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  • Review Article
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Cancer-associated fibroblasts in gastrointestinal cancer

Abstract

The tumour microenvironment, also termed the tumour stroma or tumour mesenchyme, includes fibroblasts, immune cells, blood vessels and the extracellular matrix and substantially influences the initiation, growth and dissemination of gastrointestinal cancer. Cancer-associated fibroblasts (CAFs) are one of the critical components of the tumour mesenchyme and not only provide physical support for epithelial cells but also are key functional regulators in cancer, promoting and retarding tumorigenesis in a context-dependent manner. In this Review, we outline the emerging understanding of gastrointestinal CAFs with a particular emphasis on their origin and heterogeneity, as well as their function in cancer cell proliferation, tumour immunity, angiogenesis, extracellular matrix remodelling and drug resistance. Moreover, we discuss the clinical implications of CAFs as biomarkers and potential targets for prevention and treatment of patients with gastrointestinal cancer.

Key points

  • Cancer-associated fibroblasts (CAFs) include all fibroblasts in the tumour and are involved in functionally controlling cancer progression.

  • CAFs are composed of heterogeneous subpopulations arising from distinct cellular origins such as local fibroblasts and mesenchymal stem cells.

  • Distinct CAFs influence cancer cell proliferation, tumour immunity, angiogenesis, extracellular matrix remodelling and metastasis.

  • Functionally, CAFs can be classified into subpopulations such as tumour-promoting CAFs and tumour-retarding CAFs.

  • An improved understanding of CAF biology could lead to the development of novel stroma-based diagnostics, prognostics and therapeutics.

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Fig. 1: Cellular components of the tumour microenvironment.
Fig. 2: The origins of CAFs.
Fig. 3: The functions of CAFs.
Fig. 4: Therapies that target CAFs.

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Acknowledgements

This work is supported by Cure Cancer Australia and Cancer Australia (APP1102534) and the Australian National Health and Medical Research Council (NHMRC) (APP1140236 and APP1143414). D.L.W. is supported by a NHMRC Career Development Fellowship. H.K. is supported by the Japan Society for the Promotion of Science (JSPS) Overseas Challenge Program for Young Researchers and a Takeda Science Foundation Fellowship.

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Nature Reviews Gastroenterology & Hepatology thanks M. Bijlsma, A. Mirnezami and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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All authors contributed substantially to discussion of content for the article and reviewed and/or edited the manuscript before submission. H.K., A.E. and D.L.W. researched data and wrote the manuscript.

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Correspondence to Atsushi Enomoto or Daniel L. Worthley.

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Glossary

Extracellular matrix

(ECM). An intricate network of fibrous proteins in the extracellular space, such as collagen, laminin and fibronectin.

Basement membrane

A highly specialized extracellular matrix that separates epithelial cells or endothelial cells from underlying connective tissue.

Desmoplastic reaction

An increase in a stromal component especially with prominent fibrous tissue in cancer.

Angiogenesis

The formation of new blood vessels to satisfy increased demand for nutrients and oxygen.

Gene signatures

Patterns of gene expression that are characteristic of a certain biological process.

Telocytes

Mesenchymal cells that have extending cytoplasmic processes termed telopodes.

Tumour-associated macrophages

A heterogeneous population of macrophages in the tumour that contribute to tumour progression.

Epithelial-to-mesenchymal transition

(EMT). A process by which epithelial cells gain a mesenchymal phenotype, leading to their migration and invasion.

Myofibroblasts

A specific type of fibroblast that is characterized by high expression of α-smooth muscle actin.

Single-cell RNA sequencing

Gene expression analysis of an individual cell instead of diverse cell populations.

Chimeric antigen receptor (CAR) T cells

T cells engineered to recognize a tumour-associated antigen and induce target-specific killing.

Stellate cells

Fibroblast-like cells characterized by their vitamin A storage. They are found in the pancreas and liver.

Pericytes

Fibroblast-like cells that wrap around the wall of capillaries.

Parabiosis

Two organisms joined together surgically to share blood circulation.

Lineage tracing

A method to genetically label cells of interest and all of their progenies, also known as genetic fate-mapping.

Endothelial-to-mesenchymal transition

A process by which endothelial cells lose their endothelial phenotype and acquire a mesenchymal phenotype.

Exosome

An extracellular vesicle (30–150 nm in size) that is released from many types of cells and contains proteins and RNAs.

Cancer stem cells

(CSCs). A minor subpopulation of cancer cells that have self-renewal capability and drive cancer progression, metastasis and resistance to treatment.

Immunosuppressive TME

A tumour microenvironment (TME) in which antitumour immunity is inhibited and cancer immunotherapy is ineffective.

Immune checkpoint inhibitors

Agents that unleash antitumour immunity through blocking an immune checkpoint, which is a ligand–receptor-mediated pathway to suppress an immune response.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of bone marrow-derived immune cells that suppress T cell activity.

Regulatory T cells

(Treg cells). A subset of immunosuppressive T cells that express CD4, CD25 and FOXP3, maintain immune tolerance to self-antigens and prevent activation of effector T cells.

M2 polarization of macrophages

The M2 macrophage is a subtype of tumour-associated macrophage that suppresses antitumour immunity and promotes cancer progression.

Extravasation

Leakage of blood cells from capillaries to the surrounding tissue.

Fibrocyte

A bone marrow-derived circulating cell that has features of both fibroblasts and monocytes.

Antibody–drug conjugates

Constructs that contain a small-molecule drug linked to a monoclonal antibody that recognizes a tumour-associated antigen.

Immunocytokines

Cytokines that are fused to monoclonal antibodies that recognizes a tumour-associated antigen.

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Kobayashi, H., Enomoto, A., Woods, S.L. et al. Cancer-associated fibroblasts in gastrointestinal cancer. Nat Rev Gastroenterol Hepatol 16, 282–295 (2019). https://doi.org/10.1038/s41575-019-0115-0

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