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22 pages, 10092 KiB

Open AccessArticle

Reciprocal Interactions between Fibroblast and Pancreatic Neuroendocrine Tumor Cells: Putative Impact of the Tumor Microenvironment

by Thomas Cuny, Peter M. van Koetsveld, Grégoire Mondielli, Fadime Dogan, Wouter W. de Herder, Anne Barlier and Leo J. Hofland

Cancers 2022, 14(14), 3481; https://doi.org/10.3390/cancers14143481 - 18 Jul 2022

Cited by 6 | Viewed by 1450

Abstract

Introduction: Pancreatic neuroendocrine neoplasms (PNENs) present with a fibrotic stroma that constitutes the tumor microenvironment (TME). The role played by stromal fibroblasts in the growth of PNENs and their sensitivity to the mTOR inhibitor RAD001 has not yet been established. Methods: We investigated [...] Read more.

Introduction: Pancreatic neuroendocrine neoplasms (PNENs) present with a fibrotic stroma that constitutes the tumor microenvironment (TME). The role played by stromal fibroblasts in the growth of PNENs and their sensitivity to the mTOR inhibitor RAD001 has not yet been established. Methods: We investigated reciprocal interactions between (1) human PNEN cell lines (BON-1/QGP-1) or primary cultures of human ileal neuroendocrine neoplasm (iNEN) or PNEN and (2) human fibroblast cell lines (HPF/HFL-1). Proliferation was assessed in transwell (tw) co-culture or in the presence of serum-free conditioned media (cm), with and without RAD001. Colony formation and migration of BON-1/QGP-1 were evaluated upon incubation with HPFcm. Results: Proliferation of BON-1 and QGP-1 increased in the presence of HFL-1cm, HPFcm, HFL-1tw and HPFtw (BON-1: +46–70% and QGP-1: +42–55%, p < 0.001 vs. controls) and HPFcm significantly increased the number of BON-1 or QGP-1 colonies (p < 0.05). This stimulatory effect was reversed in the presence of RAD001. Likewise, proliferation of human iNEN and PNEN primary cultures increased in the presence of HFL-1 or HPF. Reciprocally, BON-1cm and BONtw stimulated the proliferation of HPF (+90 ± 61% and +55 ± 47%, respectively, p < 0.001 vs. controls), an effect less pronounced with QGP-1cm or QGPtw (+19 to +27%, p < 0.05 vs. controls). Finally, a higher migration potential for BON-1 and QGP-1 was found in the presence of HPFcm (p < 0.001 vs. controls). Conclusions: Fibroblasts in the TME of PNENs represent a target of interest, the stimulatory effect of which over PNENs is mitigated by the mTOR inhibitor everolimus. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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27 pages, 3595 KiB

Open AccessArticle

The Extracellular Matrix Environment of Clear Cell Renal Cell Carcinoma Determines Cancer Associated Fibroblast Growth

by Kyle H. Bond, Takuto Chiba, Kieran P. H. Wynne, Calvin P. H. Vary, Sunder Sims-Lucas, Jeannine M. Coburn and Leif Oxburgh

Cancers 2021, 13(23), 5873; https://doi.org/10.3390/cancers13235873 - 23 Nov 2021

Cited by 18 | Viewed by 3060

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer and is often caused by mutations in the oxygen-sensing machinery of kidney epithelial cells. Due to its pseudo-hypoxic state, ccRCC recruits extensive vasculature and other stromal components. Conventional cell culture methods [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer and is often caused by mutations in the oxygen-sensing machinery of kidney epithelial cells. Due to its pseudo-hypoxic state, ccRCC recruits extensive vasculature and other stromal components. Conventional cell culture methods provide poor representation of stromal cell types in primary cultures of ccRCC, and we hypothesized that mimicking the extracellular environment of the tumor would promote growth of both tumor and stromal cells. We employed proteomics to identify the components of ccRCC extracellular matrix (ECM) and found that in contrast to healthy kidney cortex, laminin, collagen IV, and entactin/nidogen are minor contributors. Instead, the ccRCC ECM is composed largely of collagen VI, fibronectin, and tenascin C. Analysis of single cell expression data indicates that cancer-associated fibroblasts are a major source of tumor ECM production. Tumor cells as well as stromal cells bind efficiently to a nine-component ECM blend characteristic of ccRCC. Primary patient-derived tumor cells bind the nine-component blend efficiently, allowing to us to establish mixed primary cultures of tumor cells and stromal cells. These miniature patient-specific replicas are conducive to microscopy and can be used to analyze interactions between cells in a model tumor microenvironment. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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18 pages, 4345 KiB

Open AccessArticle

Interleukin-33-Enhanced CXCR4 Signaling Circuit Mediated by Carcinoma-Associated Fibroblasts Promotes Invasiveness of Head and Neck Cancer

by Yu-Chun Lin, Wen-Yen Huang, Tsai-Yu Lee, Yi-Ming Chang, Su-Feng Chen, Yaoh-Shiang Lin and Shin Nieh

Cancers 2021, 13(14), 3442; https://doi.org/10.3390/cancers13143442 - 09 Jul 2021

Cited by 6 | Viewed by 1812

Abstract

Despite recent advances, treatment for head and neck squamous cell carcinoma (HNSCC) has limited efficacy in preventing tumor progression. We confirmed previously that carcinoma-associated fibroblasts (CAF)-induced interleukin-33 (IL-33) contributed to cancer progression. However, the molecular mechanisms underlying the complex communication network of the [...] Read more.

Despite recent advances, treatment for head and neck squamous cell carcinoma (HNSCC) has limited efficacy in preventing tumor progression. We confirmed previously that carcinoma-associated fibroblasts (CAF)-induced interleukin-33 (IL-33) contributed to cancer progression. However, the molecular mechanisms underlying the complex communication network of the tumor microenvironment merited further evaluation. To simulate the IL-33-induced autocrine signaling, stable clones of IL-33-overexpressing HNSCC cells were established. Besides well-established IL-33/ST2 and SDF1/CXCR4 (stromal-derived factor 1/C-X-C motif chemokine receptor 4) signaling, the CAF-induced IL-33 upregulated CXCR4 via cancer cell induction of IL-33 self-production. The IL-33-enhanced-CXCR4 regulatory circuit involves SDF1/CXCR4 signaling activation and modulates tumor behavior. An in vivo study confirmed the functional role of IL-33/CXCR4 in tumor initiation and metastasis. The CXCR4 and/or IL-33 blockade reduced HNSCC cell aggressiveness, with attenuated invasions and metastases. Immunohistochemistry confirmed that IL-33 and CXCR4 expression correlated significantly with disease-free survival and IL-33-CXCR4 co-expression predicted a poor outcome. Besides paracrine signaling, the CAF-induced IL-33 reciprocally enhanced the autocrine cancer-cell self-production of IL-33 and the corresponding CXCR4 upregulation, leading to the activation of SDF1/CXCR4 signaling subsequent to cancer progression. Thus, targeting the IL-33-enhanced-CXCR4 regulatory circuit attenuates tumor aggressiveness and provides a potential therapeutic option for improving the prognosis in HNSCC patients. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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24 pages, 4067 KiB

Open AccessArticle

Orai1 Channel Regulates Human-Activated Pancreatic Stellate Cell Proliferation and TGF_β1 Secretion through the AKT Signaling Pathway

by Silviya Radoslavova, Antoine Folcher, Thibaut Lefebvre, Kateryna Kondratska, Stéphanie Guénin, Isabelle Dhennin-Duthille, Mathieu Gautier, Natalia Prevarskaya and Halima Ouadid-Ahidouch

Cancers 2021, 13(10), 2395; https://doi.org/10.3390/cancers13102395 - 15 May 2021

Cited by 13 | Viewed by 2857

Abstract

Activated pancreatic stellate cells (aPSCs), the crucial mediator of pancreatic desmoplasia, are characterized, among others, by high proliferative potential and abundant transforming growth factor _β1 (TGF_β1) secretion. Over the past years, the involvement of Ca²⁺ channels in PSC pathophysiology has [...] Read more.

Activated pancreatic stellate cells (aPSCs), the crucial mediator of pancreatic desmoplasia, are characterized, among others, by high proliferative potential and abundant transforming growth factor _β1 (TGF_β1) secretion. Over the past years, the involvement of Ca²⁺ channels in PSC pathophysiology has attracted great interest in pancreatic cancer research. We, thus, aimed to investigate the role of the Orai1 Ca²⁺ channel in these two PSC activation processes. Using the siRNA approach, we invalided Orai1 expression and assessed the channel functionality by Ca²⁺ imaging, the effect on aPSC proliferation, and TGF_β1 secretion. We demonstrated the functional expression of the Orai1 channel in human aPSCs and its implication in the store-operated Ca²⁺ entry (SOCE). Orai1 silencing led to a decrease in aPSC proliferation, TGF_β1 secretion, and AKT activation. Interestingly, TGF_β1 induced a higher SOCE response by increasing Orai1 mRNAs and proteins and promoted both AKT phosphorylation and cell proliferation, abolished by Orai1 silencing. Together, our results highlight the role of Orai1-mediated Ca²⁺ entry in human aPSC pathophysiology by controlling cell proliferation and TGF_β1 secretion through the AKT signaling pathway. Moreover, we showed a TGF_β1-induced autocrine positive feedback loop by promoting the Orai1/AKT-dependent proliferation via the stimulation of Orai1 expression and function. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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Review

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29 pages, 2394 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

by Ralf-Peter Czekay, Dong-Joo Cheon, Rohan Samarakoon, Stacie M. Kutz and Paul J. Higgins

Cancers 2022, 14(5), 1231; https://doi.org/10.3390/cancers14051231 - 27 Feb 2022

Cited by 41 | Viewed by 5666

Abstract

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, [...] Read more.

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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20 pages, 7101 KiB

Open AccessReview

Epigenetic Reprogramming of Tumor-Associated Fibroblasts in Lung Cancer: Therapeutic Opportunities

by Jordi Alcaraz, Rafael Ikemori, Alejandro Llorente, Natalia Díaz-Valdivia, Noemí Reguart and Miguel Vizoso

Cancers 2021, 13(15), 3782; https://doi.org/10.3390/cancers13153782 - 27 Jul 2021

Cited by 4 | Viewed by 2346

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. The desmoplastic stroma of lung cancer and other solid tumors is rich in tumor-associated fibroblasts (TAFs) exhibiting an activated/myofibroblast-like phenotype. There is growing awareness that TAFs support key steps of tumor progression and [...] Read more.

Lung cancer is the leading cause of cancer-related death worldwide. The desmoplastic stroma of lung cancer and other solid tumors is rich in tumor-associated fibroblasts (TAFs) exhibiting an activated/myofibroblast-like phenotype. There is growing awareness that TAFs support key steps of tumor progression and are epigenetically reprogrammed compared to healthy fibroblasts. Although the mechanisms underlying such epigenetic reprogramming are incompletely understood, there is increasing evidence that they involve interactions with either cancer cells, pro-fibrotic cytokines such as TGF-β, the stiffening of the surrounding extracellular matrix, smoking cigarette particles and other environmental cues. These aberrant interactions elicit a global DNA hypomethylation and a selective transcriptional repression through hypermethylation of the TGF-β transcription factor SMAD3 in lung TAFs. Likewise, similar DNA methylation changes have been reported in TAFs from other cancer types, as well as histone core modifications and altered microRNA expression. In this review we summarize the evidence of the epigenetic reprogramming of TAFs, how this reprogramming contributes to the acquisition and maintenance of a tumor-promoting phenotype, and how it provides novel venues for therapeutic intervention, with a special focus on lung TAFs. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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14 pages, 1269 KiB

Open AccessReview

Effects of CAF-Derived MicroRNA on Tumor Biology and Clinical Applications

by Xu Wang, Xin Wang, Midie Xu and Weiqi Sheng

Cancers 2021, 13(13), 3160; https://doi.org/10.3390/cancers13133160 - 24 Jun 2021

Cited by 13 | Viewed by 2529

Abstract

Cancer-associated fibroblasts (CAFs), prominent cell components of the tumor microenvironment (TME) in most types of solid tumor, play an essential role in tumor cell growth, proliferation, invasion, migration, and chemoresistance. MicroRNAs (miRNAs) are small, non-coding, single-strand RNAs that negatively regulate gene expression by [...] Read more.

Cancer-associated fibroblasts (CAFs), prominent cell components of the tumor microenvironment (TME) in most types of solid tumor, play an essential role in tumor cell growth, proliferation, invasion, migration, and chemoresistance. MicroRNAs (miRNAs) are small, non-coding, single-strand RNAs that negatively regulate gene expression by post-transcription modification. Increasing evidence has suggested the dysregulation of miRNAs in CAFs, which facilitates the conversion of normal fibroblasts (NFs) into CAFs, then enhances the tumor-promoting capacity of CAFs. To understand the process of tumor progression, as well as the development of chemoresistance, it is important to explore the regulatory function of CAF-derived miRNAs and the associated molecular mechanisms, which may become potential diagnostic and prognostic biomarkers and targets of anti-tumor therapeutics. In this review, we describe miRNAs that are differentially expressed by NFs and CAFs, summarize the modulating role of CAF-derived miRNAs in fibroblast activation and tumor advance, and eventually identify a potential clinical application for CAF-derived miRNAs as diagnostic/prognostic biomarkers and therapeutic targets in several tumors. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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17 pages, 1443 KiB

Open AccessReview

The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment

by Mark A. Eckert, Carlos Orozco, Jason Xiao, Melissa Javellana and Ernst Lengyel

Cancers 2021, 13(13), 3136; https://doi.org/10.3390/cancers13133136 - 23 Jun 2021

Cited by 10 | Viewed by 3096

Abstract

High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have [...] Read more.

High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor–stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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19 pages, 4521 KiB

Open AccessReview

In-Depth Characterization of Stromal Cells within the Tumor Microenvironment Yields Novel Therapeutic Targets

by Sebastian G. Walter, Sebastian Scheidt, Robert Nißler, Christopher Gaisendrees, Kourosh Zarghooni and Frank A. Schildberg

Cancers 2021, 13(6), 1466; https://doi.org/10.3390/cancers13061466 - 23 Mar 2021

Cited by 9 | Viewed by 4741

Abstract

Cells within the tumor stroma are essential for tumor progression. In particular, cancer-associated fibroblasts (CAF) and CAF precursor cells (resident fibroblasts and mesenchymal stromal cells) are responsible for the formation of the extracellular matrix in tumor tissue. Consequently, CAFs directly and indirectly mediate [...] Read more.

Cells within the tumor stroma are essential for tumor progression. In particular, cancer-associated fibroblasts (CAF) and CAF precursor cells (resident fibroblasts and mesenchymal stromal cells) are responsible for the formation of the extracellular matrix in tumor tissue. Consequently, CAFs directly and indirectly mediate inflammation, metastasis, immunomodulation, angiogenesis, and the development of tumor chemoresistance, which is orchestrated by complex intercellular cytokine-mediated crosstalk. CAFs represent a strategic target in antitumor therapy but their heterogeneity hinders effective treatment regimes. In-depth understanding of CAF subpopulations and knowledge of specific functions in tumor progression will ultimately result in more specific and effective cancer treatments. This review provides a detailed description of CAFs and CAF precursor cells and summarizes possible treatment strategies as well as molecular targets of these cells in antitumor therapies. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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22 pages, 1814 KiB

Open AccessFeature PaperReview

Fibroblast Subsets in Intestinal Homeostasis, Carcinogenesis, Tumor Progression, and Metastasis

by Hao Dang, Tom J. Harryvan and Lukas J. A. C. Hawinkels

Cancers 2021, 13(2), 183; https://doi.org/10.3390/cancers13020183 - 07 Jan 2021

Cited by 11 | Viewed by 3515

Abstract

In intestinal homeostasis, continuous renewal of the epithelium is crucial to withstand the plethora of stimuli which can damage the structural integrity of the intestines. Fibroblasts contribute to this renewal by facilitating epithelial cell differentiation as well as providing the structural framework in [...] Read more.

In intestinal homeostasis, continuous renewal of the epithelium is crucial to withstand the plethora of stimuli which can damage the structural integrity of the intestines. Fibroblasts contribute to this renewal by facilitating epithelial cell differentiation as well as providing the structural framework in which epithelial cells can regenerate. Upon dysregulation of intestinal homeostasis, (pre-) malignant neoplasms develop, a process which is accompanied by (epi) genetic alterations in epithelial cells as well as phenotypic changes in fibroblast populations. In the context of invasive carcinomas, these fibroblast populations are termed cancer-associated fibroblasts (CAFs). CAFs are the most abundant cell type in the tumor microenvironment of colorectal cancer (CRC) and consist of various functionally heterogeneous subsets which can promote or restrain cancer progression. Although most previous research has focused on the biology of epithelial cells, accumulating evidence shows that certain fibroblast subsets can also importantly contribute to tumor initiation and progression, thereby possibly providing avenues for improvement of clinical care for CRC patients. In this review, we summarized the current literature on the emerging role of fibroblasts in various stages of CRC development, ranging from adenoma initiation to the metastatic spread of cancer cells. In addition, we highlighted translational and therapeutic perspectives of fibroblasts in the different stages of intestinal tumor progression. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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23 pages, 928 KiB

Open AccessReview

Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic Intervention in Breast Cancer

by Yeuan Ting Lee, Yi Jer Tan, Marco Falasca and Chern Ein Oon

Cancers 2020, 12(10), 2949; https://doi.org/10.3390/cancers12102949 - 13 Oct 2020

Cited by 31 | Viewed by 6184

Abstract

Breast cancer is the leading cause of cancer-related mortality in women worldwide. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells in the solid tumour microenvironment. These cells are positively linked to breast cancer progression. Breast CAFs can be categorised into distinct subtypes [...] Read more.

Breast cancer is the leading cause of cancer-related mortality in women worldwide. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells in the solid tumour microenvironment. These cells are positively linked to breast cancer progression. Breast CAFs can be categorised into distinct subtypes according to their roles in breast carcinogenesis. Epigenetic modifications change gene expression patterns as a consequence of altered chromatin configuration and DNA accessibility to transcriptional machinery, without affecting the primary structure of DNA. Epigenetic dysregulation in breast CAFs may enhance breast cancer cell survival and ultimately lead to therapeutic resistance. A growing body of evidence has described epigenetic modulators that target histones, DNA, and miRNA as a promising approach to treat cancer. This review aims to summarise the current findings on the mechanisms involved in the epigenetic regulation in breast CAFs and discusses the potential therapeutic strategies via targeting these factors. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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34 pages, 3462 KiB

Open AccessReview

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment

by Debolina Ganguly, Raghav Chandra, John Karalis, Martha Teke, Todd Aguilera, Ravikanth Maddipati, Megan B. Wachsmann, Dario Ghersi, Giulia Siravegna, Herbert J. Zeh III, Rolf Brekken, David T. Ting and Matteo Ligorio

Cancers 2020, 12(9), 2652; https://doi.org/10.3390/cancers12092652 - 17 Sep 2020

Cited by 64 | Viewed by 8364

Abstract

Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our [...] Read more.

Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our current understanding of the principal differences between normal fibroblasts and CAFs, the origin of CAFs, their functions, and ultimately, highlight the intimate connection of CAFs to virtually all of the hallmarks of cancer. We address the remarkable degree of functional diversity and phenotypic plasticity displayed by CAFs and strive to stratify CAF biology among different tumor types into practical functional groups. Finally, we summarize the status of recent and ongoing trials of CAF-directed therapies and contend that the paucity of trials resulting in Food and Drug Administration (FDA) approvals thus far is a consequence of the failure to identify targets exclusive of pro-tumorigenic CAF phenotypes that are mechanistically linked to specific CAF functions. We believe that the development of a unified CAF nomenclature, the standardization of functional assays to assess the loss-of-function of CAF properties, and the establishment of rigorous definitions of CAF subpopulations and their mechanistic functions in cancer progression will be crucial to fully realize the promise of CAF-targeted therapies. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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24 pages, 1635 KiB

Open AccessReview

Communication in the Cancer Microenvironment as a Target for Therapeutic Interventions

by Agnieszka Dominiak, Beata Chełstowska, Wioletta Olejarz and Grażyna Nowicka

Cancers 2020, 12(5), 1232; https://doi.org/10.3390/cancers12051232 - 14 May 2020

Cited by 67 | Viewed by 6531

Abstract

The tumor microenvironment (TME) is a complex system composed of multiple cells, such as non-cancerous fibroblasts, adipocytes, immune and vascular cells, as well as signal molecules and mediators. Tumor cells recruit and reprogram other cells to produce factors that maintain tumor growth. Communication [...] Read more.

The tumor microenvironment (TME) is a complex system composed of multiple cells, such as non-cancerous fibroblasts, adipocytes, immune and vascular cells, as well as signal molecules and mediators. Tumor cells recruit and reprogram other cells to produce factors that maintain tumor growth. Communication between cancerous and surrounding cells is a two-way process and engages a diverse range of mechanisms that, in consequence, can lead to rapid proliferation, metastasis, and drug resistance, or can serve as a tumors-suppressor, e.g., through tumor–immune cell interaction. Cross-talk within the cancer microenvironment can be direct by cell-to-cell contact via adhesion molecules, electrical coupling, and passage through gap junctions, or indirect through classical paracrine signaling by cytokines, growth factors, and extracellular vesicles. Therapeutic approaches for modulation of cell-cell communication may be a promising strategy to combat tumors. In particular, integrative approaches targeting tumor communication in combination with conventional chemotherapy seem reasonable. Currently, special attention is paid to suppressing the formation of open-ended channels as well as blocking exosome production or ablating their cargos. However, many aspects of cell-to-cell communication have yet to be clarified, and, in particular, more work is needed in regard to mechanisms of bidirectional signal transfer. Finally, it seems that some interactions in TEM can be not only cancer-specific, but also patient-specific, and their recognition would help to predict patient response to therapy. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets)

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