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      A framework for advancing our understanding of cancer-associated fibroblasts

      review-article
      1 , , 2 , 3 , 4 , 5 , 6 , 7 , 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 5 , 15 , 16 , 17 , 18 , 5 , 19 , 32 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 5 , 28 , 29 , 30 , 31
      Nature Reviews. Cancer
      Nature Publishing Group UK
      Cancer microenvironment, Metastasis, Extracellular matrix, Cancer therapy, Cancer therapeutic resistance

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          Abstract

          Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.

          Abstract

          This Consensus Statement highlights the importance of cancer-associated fibroblasts in cancer biology and progression, and issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance our understanding of this important cell type in the tumour microenvironment.

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          Tensional homeostasis and the malignant phenotype.

          Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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            Turning foes to friends: targeting cancer-associated fibroblasts

            Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, as the cancer stroma may prompt tumour relapse and therapeutic resistance. Among all the stromal cells that populate the tumour microenvironment, cancer-associated fibroblasts (CAFs) are the most abundant and are critically involved in cancer progression. CAFs regulate the biology of tumour cells and other stromal cells via cell-cell contact, releasing numerous regulatory factors and synthesizing and remodelling the extracellular matrix, and thus these cells affect cancer initiation and development. The recent characterization of CAFs based on specific cell surface markers not only deepens our insight into their phenotypic heterogeneity and functional diversity but also brings CAF-targeting therapies for cancer treatment onto the agenda. In this Review, we discuss the current knowledge of biological hallmarks, cellular origins, phenotypical plasticity and functional heterogeneity of CAFs and underscore their contribution to cancer progression. Moreover, we highlight relevant translational advances and potential therapeutic strategies that target CAFs for cancer treatment.
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              TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

              Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFβ-activated stroma. Inhibition of the PD-1-PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1-PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.
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                Author and article information

                Contributors
                erik.sahai@crick.ac.uk
                Journal
                Nat Rev Cancer
                Nat. Rev. Cancer
                Nature Reviews. Cancer
                Nature Publishing Group UK (London )
                1474-175X
                1474-1768
                24 January 2020
                24 January 2020
                2020
                : 20
                : 3
                : 174-186
                Affiliations
                [1 ]ISNI 0000 0004 1795 1830, GRID grid.451388.3, The Francis Crick Institute, ; London, UK
                [2 ]ISNI 0000 0004 0456 6466, GRID grid.412530.1, Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, ; Philadelphia, PA USA
                [3 ]ISNI 0000 0004 0456 6466, GRID grid.412530.1, Cancer Biology Program, , Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, ; Philadelphia, PA USA
                [4 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Oncology, , Washington University Medical School, ; St Louis, MO USA
                [5 ]ISNI 0000 0004 0387 3667, GRID grid.225279.9, Cold Spring Harbor Laboratory, ; Cold Spring Harbor, NY USA
                [6 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Gene Expression Laboratory, Salk Institute for Biological Studies, ; La Jolla, CA USA
                [7 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Howard Hughes Medical Institute, Salk Institute for Biological Studies, ; La Jolla, CA USA
                [8 ]ISNI 000000041936877X, GRID grid.5386.8, Weill Cornell Medicine, ; New York, NY USA
                [9 ]ISNI 0000 0001 1088 7029, GRID grid.418483.2, Institute for Tumor Biology and Experimental Therapy, , Georg-Speyer-Haus, ; Frankfurt, Germany
                [10 ]ISNI 0000 0004 1936 9721, GRID grid.7839.5, Frankfurt Cancer Institute, Goethe University Frankfurt, ; Frankfurt, Germany
                [11 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, Fred Hutchinson Cancer Research Center, ; Seattle, WA USA
                [12 ]ISNI 0000 0001 0662 7144, GRID grid.250671.7, Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, ; La Jolla, CA USA
                [13 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, ; Cambridge, MA USA
                [14 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Edwin L Steele Laboratories, Department of Radiation Oncology, , Massachusetts General Hospital, Harvard Medical School, ; Boston, MA USA
                [15 ]ISNI 0000 0001 2168 3646, GRID grid.416477.7, Northwell Health Cancer Institute, ; New Hyde Park, NY USA
                [16 ]ISNI 0000000121662407, GRID grid.5379.8, Cancer Research UK Manchester Institute, University of Manchester, ; Nether Alderley, UK
                [17 ]ISNI 0000 0001 2109 4251, GRID grid.240324.3, Department of Radiation Oncology, Perlmutter Cancer Center, , New York University Medical Center, ; New York, NY USA
                [18 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center at Houston, ; Houston, TX USA
                [19 ]ISNI 0000 0001 2168 3646, GRID grid.416477.7, Northwell Health Cancer Institute, ; New York, NY USA
                [20 ]ISNI 0000 0001 2216 9681, GRID grid.36425.36, Department of Pathology, , Stony Brook University, ; Stony Brook, NY USA
                [21 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Department of Biomedical Sciences, , School of Veterinary Medicine, University of Pennsylvania, ; Philadelphia, PA USA
                [22 ]Zucker School of Medicine at Hofstra/Northwell Health System, New York, NY USA
                [23 ]ISNI 0000 0004 0604 7563, GRID grid.13992.30, Department of Biomolecular Sciences, , The Weizmann Institute of Science, ; Rehovot, Israel
                [24 ]ISNI 0000 0000 9758 5690, GRID grid.5288.7, Department of Cell, Developmental & Cancer Biology, , Oregon Health & Science University, ; Portland, OR USA
                [25 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Cell Biology and Physiology, Department of Medicine, , ICCE Institute, Siteman Cancer Center, Washington University School of Medicine, ; St Louis, MO USA
                [26 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, UCSF Helen Diller Comprehensive Cancer Center, ; San Francisco, CA USA
                [27 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Pathology, , UCSF, ; San Francisco, CA USA
                [28 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Centre for Stem Cells and Regenerative Medicine, , King’s College London, Guy’s Hospital, ; London, UK
                [29 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Center for Bioengineering and Tissue Regeneration, Department of Surgery, , University of California, San Francisco, ; San Francisco, CA USA
                [30 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, ; Baltimore, MD USA
                [31 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Anatomy, , University of California, San Francisco, ; San Francisco, CA USA
                [32 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Present Address: Abramson Cancer Center, University of Pennsylvania, ; Philadelphia, PA USA
                Author information
                http://orcid.org/0000-0002-3932-5086
                http://orcid.org/0000-0002-8613-1890
                http://orcid.org/0000-0002-3655-5783
                http://orcid.org/0000-0002-3928-6080
                http://orcid.org/0000-0001-7571-3548
                http://orcid.org/0000-0002-2260-9576
                http://orcid.org/0000-0001-9151-5154
                http://orcid.org/0000-0002-6525-3872
                Article
                238
                10.1038/s41568-019-0238-1
                7046529
                31980749
                cc4ede6b-f29a-4f6d-a419-dad7ac23c542
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 December 2019
                Categories
                Consensus Statement
                Custom metadata
                © Springer Nature Limited 2020

                cancer microenvironment,metastasis,extracellular matrix,cancer therapy,cancer therapeutic resistance

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