef] [PubMed]
  83. Lohneis, P.; Sinn, M.; Bischoff, S.; Jühling, A.; Pelzer, U.; Wislocka, L.; Bahra, M.; Sinn, B.V.; Denkert, C.; Oettle, H. Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected pancreatic ductal adenocarcinoma. Eur. J. Cancer 2017, 83, 290–301. [Google Scholar] [CrossRef]
  84. Gao, Z.; Zhang, Q.; Zhang, X.; Song, Y. Advance of T regulatory cells in tumor microenvironment remodeling and immunotherapy in pancreatic cancer. Eur. J. Inflamm. 2022, 20, 1721727X221092900. [Google Scholar] [CrossRef]
  85. Wachsmann, M.B.; Pop, L.M.; Vitetta, E.S. Pancreatic ductal adenocarcinoma: A review of immunologic aspects. J. Investig. Med. 2012, 60, 643–663. [Google Scholar] [CrossRef] [PubMed]
  86. Mirlekar, B.; Michaud, D.; Searcy, R.; Greene, K.; Pylayeva-Gupta, Y. IL35 Hinders Endogenous Antitumor T-cell Immunity and Responsiveness to Immunotherapy in Pancreatic CancerIL35 Regulates Antitumor Immune Response in PDA. Cancer Immunol. Res. 2018, 6, 1014–1024. [Google Scholar] [CrossRef]
  87. Bengsch, F.; Knoblock, D.M.; Liu, A.; McAllister, F.; Beatty, G.L. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol. Immunother. 2017, 66, 1609–1617. [Google Scholar] [CrossRef]
  88. Sharonov, G.V.; Serebrovskaya, E.O.; Yuzhakova, D.V.; Britanova, O.V.; Chudakov, D.M. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat. Reviews. Immunol. 2020, 20, 294–307. [Google Scholar] [CrossRef]
  89. Spear, S.; Candido, J.B.; McDermott, J.R.; Ghirelli, C.; Maniati, E.; Beers, S.A.; Balkwill, F.R.; Kocher, H.M.; Capasso, M. Discrepancies in the tumor microenvironment of spontaneous and orthotopic murine models of pancreatic cancer uncover a new immunostimulatory phenotype for B cells. Front. Immunol. 2019, 10, 542. [Google Scholar] [CrossRef]
  90. Castino, G.F.; Cortese, N.; Capretti, G.; Serio, S.; Di Caro, G.; Mineri, R.; Magrini, E.; Grizzi, F.; Cappello, P.; Novelli, F. Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma. Oncoimmunology 2016, 5, e1085147. [Google Scholar] [CrossRef]
  91. Huber, M.; Brehm, C.U.; Gress, T.M.; Buchholz, M.; Alashkar Alhamwe, B.; Pogge von Strandmann, E.; Slater, E.P.; Bartsch, J.W.; Bauer, C.; Lauth, M. The immune microenvironment in pancreatic cancer. Int. J. Mol. Sci. 2020, 21, 7307. [Google Scholar] [CrossRef] [PubMed]
  92. Peng, Y.-P.; Zhang, J.-J.; Liang, W.-b.; Tu, M.; Lu, Z.-P.; Wei, J.-S.; Jiang, K.-R.; Gao, W.-T.; Wu, J.-L.; Xu, Z.-K. Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction. BMC Cancer 2014, 14, 738. [Google Scholar] [CrossRef] [PubMed]
  93. Lim, S.A.; Kim, J.; Jeon, S.; Shin, M.H.; Kwon, J.; Kim, T.-J.; Im, K.; Han, Y.; Kwon, W.; Kim, S.-W. Defective localization with impaired tumor cytotoxicity contributes to the immune escape of NK cells in pancreatic cancer patients. Front. Immunol. 2019, 10, 496. [Google Scholar] [CrossRef] [PubMed]
  94. Zhu, Y.; Herndon, J.M.; Sojka, D.K.; Kim, K.-W.; Knolhoff, B.L.; Zuo, C.; Cullinan, D.R.; Luo, J.; Bearden, A.R.; Lavine, K.J. Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 2017, 47, 323–338.e6. [Google Scholar] [CrossRef]
  95. Zhou, X.; Yan, Y.; Xu, M. Immune cell responses in pancreatic cancer and their clinical application. Eur. J. Inflamm. 2022, 20, 20587392211044381. [Google Scholar] [CrossRef]
  96. Wang, K.; He, H. Pancreatic Tumor Microenvironment. In Tumor Microenvironments in Organs; Springer: Berlin/Heidelberg, Germany, 2020; pp. 243–257. [Google Scholar]
  97. Poh, A.R.; Ernst, M. Tumor-associated macrophages in pancreatic ductal adenocarcinoma: Therapeutic opportunities and clinical challenges. Cancers 2021, 13, 2860. [Google Scholar] [CrossRef]
  98. Yao, Y.; Xu, X.-H.; Jin, L. Macrophage polarization in physiological and pathological pregnancy. Front. Immunol. 2019, 10, 792. [Google Scholar] [CrossRef] [PubMed]
  99. Yang, S.; Liu, Q.; Liao, Q. Tumor-associated macrophages in pancreatic ductal adenocarcinoma: Origin, polarization, function, and reprogramming. Front. Cell Dev. Biol. 2021, 8, 607209. [Google Scholar] [CrossRef]
  100. Liou, G.-Y.; Döppler, H.; Necela, B.; Edenfield, B.; Zhang, L.; Dawson, D.W.; Storz, P. Mutant KRAS–Induced Expression of ICAM-1 in Pancreatic Acinar Cells Causes Attraction of Macrophages to Expedite the Formation of Precancerous LesionsKRAS and Macrophages Cooperate to Initiate PanIN Formation. Cancer Discov. 2015, 5, 52–63. [Google Scholar] [CrossRef]
  101. Thyagarajan, A.; Alshehri, M.S.A.; Miller, K.L.; Sherwin, C.M.; Travers, J.B.; Sahu, R.P. Myeloid-derived suppressor cells and pancreatic cancer: Implications in novel therapeutic approaches. Cancers 2019, 11, 1627. [Google Scholar] [CrossRef]
  102. Draghiciu, O.; Lubbers, J.; Nijman, H.W.; Daemen, T. Myeloid derived suppressor cells—An overview of combat strategies to increase immunotherapy efficacy. Oncoimmunology 2015, 4, e954829. [Google Scholar] [CrossRef] [PubMed]
  103. Porembka, M.R.; Mitchem, J.B.; Belt, B.A.; Hsieh, C.-S.; Lee, H.-M.; Herndon, J.; Gillanders, W.E.; Linehan, D.C.; Goedegebuure, P. Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth. Cancer Immunol. Immunother. 2012, 61, 1373–1385. [Google Scholar] [CrossRef] [PubMed]
  104. Stromnes, I.M.; Brockenbrough, J.S.; Izeradjene, K.; Carlson, M.A.; Cuevas, C.; Simmons, R.M.; Greenberg, P.D.; Hingorani, S.R. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut 2014, 63, 1769–1781. [Google Scholar] [CrossRef]
  105. Ma, Y.; Aymeric, L.; Locher, C.; Kroemer, G.; Zitvogel, L. The dendritic cell–tumor cross-talk in cancer. Curr. Opin. Immunol. 2011, 23, 146–152. [Google Scholar] [CrossRef] [PubMed]
  106. Yamamoto, T.; Yanagimoto, H.; Satoi, S.; Toyokawa, H.; Yamao, J.; Kim, S.; Terakawa, N.; Takahashi, K.; Kwon, A.-H. Circulating myeloid dendritic cells as prognostic factors in patients with pancreatic cancer who have undergone surgical resection. J. Surg. Res. 2012, 173, 299–308. [Google Scholar] [CrossRef]
  107. Fukunaga, A.; Miyamoto, M.; Cho, Y.; Murakami, S.; Kawarada, Y.; Oshikiri, T.; Kato, K.; Kurokawa, T.; Suzuoki, M.; Nakakubo, Y. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 2004, 28, e26–e31. [Google Scholar] [CrossRef]
  108. Kleger, A.; Perkhofer, L.; Seufferlein, T. Smarter drugs emerging in pancreatic cancer therapy. Ann. Oncol. 2014, 25, 1260–1270. [Google Scholar] [CrossRef]
  109. Neoptolemos, J.P.; Kleeff, J.; Michl, P.; Costello, E.; Greenhalf, W.; Palmer, D.H. Therapeutic developments in pancreatic cancer: Current and future perspectives. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 333–348. [Google Scholar] [CrossRef]
  110. Elbanna, K.Y.; Jang, H.-J.; Kim, T.K. Imaging diagnosis and staging of pancreatic ductal adenocarcinoma: A comprehensive review. Insights Imaging 2020, 11, 58. [Google Scholar] [CrossRef]
  111. Conroy, T.; Desseigne, F.; Ychou, M.; Bouché, O.; Guimbaud, R.; Bécouarn, Y.; Adenis, A.; Raoul, J.-L.; Gourgou-Bourgade, S.; de la Fouchardière, C. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011, 364, 1817–1825. [Google Scholar] [CrossRef]
  112. Li, S.; Xu, H.-X.; Wu, C.-T.; Wang, W.-Q.; Jin, W.; Gao, H.-L.; Li, H.; Zhang, S.-R.; Xu, J.-Z.; Qi, Z.-H.; et al. Angiogenesis in pancreatic cancer: Current research status and clinical implications. Angiogenesis 2019, 22, 15–36. [Google Scholar] [CrossRef]
  113. Nieskoski, M.D.; Marra, K.; Gunn, J.R.; Hoopes, P.J.; Doyley, M.M.; Hasan, T.; Trembly, B.S.; Pogue, B.W. Collagen Complexity Spatially Defines Microregions of Total Tissue Pressure in Pancreatic Cancer. Sci. Rep. 2017, 7, 10093. [Google Scholar] [CrossRef] [PubMed]
  114. Adiseshaiah, P.P.; Crist, R.M.; Hook, S.S.; McNeil, S.E. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat. Rev. Clin. Oncol. 2016, 13, 750–765. [Google Scholar] [CrossRef] [PubMed]
  115. Moore, M.J.; Goldstein, D.; Hamm, J.; Figer, A.; Hecht, J.R.; Gallinger, S.; Au, H.J.; Murawa, P.; Walde, D.; Wolff, R.A.; et al. Erlotinib Plus Gemcitabine Compared with Gemcitabine Alone in Patients with Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 2007, 25, 1960–1966. [Google Scholar] [CrossRef] [PubMed]
  116. Williams, M.; Lomberk, G.; Urrutia, R. EGFR (ErbB) Signaling Pathways in Pancreatic Cancer Pathogenesis. In Pancreatic Cancer; Neoptolemos, J.P., Urrutia, R., Abbruzzese, J., Büchler, M.W., Eds.; Springer: New York, NY, USA, 2017; pp. 1–26. [Google Scholar] [CrossRef]
  117. Chi, J.; Chung, S.Y.; Parakrama, R.; Fayyaz, F.; Jose, J.; Saif, M.W. The role of PARP inhibitors in BRCA mutated pancreatic cancer. Ther. Adv. Gastroenterol. 2021, 14, 17562848211014818. [Google Scholar] [CrossRef]
  118. Golan, T.; Hammel, P.; Reni, M.; Van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.-O.; Hochhauser, D.; Arnold, D.; Oh, D.-Y.; et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med. 2019, 381, 317–327. [Google Scholar] [CrossRef]
  119. Ruoslahti, E. Specialization of tumour vasculature. Nat. Rev. Cancer 2002, 2, 83–90. [Google Scholar] [CrossRef]
  120. Weiss, G.J.; Waypa, J.; Blaydorn, L.; Coats, J.; McGahey, K.; Sangal, A.; Niu, J.; Lynch, C.A.; Farley, J.H.; Khemka, V. A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). Br. J. Cancer 2017, 117, 33–40. [Google Scholar] [CrossRef]
  121. O’Reilly, E.M.; Oh, D.-Y.; Dhani, N.; Renouf, D.J.; Lee, M.A.; Sun, W.; Fisher, G.; Hezel, A.; Chang, S.-C.; Vlahovic, G. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: A phase 2 randomized clinical trial. JAMA Oncol. 2019, 5, 1431–1438. [Google Scholar] [CrossRef]
  122. Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.-J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465. [Google Scholar] [CrossRef]
  123. Jiang, Y.; Chen, M.; Nie, H.; Yuan, Y. PD-1 and PD-L1 in cancer immunotherapy: Clinical implications and future considerations. Hum. Vaccines Immunother. 2019, 15, 1111–1122. [Google Scholar] [CrossRef] [PubMed]
  124. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264. [Google Scholar] [CrossRef]
  125. Kocher, H.M.; Basu, B.; Froeling, F.E.M.; Sarker, D.; Slater, S.; Carlin, D.; deSouza, N.M.; De Paepe, K.N.; Goulart, M.R.; Hughes, C.; et al. Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. Nat. Commun. 2020, 11, 4841. [Google Scholar] [CrossRef] [PubMed]
  126. Diop-Frimpong, B.; Chauhan, V.P.; Krane, S.; Boucher, Y.; Jain, R.K. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl. Acad. Sci. USA 2011, 108, 2909–2914. [Google Scholar] [CrossRef]
  127. Chauhan, V.P.; Martin, J.D.; Liu, H.; Lacorre, D.A.; Jain, S.R.; Kozin, S.V.; Stylianopoulos, T.; Mousa, A.S.; Han, X.; Adstamongkonkul, P.; et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 2013, 4, 2516. [Google Scholar] [CrossRef] [PubMed]
  128. Hauge, A.; Rofstad, E.K. Antifibrotic therapy to normalize the tumor microenvironment. J. Transl. Med. 2020, 18, 207. [Google Scholar] [CrossRef] [PubMed]
  129. Neesse, A.; Frese, K.K.; Bapiro, T.E.; Nakagawa, T.; Sternlicht, M.D.; Seeley, T.W.; Pilarsky, C.; Jodrell, D.I.; Spong, S.M.; Tuveson, D.A. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 12325–12330. [Google Scholar] [CrossRef]
  130. Ho, W.J.; Jaffee, E.M.; Zheng, L. The tumour microenvironment in pancreatic cancer—Clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 2020, 17, 527–540. [Google Scholar] [CrossRef]
  131. Li, K.-Y.; Yuan, J.-L.; Trafton, D.; Wang, J.-X.; Niu, N.; Yuan, C.-H.; Liu, X.-B.; Zheng, L. Pancreatic ductal adenocarcinoma immune microenvironment and immunotherapy prospects. Chronic Dis. Transl. Med. 2020, 6, 6–17. [Google Scholar] [CrossRef]
  132. Timmer, F.E.; Geboers, B.; Nieuwenhuizen, S.; Dijkstra, M.; Schouten, E.A.; Puijk, R.S.; de Vries, J.J.; van den Tol, M.P.; Bruynzeel, A.M.; Streppel, M.M. Pancreatic cancer and immunotherapy: A clinical overview. Cancers 2021, 13, 4138. [Google Scholar] [CrossRef]
  133. Kindler, H.L.; Niedzwiecki, D.; Hollis, D.; Sutherland, S.; Schrag, D.; Hurwitz, H.; Innocenti, F.; Mulcahy, M.F.; O’Reilly, E.; Wozniak, T.F.; et al. Gemcitabine Plus Bevacizumab Compared with Gemcitabine Plus Placebo in Patients with Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303). J. Clin. Oncol. 2010, 28, 3617–3622. [Google Scholar] [CrossRef]
  134. Kindler, H.L.; Wroblewski, K.; Wallace, J.A.; Hall, M.J.; Locker, G.; Nattam, S.; Agamah, E.; Stadler, W.M.; Vokes, E.E. Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: A phase II trial of the University of Chicago Phase II Consortium. Investig. New Drugs 2012, 30, 382–386. [Google Scholar] [CrossRef] [PubMed]
  135. Yamaue, H.; Tsunoda, T.; Tani, M.; Miyazawa, M.; Yamao, K.; Mizuno, N.; Okusaka, T.; Ueno, H.; Boku, N.; Fukutomi, A. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer Sci. 2015, 106, 883–890. [Google Scholar] [CrossRef]
  136. Infante, J.R.; Somer, B.G.; Park, J.O.; Li, C.P.; Scheulen, M.E.; Kasubhai, S.M.; Oh, D.Y.; Liu, Y.; Redhu, S.; Steplewski, K.; et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur. J. Cancer 2014, 50, 2072–2081. [Google Scholar] [CrossRef]
  137. BusinessWire. Infinity Reports Update from Phase 2 Study of Saridegib Plus Gemcitabine in Patients with Metastatic Pancreatic Cancer; BusinessWire: San Francisco, CA, USA, 2012. [Google Scholar]
  138. Catenacci, D.V.T.; Junttila, M.R.; Karrison, T.; Bahary, N.; Horiba, M.N.; Nattam, S.R.; Marsh, R.; Wallace, J.; Kozloff, M.; Rajdev, L.; et al. Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients with Metastatic Pancreatic Cancer. J. Clin. Oncol. 2015, 33, 4284–4292. [Google Scholar] [CrossRef] [PubMed]
  139. Van Cutsem, E.; Tempero, M.A.; Sigal, D.; Oh, D.Y.; Fazio, N.; Macarulla, T.; Hitre, E.; Hammel, P.; Hendifar, A.E.; Bates, S.E.; et al. Randomized Phase III Trial of Pegvorhyaluronidase Alfa with Nab-Paclitaxel Plus Gemcitabine for Patients with Hyaluronan-High Metastatic Pancreatic Adenocarcinoma. J. Clin. Oncol. 2020, 38, 3185–3194. [Google Scholar] [CrossRef] [PubMed]
  140. Murphy, J.E.; Wo, J.Y.; Ryan, D.P.; Clark, J.W.; Jiang, W.; Yeap, B.Y.; Drapek, L.C.; Ly, L.; Baglini, C.V.; Blaszkowsky, L.S.; et al. Total Neoadjuvant Therapy with FOLFIRINOX in Combination with Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 2019, 5, 1020–1027. [Google Scholar] [CrossRef]
  141. Royal, R.E.; Levy, C.; Turner, K.; Mathur, A.; Hughes, M.; Kammula, U.S.; Sherry, R.M.; Topalian, S.L.; Yang, J.C.; Lowy, I.; et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 2010, 33, 828–833. [Google Scholar] [CrossRef]
  142. Lutz, E.; Yeo, C.J.; Lillemoe, K.D.; Biedrzycki, B.; Kobrin, B.; Herman, J.; Sugar, E.; Piantadosi, S.; Cameron, J.L.; Solt, S.; et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann. Surg. 2011, 253, 328–335. [Google Scholar] [CrossRef]
  143. Tempero, M. Ibrutinib Combined with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Cancer. 2015. Available online: https://clinicaltrials.gov/ct2/show/NCT02562898 (accessed on 20 January 2023).
  144. Meng, R.; Chen, J.W.; D’Onise, K.; Barreto, S.G. Pancreatic ductal adenocarcinoma survival in South Australia: Time trends and impact of tumour location. ANZ J. Surg. 2021, 91, 921–926. [Google Scholar] [CrossRef]
  145. Barreto, S.G. Does biology determine survival in pancreatic cancer? Future Oncol. 2020, 16, 1–4. [Google Scholar] [CrossRef] [PubMed]
  146. Barreto, S.G.; Kleeff, J. Synchronous arterial resections in pancreatic cancer–Still a matter of debate? Eur. J. Surg. Oncol. 2021, 47, 480–482. [Google Scholar] [CrossRef] [PubMed]
Cancers 15 02354 g001 550
Figure 1. Progression and development of PDAC. Acinar cells in a normal pancreatic duct transform into ductal epithelial cells during the development of pancreatic intraepithelial neoplasia (PanIN) stages 1–3, which can further develop into pancreatic ductal adenocarcinoma (PDAC) after key oncogenic genetic mutation events (KRAS activation, CDKN2A/TP53/SMAD4 deactivation).
Figure 1. Progression and development of PDAC. Acinar cells in a normal pancreatic duct transform into ductal epithelial cells during the development of pancreatic intraepithelial neoplasia (PanIN) stages 1–3, which can further develop into pancreatic ductal adenocarcinoma (PDAC) after key oncogenic genetic mutation events (KRAS activation, CDKN2A/TP53/SMAD4 deactivation).
Cancers 15 02354 g001
Cancers 15 02354 g002 550
Figure 2. PDAC tumour microenvironment and therapeutic targets. A key feature of PDAC is the presence of dense fibrotic stroma or desmoplasia. PDAC tumours consist of ECM components such as collagen and hyaluronan, as well as pro-tumourigenic and anti-tumorigenic cellular components such as fibroblasts, vessel forming endothelial cells, vasculogenic mimicry (VM) vessels, cancer associated fibroblasts (CAFs), pancreatic stellate cells, lymphocytes, dendritic cells (DCs), tumour associated macrophages (TAMs), natural killer (NK) cells, and myeloid derived suppressor cells (MDSCs).
Figure 2. PDAC tumour microenvironment and therapeutic targets. A key feature of PDAC is the presence of dense fibrotic stroma or desmoplasia. PDAC tumours consist of ECM components such as collagen and hyaluronan, as well as pro-tumourigenic and anti-tumorigenic cellular components such as fibroblasts, vessel forming endothelial cells, vasculogenic mimicry (VM) vessels, cancer associated fibroblasts (CAFs), pancreatic stellate cells, lymphocytes, dendritic cells (DCs), tumour associated macrophages (TAMs), natural killer (NK) cells, and myeloid derived suppressor cells (MDSCs).
Cancers 15 02354 g002
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Myo Min, K.K.; Ffrench, C.B.; Jessup, C.F.; Shepherdson, M.; Barreto, S.G.; Bonder, C.S. Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities. Cancers 2023, 15, 2354. https://doi.org/10.3390/cancers15082354

AMA Style

Myo Min KK, Ffrench CB, Jessup CF, Shepherdson M, Barreto SG, Bonder CS. Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities. Cancers. 2023; 15(8):2354. https://doi.org/10.3390/cancers15082354

Chicago/Turabian Style

Myo Min, Kay K., Charlie B. Ffrench, Claire F. Jessup, Mia Shepherdson, Savio George Barreto, and Claudine S. Bonder. 2023. "Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities" Cancers 15, no. 8: 2354. https://doi.org/10.3390/cancers15082354

APA Style

Myo Min, K. K., Ffrench, C. B., Jessup, C. F., Shepherdson, M., Barreto, S. G., & Bonder, C. S. (2023). Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities. Cancers, 15(8), 2354. https://doi.org/10.3390/cancers15082354

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