Review

. 2020 Mar;20(3):174-186.

doi: 10.1038/s41568-019-0238-1. Epub 2020 Jan 24.

A framework for advancing our understanding of cancer-associated fibroblasts

Erik Sahai¹, Igor Astsaturov², Edna Cukierman³, David G DeNardo⁴, Mikala Egeblad⁵, Ronald M Evans^{6

7}, Douglas Fearon^{5

8}, Florian R Greten^{9

10}, Sunil R Hingorani¹¹, Tony Hunter¹², Richard O Hynes¹³, Rakesh K Jain¹⁴, Tobias Janowitz^{5

15}, Claus Jorgensen¹⁶, Alec C Kimmelman¹⁷, Mikhail G Kolonin¹⁸, Robert G Maki^{5

19

20}, R Scott Powers²¹, Ellen Puré²², Daniel C Ramirez²³, Ruth Scherz-Shouval²⁴, Mara H Sherman²⁵, Sheila Stewart²⁶, Thea D Tlsty^{27

28}, David A Tuveson⁵, Fiona M Watt²⁹, Valerie Weaver³⁰, Ashani T Weeraratna³¹, Zena Werb³²

Affiliations

¹ The Francis Crick Institute, London, UK. erik.sahai@crick.ac.uk.
² Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
³ Cancer Biology Program, Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴ Division of Oncology, Washington University Medical School, St Louis, MO, USA.
⁵ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
⁶ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
⁷ Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.
⁸ Weill Cornell Medicine, New York, NY, USA.
⁹ Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
¹⁰ Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany.
¹¹ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹² Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
¹³ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Edwin L Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Northwell Health Cancer Institute, New Hyde Park, NY, USA.
¹⁶ Cancer Research UK Manchester Institute, University of Manchester, Nether Alderley, UK.
¹⁷ Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY, USA.
¹⁸ Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center at Houston, Houston, TX, USA.
¹⁹ Northwell Health Cancer Institute, New York, NY, USA.
²⁰ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
²¹ Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
²² Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Zucker School of Medicine at Hofstra/Northwell Health System, New York, NY, USA.
²⁴ Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel.
²⁵ Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
²⁶ Department of Cell Biology and Physiology, Department of Medicine, ICCE Institute, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.
²⁷ UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA.
²⁸ Department of Pathology, UCSF, San Francisco, CA, USA.
²⁹ Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, London, UK.
³⁰ Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
³¹ Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³² Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

PMID: 31980749
PMCID: PMC7046529
DOI: 10.1038/s41568-019-0238-1

Review

A framework for advancing our understanding of cancer-associated fibroblasts

Erik Sahai et al. Nat Rev Cancer. 2020 Mar.

. 2020 Mar;20(3):174-186.

doi: 10.1038/s41568-019-0238-1. Epub 2020 Jan 24.

Authors

Affiliations

¹ The Francis Crick Institute, London, UK. erik.sahai@crick.ac.uk.
² Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
³ Cancer Biology Program, Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁴ Division of Oncology, Washington University Medical School, St Louis, MO, USA.
⁵ Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
⁶ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
⁷ Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.
⁸ Weill Cornell Medicine, New York, NY, USA.
⁹ Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.
¹⁰ Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, Germany.
¹¹ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹² Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
¹³ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁴ Edwin L Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Northwell Health Cancer Institute, New Hyde Park, NY, USA.
¹⁶ Cancer Research UK Manchester Institute, University of Manchester, Nether Alderley, UK.
¹⁷ Department of Radiation Oncology, Perlmutter Cancer Center, New York University Medical Center, New York, NY, USA.
¹⁸ Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center at Houston, Houston, TX, USA.
¹⁹ Northwell Health Cancer Institute, New York, NY, USA.
²⁰ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
²¹ Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
²² Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Zucker School of Medicine at Hofstra/Northwell Health System, New York, NY, USA.
²⁴ Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel.
²⁵ Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
²⁶ Department of Cell Biology and Physiology, Department of Medicine, ICCE Institute, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO, USA.
²⁷ UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA.
²⁸ Department of Pathology, UCSF, San Francisco, CA, USA.
²⁹ Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, London, UK.
³⁰ Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
³¹ Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³² Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.

PMID: 31980749
PMCID: PMC7046529
DOI: 10.1038/s41568-019-0238-1

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.

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Conflict of interest statement

S.R.H. is a consultant for Halozyme Therapeutics, from which the Fred Hutchinson Cancer Research Center receives research funding. R.K.J. received honorarium from Amgen, consultant fees from Chugai, Merck, Ophthotech, Pfizer, SPARC, SynDevRx and XTuit, owns equity in Enlight, Ophthotech and SynDevRx and serves on the boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study. A.C.K. has financial interests in Vescor Therapeutics, is an inventor named on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach and the autophagic control of iron metabolism, is on the Scientific Advisory Board of Rafael Pharmaceuticals and has been a consultant for Deciphera Pharmaceuticals. R.G.M. receives consulting fees from Bayer, Deciphera, Karyopharm, Springworks, the American Society of Clinical Oncology and UptoDate. E.P. receives research funds in the form of a sponsored research agreement from TMUNITY and a collaborative research agreement from Boehringer Ingelheim; prior funding was provided by Novartis. D.A.T. has received commercial research grants from Fibrogen and ONO, has ownership interest (including stock, patents and so on) in Leap Therapeutics and Surface Oncology and is a consultant/advisory board member for Leap Oncology, Surface Oncology, Cygnal and Merck. D.A.T. is Director and Chief Scientist of the Lustgarten Foundation, a designated laboratory of pancreatic cancer research. F.M.W. is currently on secondment as Executive Chair of the UK Medical Research Council. Z.W. is on the Advisory Board of Maverick Therapeutics. E.S., I.A., E.C., D.D., M.E., R.M.E., D.F., F.R.G., T.H., R.O.H., T.J., C.J., M.G.K, R.S.P., D.C.R., R.S-S., M.H.S., S.S., T.D.T., V.W. and A.T.W. declare no competing interests.

Figures

**Fig. 1. Diverse mechanisms of cancer-associated fibroblast activation.**
This schematic highlights the multiple mechanisms that can contribute to cancer-associated fibroblast (CAF) activation. FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor.

**Fig. 2. Summary of cancer-associated fibroblast functions and the mechanisms by which they are achieved.**
Dark blue text boxes indicate the biological functions being regulated, with light blue, green, purple and grey text boxes indicating the processes and mechanisms leading to the control of function. Lines connect mechanisms to functions. Both matrix remodelling and the production of soluble factors contribute to increased tumour cell invasion. Soluble factors also contribute to changes in tumour growth and the immune microenvironment, which is also affected by the altered metabolic state of the tumour. CAF, cancer-associated fibroblast; CCL2, CC-chemokine ligand 2; CXCL12, CXC-chemokine ligand 12; IL-6, interleukin-6; GAS6, growth arrest-specific protein 6; HGF, hepatocyte growth factor; TGFβ, transforming growth factor-β; VEGF, vascular endothelial growth factor.

See this image and copyright information in PMC

References

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A framework for advancing our understanding of cancer-associated fibroblasts

Affiliations

A framework for advancing our understanding of cancer-associated fibroblasts

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials