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The Shaping of Cancer by the Tumour Microenvironment and Its...
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The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 68993

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Patrícia Alexandra Saraiva Madureira

E-Mail Website
Guest Editor
Centre for Biomedical Research (CBMR), Cancer Biology and Progression Lab, University of Algarve, Campus of Gambelas, Building 8, room 2.22, 8005-139, Faro, Portugal
Interests: cancer cell biology; cancer cell signalling; cancer invasion/metastasis; reactive oxygen species (ROS); hypoxia; cancer therapy

Special Issue Information

Dear Colleagues,

The simplistic view of a tumour as the sole result of the uncontrolled proliferation of transformed cells has long been refuted. It is well established that cancer is not an independent entity, and that the tumour microenvironment plays a pivotal role in shaping the evolution of cancer cells and consequently the progression of the tumour. To survive and spread/metastasize, cancer cells need to adapt to the pressures imposed by their microenvironment. These include high oxidative stress conditions, reduced oxygen (hypoxia), immune system surveillance and exposure to chemo- and radio-therapy. It is crucial to understand the interplay between the cancer cells and the tumour microenvironment to develop efficient therapies against primary and, importantly, recurrent cancers that have evolved in response to treatment. For this Special Issue, we invite renowned researchers to contribute with original research articles as well as review articles that will improve our understanding of the molecular and cellular mechanisms by which cancer cells adapt to their microenvironment and the relevance of these findings to cancer therapy (e.g., identification of novel cancer markers and therapeutic targets).

Potential topics include, but are not limited to:

  • the role of oxidative stress in cancer cell signalling and tumour progression;
  • the role of hypoxia in cancer cell signalling and tumour progression;
  • the role of the immune system in cancer cell signalling and tumour progression;
  • novel therapies targeting adaptation of cancer cells to the tumour microenvironment; and identification of novel cancer biomarkers.

Dr. Patrícia Alexandra Saraiva Madureira
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • reactive oxygen species (ROS)
  • hypoxia
  • immune system
  • tumor microenvironment
  • cancer cell signalling
  • invasion/metastasis
  • cancer therapy

Published Papers (16 papers)

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Research

Jump to: Review

15 pages, 2518 KiB  
Article
Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities
by Bryce Ordway, Michal Tomaszewski, Samantha Byrne, Dominique Abrahams, Pawel Swietach, Robert J. Gillies and Mehdi Damaghi
Cancers 2021, 13(1), 64; https://doi.org/10.3390/cancers13010064 - 28 Dec 2020
Cited by 7 | Viewed by 2573
Abstract
Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity [...] Read more.
Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic interaction among subpopulations through the application of small, but selective biological forces such as intracellular pH (pHi) and/or extracellular pH (pHe) vulnerabilities. Increased glycolysis is a prominent phenotype of cancer cells under hypoxia or normoxia (Warburg effect). Glycolysis leads to an important aspect of cancer metabolism: reduced pHe and higher pHi. We recently showed that decreasing pHi and targeting pHi sensitive enzymes can reverse the Warburg effect (WE) phenotype and inhibit tumor progression. Herein, we used diclofenac (DIC) repurposed to control MCT activity, and Koningic acid (KA) that is a GAPDH partial inhibitor, and observed that we can control the subpopulation of cancer cells with WE phenotype within a tumor in favor of a less aggressive phenotype without a WE to control progression and metastasis. In a 3D spheroid co-cultures, we showed that our strategy can control the growth of more aggressive MDA-MB-231 cells, while sparing the less aggressive MCF7 cells. In an animal model, we show that our approach can reduce tumor growth and metastasis. We thus propose that evolutionary dynamics can be used to control tumor cells’ clonal or sub-clonal populations in favor of slower growth and less damage to patients. We propose that this can result in cancer control for tumors where cure is not an option. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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22 pages, 7067 KiB  
Article
S100A10 Has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights Using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis
by Alamelu G. Bharadwaj, Margaret L. Dahn, Rong-Zong Liu, Patricia Colp, Lynn N. Thomas, Ryan W. Holloway, Paola A. Marignani, Catherine K. L. Too, Penelope J. Barnes, Roseline Godbout, Paola Marcato and David M. Waisman
Cancers 2020, 12(12), 3673; https://doi.org/10.3390/cancers12123673 - 07 Dec 2020
Cited by 10 | Viewed by 3663
Abstract
S100A10 (p11) is a plasminogen receptor that regulates cellular plasmin generation by cancer cells. In the current study, we used the MMTV-PyMT mouse breast cancer model, patient tumor microarray, and immunohistochemical (IHC) analysis to investigate the role of p11 in oncogenesis. The genetic [...] Read more.
S100A10 (p11) is a plasminogen receptor that regulates cellular plasmin generation by cancer cells. In the current study, we used the MMTV-PyMT mouse breast cancer model, patient tumor microarray, and immunohistochemical (IHC) analysis to investigate the role of p11 in oncogenesis. The genetic deletion of p11 resulted in significantly decreased tumor onset, growth rate, and spontaneous pulmonary metastatic burden in the PyMT/p11-KO (knock-out) mice. This phenotype was accompanied by substantial reduction in Ki67 positivity, macrophage infiltration, decreased vascular density in the primary tumors, and decrease in invasive carcinoma and pulmonary metastasis. Surprisingly, IHC analysis of wild-type MMTV-PyMT mice failed to detect p11 expression in the tumors or metastatic tumor cells and loss of p11 did not decrease plasmin generation in the PyMT tumors and cells. Furthermore, tumor cells expressing p11 displayed dramatically reduced lung metastasis when injected into p11-depleted mice, further strengthening the stromal role of p11 in tumor growth and metastasis. Transcriptome analysis of the PyMT tumors from p11-KO mice showed marked reduction in genes such as Areg, Muc1, and S100a8 involved in breast cancer development, progression, and inflammation. The PyMT/p11-KO tumors displayed a remarkable increase in inflammatory cytokines such as interleukin (Il)-6, Il-10, and interferon (Ifn)-γ. Gene expression profiling and IHC of primary breast cancer samples showed that p11 mRNA and protein levels were significantly higher in tumor tissues compared to normal mammary tissue. P11 mRNA expression was significantly associated with poor patient prognosis and significantly elevated in high grade, triple negative (TN) tumors, and tumors with high proliferative index. This is the first study examining the crucial role of p11 in breast tumor development and metastasis, thus emphasizing its potential as a diagnostic and prognostic biomarker in breast cancer. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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20 pages, 3470 KiB  
Article
Investigating Radiotherapy Response in a Novel Syngeneic Model of Prostate Cancer
by Charles M. Haughey, Debayan Mukherjee, Rebecca E. Steele, Amy Popple, Lara Dura-Perez, Adam Pickard, Mehjabin Patel, Suneil Jain, Paul B. Mullan, Rich Williams, Pedro Oliveira, Niamh E. Buckley, Jamie Honeychurch, Simon S. McDade, Timothy Illidge, Ian G. Mills and Sharon L. Eddie
Cancers 2020, 12(10), 2804; https://doi.org/10.3390/cancers12102804 - 29 Sep 2020
Cited by 8 | Viewed by 4362
Abstract
The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the Pten−/−/trp53−/− mouse, termed DVL3 which when subcutaneously [...] Read more.
The prostate cancer (PCa) field lacks clinically relevant, syngeneic mouse models which retain the tumour microenvironment observed in PCa patients. This study establishes a cell line from prostate tumour tissue derived from the Pten−/−/trp53−/− mouse, termed DVL3 which when subcutaneously implanted in immunocompetent C57BL/6 mice, forms tumours with distinct glandular morphology, strong cytokeratin 8 and androgen receptor expression, recapitulating high-risk localised human PCa. Compared to the commonly used TRAMP C1 model, generated with SV40 large T-antigen, DVL3 tumours are immunologically cold, with a lower proportion of CD8+ T-cells, and high proportion of immunosuppressive myeloid derived suppressor cells (MDSCs), thus resembling high-risk PCa. Furthermore, DVL3 tumours are responsive to fractionated RT, a standard treatment for localised and metastatic PCa, compared to the TRAMP C1 model. RNA-sequencing of irradiated DVL3 tumours identified upregulation of type-1 interferon and STING pathways, as well as transcripts associated with MDSCs. Upregulation of STING expression in tumour epithelium and the recruitment of MDSCs following irradiation was confirmed by immunohistochemistry. The DVL3 syngeneic model represents substantial progress in preclinical PCa modelling, displaying pathological, micro-environmental and treatment responses observed in molecular high-risk disease. Our study supports using this model for development and validation of treatments targeting PCa, especially novel immune therapeutic agents. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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16 pages, 1959 KiB  
Article
Serum PD-1/PD-L1 Levels, Tumor Expression and PD-L1 Somatic Mutations in HER2-Positive and Triple Negative Normal-Like Feline Mammary Carcinoma Subtypes
by Catarina Nascimento, Ana Catarina Urbano, Andreia Gameiro, João Ferreira, Jorge Correia and Fernando Ferreira
Cancers 2020, 12(6), 1386; https://doi.org/10.3390/cancers12061386 - 28 May 2020
Cited by 33 | Viewed by 4613
Abstract
Tumor microenvironment has gained great relevance due to its ability to regulate distinct checkpoints mediators, orchestrating tumor progression. Serum programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) levels were compared with healthy controls and with serum cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) [...] Read more.
Tumor microenvironment has gained great relevance due to its ability to regulate distinct checkpoints mediators, orchestrating tumor progression. Serum programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) levels were compared with healthy controls and with serum cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and tumor necrosis factor-alpha (TNF-α) levels in order to understand the role of PD-1/PD-L1 axis in cats with mammary carcinoma. PD-1 and PD-L1 expression was evaluated in tumor-infiltrating lymphocytes (TILs) and cancer cells, as the presence of somatic mutations. Results showed that serum PD-1 and PD-L1 levels were significantly higher in cats with HER2-positive (p = 0.017; p = 0.032) and triple negative (TN) normal-like mammary carcinomas (p = 0.004; p = 0.015), showing a strong positive correlation between serum CTLA-4 and TNF-α levels. In tumors, PD-L1 expression in cancer cells was significantly higher in HER2-positive samples than in TN normal-like tumors (p = 0.010), as the percentage of PD-L1-positive TILs (p = 0.037). PD-L1 gene sequencing identified two heterozygous mutations in exon 4 (A245T; V252M) and one in exon 5 (T267S). In summary, results support the use of spontaneous feline mammary carcinoma as a model for human breast cancer and suggest that the development of monoclonal antibodies may be a therapeutic strategy. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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23 pages, 7755 KiB  
Article
Hypoxia and Macrophages Act in Concert Towards a Beneficial Outcome in Colon Cancer
by Flávia Martins, Rosa Oliveira, Bruno Cavadas, Filipe Pinto, Ana Patrícia Cardoso, Flávia Castro, Bárbara Sousa, Marta Laranjeiro Pinto, Ana João Silva, Diogo Adão, José Pedro Loureiro, Nicole Pedro, Rui Manuel Reis, Luísa Pereira, Maria José Oliveira and Angela Margarida Costa
Cancers 2020, 12(4), 818; https://doi.org/10.3390/cancers12040818 - 28 Mar 2020
Cited by 5 | Viewed by 4243
Abstract
In colon cancer, the prognostic value of macrophages is controversial, and it is still unknown how hypoxia modulates macrophage–cancer cell crosstalk. To unravel this, co-cultures of human primary macrophages and colon cancer cells were performed at 20% and 1% O2, followed [...] Read more.
In colon cancer, the prognostic value of macrophages is controversial, and it is still unknown how hypoxia modulates macrophage–cancer cell crosstalk. To unravel this, co-cultures of human primary macrophages and colon cancer cells were performed at 20% and 1% O2, followed by characterization of both cellular components. Different colon cancer patient cohorts were analyzed for hypoxia and immune markers, and their association with patient overall survival was established. A positive correlation between HIF1A and CD68 in colon cancer patients was identified but, unexpectedly, in cases with higher macrophage infiltration, HIF1A expression was associated with a better prognosis, in contrast to breast, gastric, and lung cancers. Under hypoxia, co-cultures’ secretome indicated a shift towards a pro-inflammatory phenotype. These alterations occurred along with increased macrophage phagocytic activity and decreased SIRPα expression. Cancer cells were more invasive and exhibited higher CD47 expression. We hypothesize that the better prognosis associated with HIF1AHighCD68High tumors could occur due to macrophagic pro-inflammatory pressure. Indeed, we found that tumors HIF1AHighCD68High expressed increased levels of CD8A, which is positively correlated with HIF1A. In conclusion, we show that in colon cancer, hypoxia drives macrophages into a pro-inflammatory phenotype, concomitant with increased infiltration of anti-tumor immune cells, favoring better disease outcome. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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Review

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19 pages, 15276 KiB  
Review
Therapeutic Targeting of Cancer Stem Cells in Lung, Head and Neck, and Bladder Cancers
by Sarah E. Mudra, Pritam Sadhukhan, M. Talha Ugurlu, Shorna Alam and Mohammad O. Hoque
Cancers 2021, 13(20), 5098; https://doi.org/10.3390/cancers13205098 - 12 Oct 2021
Cited by 8 | Viewed by 2828
Abstract
Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)—a subpopulation of tumor cells with capacities [...] Read more.
Resistance to cancer therapy remains a significant obstacle in treating patients with various solid malignancies. Exposure to current chemotherapeutics and targeted agents invariably leads to therapy resistance, heralding the need for novel agents. Cancer stem cells (CSCs)—a subpopulation of tumor cells with capacities for self-renewal and multi-lineage differentiation—represent a pool of therapeutically resistant cells. CSCs often share physical and molecular characteristics with the stem cell population of the human body. It remains challenging to selectively target CSCs in therapeutically resistant tumors. The generation of CSCs and induction of therapeutic resistance can be attributed to several deregulated critical growth regulatory signaling pathways such as WNT/β-catenin, Notch, Hippo, and Hedgehog. Beyond growth regulatory pathways, CSCs also change the tumor microenvironment and resist endogenous immune attack. Thus, CSCs can interfere with each stage of carcinogenesis from malignant transformation to the onset of metastasis to tumor recurrence. A thorough review of novel targeted agents to act against CSCs is fundamental for advancing cancer treatment in the setting of both intrinsic and acquired resistance. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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34 pages, 1965 KiB  
Review
Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy
by Alamelu G. Bharadwaj, Ryan W. Holloway, Victoria A. Miller and David M. Waisman
Cancers 2021, 13(8), 1838; https://doi.org/10.3390/cancers13081838 - 12 Apr 2021
Cited by 53 | Viewed by 5924
Abstract
The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM [...] Read more.
The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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23 pages, 933 KiB  
Review
Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy
by Nada S. Aboelella, Caitlin Brandle, Timothy Kim, Zhi-Chun Ding and Gang Zhou
Cancers 2021, 13(5), 986; https://doi.org/10.3390/cancers13050986 - 27 Feb 2021
Cited by 80 | Viewed by 7362
Abstract
It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety [...] Read more.
It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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16 pages, 1830 KiB  
Review
The Role of Hypoxia in Glioblastoma Radiotherapy Resistance
by Agathe L. Chédeville and Patricia A. Madureira
Cancers 2021, 13(3), 542; https://doi.org/10.3390/cancers13030542 - 01 Feb 2021
Cited by 53 | Viewed by 4109
Abstract
Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, [...] Read more.
Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains the most clinically effective treatment for these patients. Nevertheless, radiotherapy resistance (radioresistance) is commonly observed in GB patients leading to tumor recurrence and eventually patient death. It is therefore essential to unravel the molecular mechanisms underpinning GB cell radioresistance in order to develop novel strategies and combinational therapies focused on enhancing tumor cell sensitivity to radiotherapy. In this review, we present a comprehensive examination of the current literature regarding the role of hypoxia (O2 partial pressure less than 10 mmHg), a main GB microenvironmental factor, in radioresistance with the ultimate goal of identifying potential molecular markers and therapeutic targets to overcome this issue in the future. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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18 pages, 1518 KiB  
Review
The Match between Molecular Subtypes, Histology and Microenvironment of Pancreatic Cancer and Its Relevance for Chemoresistance
by Javier Martinez-Useros, Mario Martin-Galan and Jesus Garcia-Foncillas
Cancers 2021, 13(2), 322; https://doi.org/10.3390/cancers13020322 - 17 Jan 2021
Cited by 19 | Viewed by 3826
Abstract
In the last decade, several studies based on whole transcriptomic and genomic analyses of pancreatic tumors and their stroma have come to light to supplement histopathological stratification of pancreatic cancers with a molecular point-of-view. Three main molecular studies: Collisson et al. 2011, Moffitt [...] Read more.
In the last decade, several studies based on whole transcriptomic and genomic analyses of pancreatic tumors and their stroma have come to light to supplement histopathological stratification of pancreatic cancers with a molecular point-of-view. Three main molecular studies: Collisson et al. 2011, Moffitt et al. 2015 and Bailey et al. 2016 have found specific gene signatures, which identify different molecular subtypes of pancreatic cancer and provide a comprehensive stratification for both a personalized treatment or to identify potential druggable targets. However, the routine clinical management of pancreatic cancer does not consider a broad molecular analysis of each patient, due probably to the lack of target therapies for this tumor. Therefore, the current treatment decision is taken based on patients´ clinicopathological features and performance status. Histopathological evaluation of tumor samples could reveal many other attributes not only from tumor cells but also from their microenvironment specially about the presence of pancreatic stellate cells, regulatory T cells, tumor-associated macrophages, myeloid derived suppressor cells and extracellular matrix structure. In the present article, we revise the four molecular subtypes proposed by Bailey et al. and associate each subtype with other reported molecular subtypes. Moreover, we provide for each subtype a potential description of the tumor microenvironment that may influence treatment response according to the gene expression profile, the mutational landscape and their associated histology. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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30 pages, 1729 KiB  
Review
Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells
by Marcin Domagala, Chloé Laplagne, Edouard Leveque, Camille Laurent, Jean-Jacques Fournié, Eric Espinosa and Mary Poupot
Cancers 2021, 13(2), 165; https://doi.org/10.3390/cancers13020165 - 06 Jan 2021
Cited by 19 | Viewed by 3922
Abstract
Interactions between malignant cells and neighboring stromal and immune cells profoundly shape cancer progression. New forms of therapies targeting these cells have revolutionized the treatment of cancer. However, in order to specifically address each population, it was essential to identify and understand their [...] Read more.
Interactions between malignant cells and neighboring stromal and immune cells profoundly shape cancer progression. New forms of therapies targeting these cells have revolutionized the treatment of cancer. However, in order to specifically address each population, it was essential to identify and understand their individual roles in interaction between malignant cells, and the formation of the tumor microenvironment (TME). In this review, we focus on the myeloid cell compartment, a prominent, and heterogeneous group populating TME, which can initially exert an anti-tumoral effect, but with time actively participate in disease progression. Macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells, eosinophils, and basophils act alone or in concert to shape tumor cells resistance through cellular interaction and/or release of soluble factors favoring survival, proliferation, and migration of tumor cells, but also immune-escape and therapy resistance. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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16 pages, 489 KiB  
Review
Pro-Inflammatory Cytokines in the Formation of the Pre-Metastatic Niche
by Ru Li, Annie Wen and Jun Lin
Cancers 2020, 12(12), 3752; https://doi.org/10.3390/cancers12123752 - 13 Dec 2020
Cited by 43 | Viewed by 4527
Abstract
In the presence of a primary tumor, the pre-metastatic niche is established in secondary organs as a favorable microenvironment for subsequent tumor metastases. This process is orchestrated by bone marrow-derived cells, primary tumor-derived factors, and extracellular matrix. In this review, we summarize the [...] Read more.
In the presence of a primary tumor, the pre-metastatic niche is established in secondary organs as a favorable microenvironment for subsequent tumor metastases. This process is orchestrated by bone marrow-derived cells, primary tumor-derived factors, and extracellular matrix. In this review, we summarize the role of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, CC-chemokine ligand 2 (CCL2), granulocyte-colony stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), stromal cell-derived factor (SDF)-1, macrophage migration inhibitory factor (MIF), and Chemokine (C–X–C motif) ligand 1 (CXCL1) in the formation of the pre-metastatic niche according to the most recent studies. Pro-inflammatory cytokines released from tumor cells or stromal cells act in both autocrine and paracrine manners to induce phenotype changes in tumor cells, recruit bone marrow-derived cells, and form an inflammatory milieu, all of which prime a secondary organ’s microenvironment for metastatic cell colonization. Considering the active involvement of pro-inflammatory cytokines in niche formation, clinical strategies targeting them offer ways to inhibit the establishment of the pre-metastatic niche and therefore attenuate metastatic progression. We review clinical trials targeting different inflammatory cytokines in patients with metastatic cancers. Due to the pleiotropy and redundancy of pro-inflammatory cytokines, combined therapies should be designed in the future. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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25 pages, 1798 KiB  
Review
Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance
by Varintra E. Krisnawan, Jennifer A. Stanley, Julie K. Schwarz and David G. DeNardo
Cancers 2020, 12(10), 2916; https://doi.org/10.3390/cancers12102916 - 11 Oct 2020
Cited by 57 | Viewed by 4561
Abstract
A tumor is a complex “organ” composed of malignant cancer cells harboring genetic aberrations surrounded by a stroma comprised of non-malignant cells and an extracellular matrix. Considerable evidence has demonstrated that components of the genetically “normal” tumor stroma contribute to tumor progression and [...] Read more.
A tumor is a complex “organ” composed of malignant cancer cells harboring genetic aberrations surrounded by a stroma comprised of non-malignant cells and an extracellular matrix. Considerable evidence has demonstrated that components of the genetically “normal” tumor stroma contribute to tumor progression and resistance to a wide array of treatment modalities, including radiotherapy. Cancer-associated fibroblasts can promote radioresistance through their secreted factors, contact-mediated signaling, downstream pro-survival signaling pathways, immunomodulatory effects, and cancer stem cell-generating role. The extracellular matrix can govern radiation responsiveness by influencing oxygen availability and controlling the stability and bioavailability of growth factors and cytokines. Immune status regarding the presence of pro- and anti-tumor immune cells can regulate how tumors respond to radiation therapy. Furthermore, stromal cells including endothelial cells and adipocytes can modulate radiosensitivity through their roles in angiogenesis and vasculogenesis, and their secreted adipokines, respectively. Thus, to successfully eradicate cancers, it is important to consider how tumor stroma components interact with and regulate the response to radiation. Detailed knowledge of these interactions will help build a preclinical rationale to support the use of stromal-targeting agents in combination with radiotherapy to increase radiosensitivity. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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20 pages, 1219 KiB  
Review
Understanding the Effects of Radiotherapy on the Tumour Immune Microenvironment to Identify Potential Prognostic and Predictive Biomarkers of Radiotherapy Response
by Shuhui Cheng, Eleanor J. Cheadle and Timothy M. Illidge
Cancers 2020, 12(10), 2835; https://doi.org/10.3390/cancers12102835 - 30 Sep 2020
Cited by 7 | Viewed by 3115
Abstract
Radiotherapy (RT) is a highly effective anti-cancer treatment. Immunotherapy using immune checkpoint blockade (ICI) has emerged as a new and robust pillar in cancer therapy; however, the response rate to single agent ICI is low whilst toxicity remains. Radiotherapy has been shown to [...] Read more.
Radiotherapy (RT) is a highly effective anti-cancer treatment. Immunotherapy using immune checkpoint blockade (ICI) has emerged as a new and robust pillar in cancer therapy; however, the response rate to single agent ICI is low whilst toxicity remains. Radiotherapy has been shown to have local and systemic immunomodulatory effects. Therefore, combining RT and immunotherapy is a rational approach to enhance anti-tumour immune responses. However, the immunomodulatory effects of RT can be both immunostimulatory or immunosuppressive and may be different across different tumour types and patients. Therefore, there is an urgent medical need to establish biomarkers to guide clinical decision making in predicting responses or in patient selection for RT-based combination treatments. In this review, we summarize the immunological effects of RT on the tumour microenvironment and emerging biomarkers to help better understand the implications of these immunological changes, and we provide new insights into the potential for combination therapies with RT and immunotherapy. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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13 pages, 659 KiB  
Review
Cancer Acidity and Hypertonicity Contribute to Dysfunction of Tumor-Associated Dendritic Cells: Potential Impact on Antigen Cross-Presentation Machinery
by Sven Burgdorf, Stefan Porubsky, Alexander Marx and Zoran V. Popovic
Cancers 2020, 12(9), 2403; https://doi.org/10.3390/cancers12092403 - 24 Aug 2020
Cited by 23 | Viewed by 3418
Abstract
Macrophages (MΦ) and dendritic cells (DC), major players of the mononuclear phagocyte system (MoPh), are potent antigen presenting cells that steadily sense and respond to signals from the surrounding microenvironment, leading to either immunogenic or tolerogenic outcomes. Next to classical MHC-I/MHC-II antigen-presentation pathways [...] Read more.
Macrophages (MΦ) and dendritic cells (DC), major players of the mononuclear phagocyte system (MoPh), are potent antigen presenting cells that steadily sense and respond to signals from the surrounding microenvironment, leading to either immunogenic or tolerogenic outcomes. Next to classical MHC-I/MHC-II antigen-presentation pathways described in the vast majority of cell types, a subset of MoPh (CD8+, XCR1+, CLEC9A+, BDCA3+ conventional DCs in human) is endowed with a high competence to cross-present external (engulfed) antigens on MHC-I molecules to CD8+ T-cells. This exceptional DC function is thought to be a crucial crossroad in cytotoxic antitumor immunity and has been extensively studied in the past decades. Biophysical and biochemical fingerprints of tumor micromilieus show significant spatiotemporal differences in comparison to non-neoplastic tissue. In tumors, low pH (mainly due to extracellular lactate accumulation via the Warburg effect and via glutaminolysis) and high oncotic and osmotic pressure (resulting from tumor debris, increased extracellular matrix components but in part also triggered by nutritive aspects) are—despite fluctuations and difficulties in measurement—likely the most constant general hallmarks of tumor microenvironment. Here, we focus on the influence of acidic and hypertonic micromilieu on the capacity of DCs to cross-present tumor-specific antigens. We discuss complex and in part controversial scientific data on the interference of these factors with to date reported mechanisms of antigen uptake, processing and cross-presentation, and we highlight their potential role in cancer immune escape and poor clinical response to DC vaccines. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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16 pages, 3104 KiB  
Review
Histone Demethylase KDM5B as a Therapeutic Target for Cancer Therapy
by Anmi Jose, Gautham G. Shenoy, Gabriel Sunil Rodrigues, Naveena A. N. Kumar, Murali Munisamy, Levin Thomas, Jill Kolesar, Ganesha Rai, Praveen P. N. Rao and Mahadev Rao
Cancers 2020, 12(8), 2121; https://doi.org/10.3390/cancers12082121 - 31 Jul 2020
Cited by 24 | Viewed by 4700
Abstract
Lysine-specific demethylase 5B (KDM5B/PLU1/JARID1B) is found to be overexpressed in numerous malignancies, including breast, lung, skin, liver, and prostate cancer. Identification of molecules targeting the KDM5B enzyme could be a potential lead in cancer research. Although many KDM5B inhibitors with promising outcomes have [...] Read more.
Lysine-specific demethylase 5B (KDM5B/PLU1/JARID1B) is found to be overexpressed in numerous malignancies, including breast, lung, skin, liver, and prostate cancer. Identification of molecules targeting the KDM5B enzyme could be a potential lead in cancer research. Although many KDM5B inhibitors with promising outcomes have been developed so far, its further application in clinical practice is limited due to toxicity and lack of target specificity. Here, we summarize the significance of targeting KDM5B in anticancer therapy and report the molecular docking studies of some known anti-viral agents, decitabine, entecavir, abacavir, penciclovir, and 3-deazaneplanocin A in the catalytic domain JmjC of KDM5B. These studies show the repurposing potential of identified anti-viral agents in cancer therapy. Full article
(This article belongs to the Special Issue The Shaping of Cancer by the Tumour Microenvironment and Its Relevance for Cancer Therapy)
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