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      Cancer associated fibroblasts: An essential role in the tumor microenvironment

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          Abstract

          Fibroblasts in the tumor stroma are well recognized as having an indispensable role in carcinogenesis, including in the initiation of epithelial tumor formation. The association between cancer cells and fibroblasts has been highlighted in several previous studies. Regulation factors released from cancer-associated fibroblasts (CAFs) into the tumor microenvironment have essential roles, including the support of tumor growth, angiogenesis, metastasis and therapy resistance. A mutual interaction between tumor-induced fibroblast activation, and fibroblast-induced tumor proliferation and metastasis occurs, thus CAFs act as tumor supporters. Previous studies have reported that by developing fibroblast-targeting drugs, it may be possible to interrupt the interaction between fibroblasts and the tumor, thus resulting in the suppression of tumor growth, and metastasis. The present review focused on the reciprocal feedback loop between fibroblasts and cancer cells, and evaluated the potential application of anti-CAF agents in the treatment of cancer.

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          Dependency of colorectal cancer on a TGF-β-driven program in stromal cells for metastasis initiation.

          Alexandre Calon, Elisa Espinet, Sergio Palomo-Ponce … (2012)
          A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC. Copyright © 2012 Elsevier Inc. All rights reserved.
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            BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.

            Frank Hilberg, Gerald Roth, Martin Krššák … (2008)
            Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.
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              Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.

              Thea Tlsty, Scott Carroll, Aria F. Olumi … (1999)
              The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncol Lett
                Journal ID (iso-abbrev): Oncol Lett
                Journal ID (publisher-id): OL
                Title: Oncology Letters
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-1074
                ISSN (Electronic): 1792-1082
                Publication date (Print): September 2017
                Publication date (Electronic): 30 June 2017
                Publication date PMC-release: 30 June 2017
                Volume: 14
                Issue: 3
                Pages: 2611-2620
                Affiliations
                Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
                Author notes
                Correspondence to: Dr Longbang Chen, Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan Eastern Road, Nanjing, Jiangsu 210002, P.R. China, E-mail: drchenlb@ 123456nju.edu.cn
                Article
                Publisher ID: OL-0-0-6497
                DOI: 10.3892/ol.2017.6497
                PMC ID: 5588104
                PubMed ID: 28927027
                SO-VID: 49a32964-6d60-4563-87f8-47585b521e61
                Copyright © Copyright: © Tao et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 24 October 2015
                Date accepted : 08 May 2017
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer associated fibroblasts,cancer,interaction,loop,therapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: cancer associated fibroblasts, cancer, interaction, loop, therapy

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