Dataset Information

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment.

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 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.

SUBMITTER: Ganguly D

PROVIDER: S-EPMC7564346 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment.

Ganguly Debolina D Chandra Raghav R Karalis John J Teke Martha M Aguilera Todd T Maddipati Ravikanth R Wachsmann Megan B MB Ghersi Dario D Siravegna Giulia G Zeh Herbert J HJ Brekken Rolf R Ting David T DT Ligorio Matteo M

Cancers 20200917 9

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 ...[more]

PMID: 32957515

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Project description:BackgroundThe tumor microenvironment has recently emerged as a new target of anticancer chemotherapy. Selective activation of anticancer chemotherapy in the tumor microenvironment would further reduce the toxicity of anticancer drugs toward normal tissues. Fibroblast activation protein (FAP) is known to be selectively overexpressed on cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Here, we designed an anticancer chemotherapeutic system based on promelittin, a peptide toxin that is selectively converted from an inactive form to the pore-forming melittin upon cleavage by FAP in the tumor microenvironment.MethodsWe conjugated promelittin-containing FAP-cleavable sequences to pegylated phospholipids and anchored them to reduced graphene oxide (rGO) nanosheets. The resulting nanosheets, PL-rGO, were tested for hemolysis and used for doxorubicin delivery. In vitro cocultures and in vivo tumor growth (n?=?5 mice per group) with tissue immunostaining were used to test the selective activation of anticancer chemotherapy by FAP expressed on CAFs.ResultsFAP-specific hemolytic activity of PL-rGO was observed in cocultures of CAFs and HT29 cells but not in HT29 cells alone. Doxorubicin-loaded PL-rGO (Dox/PL-rGO) showed 3.4-fold greater cell-killing efficacy (compared with free Dox in the CAF/HT29 coculture system, effects that were not observed in HT29 cells alone). Intravenously administered Dox/PL-rGO reduced the growth of HT29 tumors more effectively than other treatments (Dox/PL-rGO: mean = 200.6?mm(3), 95% confidence interval [CI] = 148.7 to 252.5?mm(3); free Dox: mean = 697.0?mm(3), 95% CI?=?646.9 to 747.1?mm(3), PL: mean = 565.0?mm(3), 95% CI?=?550.5 to 579.6?mm(3); Dox/rGO: mean = 637.6?mm(3), 95% CI?=?619.5 to 655.7?mm(3); PL-rGO: mean = 464.4?mm(3), 95% CI?=?433.0 to 495.8?mm(3)). Immunostaining of tumor tissues revealed that survival of CAFs and HT29 cells was lowest in the group treated with Dox/PL-rGO.ConclusionsThe demonstration of selective activation of PL-rGO by FAP on CAFs suggests that PL-rGO may serve as a tumor microenvironment-responsive anticancer chemotherapy system.

Project description:BackgroundThe tumor-promoting role of tumor microenvironment (TME) in colorectal cancer has been widely investigated in cancer biology. Cancer-associated fibroblasts (CAFs), as the main stromal component in TME, play an important role in promoting tumor progression and metastasis. Hence, we explored the crosstalk between CAFs and microenvironment in the pathogenesis of colorectal cancer in order to provide basis for precision therapy.MethodsWe integrated spatial transcriptomics (ST) and bulk-RNA sequencing datasets to explore the functions of CAFs in the microenvironment of CRC. In detail, single sample gene set enrichment analysis (ssGSEA), gene set variation analysis (GSVA), pseudotime analysis and cell proportion analysis were utilized to identify the cell types and functions of each cell cluster. Immunofluorescence and immunohistochemistry were applied to confirm the results based on bioinformatics analysis.ResultsWe profiled the tumor heterogeneity landscape and identified two distinct types of CAFs, which myo-cancer-associated fibroblasts (mCAFs) is associated with myofibroblast-like cells and inflammatory-cancer-associated fibroblasts (iCAFs) is related to immune inflammation. When we carried out functional analysis of two types of CAFs, we uncovered an extensive crosstalk between iCAFs and stromal components in TME to promote tumor progression and metastasis. Noticeable, some anti-tumor immune cells such as NK cells, monocytes were significantly reduced in iCAFs-enriched cluster. Then, ssGSEA analysis results showed that iCAFs were related to EMT, lipid metabolism and bile acid metabolism etc. Besides, when we explored the relationship of chemotherapy and microenvironment, we detected that iCAFs influenced immunosuppressive cells and lipid metabolism reprogramming in patient who underwent chemotherapy. Additionally, we identified the clinical role of iCAFs through a public database and confirmed it were related to poor prognosis.ConclusionsIn summary, we identified two types of CAFs using integrated data and explored their functional significance in TME. This in-depth understanding of CAFs in microenvironment may help us to elucidate its cancer-promoting functions and offer hints for therapeutic studies.

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Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment.

Publications

Cancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment.

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