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Cancers
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Cancer-Associated Fibroblast
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Cancer-Associated Fibroblast

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

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 45297

Special Issue Editor

Dr. Corinne Bousquet

E-Mail Website
Guest Editor
INSERM UMR-1037, Centre de Recherches en Cancérologie de Toulouse (CRCT), 2 avenue Hubert Curien, Oncopôle Entrée C, CS53717, 31037 Toulouse CEDEX1, France
Interests: pancreatic cancer; tumor cell with cancer-associated dialogues; extracellular matrices and mechanosignaling; mRNA translation and signal transduction; protein secretion

Special Issue Information

Dear Colleagues,

It is now well-admitted that tumors are heterogeneous in their composition, comprising, in addition to cancer cells, stromal cells and extracellular matrices that can represent up to 90% of certain solid tumor masses. Concepts of “local” and “distant” niches whereby tumor cells and stromal cells set up juxtacrine and paracrine dialogues in the primary tumor, or endocrine signals with distant “pre-metastatic” sites, respectively, have emerged and greatly increased our understanding of tumor biology at the scale of the whole organism. Cancer-associated fibroblasts are the most numerous stromal cells present in the majority of solid tumors, and also master secretors of molecules involved in such dialogues, mainly providing to cancer cells protumoral, metastatic, and drug-protective signals. Nonetheless, the recent demonstration of CAF molecular and phenotypic heterogeneity has further complicated our understanding of their biological roles.

This Special Issue focuses on latest advances in understanding which CAF populations are present during the different steps of the tumorigenesis or under therapies, which role they have to play within the primary tumor or metastases and how, and what the molecular mechanisms underlying their specific gene programming/phenotype are.

Dr. Corinne Bousquet
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

  • Cancer-associated fibroblasts
  • Molecular and phenotypic heterogeneity
  • Epigenetic reprogramming
  • Genome stability/instability
  • Metabolic dialogues
  • Exosomes
  • Extracellular matrices and mechanosignaling
  • Immunomodulation
  • Therapeutic resistance
  • Tumor invasion and metastasis

Published Papers (7 papers)

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Research

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22 pages, 4459 KiB  
Article
Single-Cell Transcriptomic Analysis of Tumor-Derived Fibroblasts and Normal Tissue-Resident Fibroblasts Reveals Fibroblast Heterogeneity in Breast Cancer
by Aimy Sebastian, Nicholas R. Hum, Kelly A. Martin, Sean F. Gilmore, Ivana Peran, Stephen W. Byers, Elizabeth K. Wheeler, Matthew A. Coleman and Gabriela G. Loots
Cancers 2020, 12(5), 1307; https://doi.org/10.3390/cancers12051307 - 21 May 2020
Cited by 143 | Viewed by 16070
Abstract
Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role in tumor progression and metastasis. CAFs coexist as heterogeneous populations with potentially different biological functions. Although CAFs are a major component of [...] Read more.
Cancer-associated fibroblasts (CAFs) are a prominent stromal cell type in solid tumors and molecules secreted by CAFs play an important role in tumor progression and metastasis. CAFs coexist as heterogeneous populations with potentially different biological functions. Although CAFs are a major component of the breast cancer stroma, molecular and phenotypic heterogeneity of CAFs in breast cancer is poorly understood. In this study, we investigated CAF heterogeneity in triple-negative breast cancer (TNBC) using a syngeneic mouse model, BALB/c-derived 4T1 mammary tumors. Using single-cell RNA sequencing (scRNA-seq), we identified six CAF subpopulations in 4T1 tumors including: 1) myofibroblastic CAFs, enriched for α-smooth muscle actin and several other contractile proteins; 2) ‘inflammatory’ CAFs with elevated expression of inflammatory cytokines; and 3) a CAF subpopulation expressing major histocompatibility complex (MHC) class II proteins that are generally expressed in antigen-presenting cells. Comparison of 4T1-derived CAFs to CAFs from pancreatic cancer revealed that these three CAF subpopulations exist in both tumor types. Interestingly, cells with inflammatory and MHC class II-expressing CAF profiles were also detected in normal breast/pancreas tissue, suggesting that these phenotypes are not tumor microenvironment-induced. This work enhances our understanding of CAF heterogeneity, and specifically targeting these CAF subpopulations could be an effective therapeutic approach for treating highly aggressive TNBCs. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblast)
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Review

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19 pages, 1611 KiB  
Review
Colon Fibroblasts and Inflammation: Sparring Partners in Colorectal Cancer Initiation?
by Lauriane Onfroy-Roy, Dimitri Hamel, Laurent Malaquin and Audrey Ferrand
Cancers 2021, 13(8), 1749; https://doi.org/10.3390/cancers13081749 - 7 Apr 2021
Cited by 7 | Viewed by 3494
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related death. Significant improvements in CRC treatment have been made for the last 20 years, on one hand thanks to a better detection, allowing surgical resection of the incriminated area, and on the [...] Read more.
Colorectal cancer (CRC) is the third most common cause of cancer-related death. Significant improvements in CRC treatment have been made for the last 20 years, on one hand thanks to a better detection, allowing surgical resection of the incriminated area, and on the other hand, thanks to a better knowledge of CRC’s development allowing the improvement of drug strategies. Despite this crucial progress, CRC remains a public health issue. The current model for CRC initiation and progression is based on accumulation of sequential known genetic mutations in the colon epithelial cells’ genome leading to a loss of control over proliferation and survival. However, increasing evidence reveals that CRC initiation is more complex. Indeed, chronic inflammatory contexts, such as inflammatory bowel diseases, have been shown to increase the risk for CRC development in mice and humans. In this manuscript, we review whether colon fibroblasts can go from the main regulators of the ISC homeostasis, regulating not only the renewal process but also the epithelial cells’ differentiation occurring along the colon crypt, to the main player in the initiation of the colorectal cancer process due to chronic inflammation. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblast)
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17 pages, 1420 KiB  
Review
Cancer-Associated Fibroblast-Induced Resistance to Chemotherapy and Radiotherapy in Gastrointestinal Cancers
by In-Hye Ham, Dagyeong Lee and Hoon Hur
Cancers 2021, 13(5), 1172; https://doi.org/10.3390/cancers13051172 - 9 Mar 2021
Cited by 32 | Viewed by 5163
Abstract
In the past few decades, the role of cancer-associated fibroblasts (CAFs) in resistance to therapies for gastrointestinal (GI) cancers has emerged. Clinical studies focusing on GI cancers have revealed that the high expression of CAF-related molecules within tumors is significantly correlated with unfavorable [...] Read more.
In the past few decades, the role of cancer-associated fibroblasts (CAFs) in resistance to therapies for gastrointestinal (GI) cancers has emerged. Clinical studies focusing on GI cancers have revealed that the high expression of CAF-related molecules within tumors is significantly correlated with unfavorable therapeutic outcomes; however, the exact mechanisms whereby CAFs enhance resistance to chemotherapy and radiotherapy in GI cancers remain unclear. The cells of origin of CAFs in GI cancers include normal resident fibroblasts, mesenchymal stem cells, endothelial cells, pericytes, and even epithelial cells. CAFs accumulated within GI cancers produce cytokines, chemokines, and growth factors involved in resistance to therapies. CAF-derived exosomes can be engaged in stroma-related resistance to treatments, and several non-coding RNAs, such as miR-92a, miR-106b, CCAL, and H19, are present in CAF-derived exosomes and transferred to GI cancer cells. The CAF-induced desmoplastic reaction interferes with drug delivery to GI cancer cells, evoking resistance to chemotherapy. However, due to the heterogeneity of CAFs in GI cancers, identifying the exact mechanism underlying CAF-induced resistance may be difficult. Recent advancements in single-cell “omics” technologies could offer clues for revealing the specific subtypes and biomarkers related to resistance. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblast)
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28 pages, 1758 KiB  
Review
Cancer-Associated Fibroblasts: Understanding Their Heterogeneity
by Kévin Louault, Rong-Rong Li and Yves A. DeClerck
Cancers 2020, 12(11), 3108; https://doi.org/10.3390/cancers12113108 - 24 Oct 2020
Cited by 71 | Viewed by 8406
Abstract
The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other [...] Read more.
The tumor microenvironment (TME) plays a critical role in tumor progression. Among its multiple components are cancer-associated fibroblasts (CAFs) that are the main suppliers of extracellular matrix molecules and important contributors to inflammation. As a source of growth factors, cytokines, chemokines and other regulatory molecules, they participate in cancer progression, metastasis, angiogenesis, immune cell reprogramming and therapeutic resistance. Nevertheless, their role is not fully understood, and is sometimes controversial due to their heterogeneity. CAFs are heterogeneous in their origin, phenotype, function and presence within tumors. As a result, strategies to target CAFs in cancer therapy have been hampered by the difficulties in better defining the various populations of CAFs and by the lack of clear recognition of their specific function in cancer progression. This review discusses how a greater understanding of the heterogeneous nature of CAFs could lead to better approaches aimed at their use or at their targeting in the treatment of cancer. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblast)
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17 pages, 1280 KiB  
Review
Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression
by Lisa Nocquet, Philippe P. Juin and Frédérique Souazé
Cancers 2020, 12(10), 3017; https://doi.org/10.3390/cancers12103017 - 17 Oct 2020
Cited by 14 | Viewed by 3511
Abstract
Resistance of solid cancer cells to chemotherapies and targeted therapies is not only due to the mutational status of cancer cells but also to the concurring of stromal cells of the tumor ecosystem, such as immune cells, vasculature and cancer-associated fibroblasts (CAFs). The [...] Read more.
Resistance of solid cancer cells to chemotherapies and targeted therapies is not only due to the mutational status of cancer cells but also to the concurring of stromal cells of the tumor ecosystem, such as immune cells, vasculature and cancer-associated fibroblasts (CAFs). The reciprocal education of cancer cells and CAFs favors tumor growth, survival and invasion. Mitochondrial function control, including the regulation of mitochondrial metabolism, oxidative stress and apoptotic stress are crucial for these different tumor progression steps. In this review, we focus on how CAFs participate in cancer progression by modulating cancer cells metabolic functions and mitochondrial apoptosis. We emphasize that mitochondria from CAFs influence their activation status and pro-tumoral effects. We thus advocate that understanding mitochondria-mediated tumor–stroma interactions provides the possibility to consider cancer therapies that improve current treatments by targeting these interactions or mitochondria directly in tumor and/or stromal cells. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblast)
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23 pages, 611 KiB  
Review
Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion
by Marc Hilmi, Rémy Nicolle, Corinne Bousquet and Cindy Neuzillet
Cancers 2020, 12(10), 2969; https://doi.org/10.3390/cancers12102969 - 14 Oct 2020
Cited by 23 | Viewed by 3002
Abstract
Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential [...] Read more.
Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblast)
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Graphical abstract

16 pages, 711 KiB  
Review
Cancer-Associated Fibroblast Mediated Inhibition of CD8+ Cytotoxic T Cell Accumulation in Tumours: Mechanisms and Therapeutic Opportunities
by Patrick Freeman and Ainhoa Mielgo
Cancers 2020, 12(9), 2687; https://doi.org/10.3390/cancers12092687 - 21 Sep 2020
Cited by 48 | Viewed by 4396
Abstract
The tumour microenvironment (TME) is the complex environment in which various non-cancerous stromal cell populations co-exist, co-evolve and interact with tumour cells, having a profound impact on the progression of solid tumours. The TME is comprised of various extracellular matrix (ECM) proteins in [...] Read more.
The tumour microenvironment (TME) is the complex environment in which various non-cancerous stromal cell populations co-exist, co-evolve and interact with tumour cells, having a profound impact on the progression of solid tumours. The TME is comprised of various extracellular matrix (ECM) proteins in addition to a variety of immune and stromal cells. These include tumour-associated macrophages, regulatory T cells (Tregs), myeloid-derived suppressor cells, as well as endothelial cells, pericytes and cancer-associated fibroblasts (CAFs). CAFs are the most abundant stromal cell population in many tumours and support cancer progression, metastasis and resistance to therapies through bidirectional signalling with both tumour cells and other cells within the TME. More recently, CAFs have been shown to also affect the anti-tumour immune response through direct and indirect interactions with immune cells. In this review, we specifically focus on the interactions between CAFs and cytotoxic CD8+ T cells, and on how these interactions affect T cell recruitment, infiltration and function in the tumour. We additionally provide insight into the therapeutic implications of targeting these interactions, particularly in the context of cancer immunotherapy. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblast)
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