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Turning foes to friends: targeting cancer-associated fibroblasts

Nature Reviews Drug Discovery volume 18, pages 99–115 (2019)Cite this article

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Abstract

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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Fig. 1: Timeline of discoveries in normal fibroblasts and CAFs.
Fig. 2: Potential cellular sources of CAFs.
Fig. 3: Principal strategies for CAF-directed anticancer therapy.

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Acknowledgements

The authors thank P. Cai and Q. Liu for proofreading the manuscript.

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  1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Xueman Chen & Erwei Song

  2. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Xueman Chen & Erwei Song

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Glossary

‘Seed and soil’ theory

A theory proposing that the pro-metastatic tumour cells (the ‘seeds’) and the supportive microenvironment in specific organ sites (the ‘soil’) are essential prerequisites for tumour metastasis.

Extracellular matrix

(ECM). A collection of fibrous proteins, such as collagens and fibronectins, that is secreted by mesenchymal cells and provides structural and biochemical support to the surrounding cells.

Fibrosis

A pathological deposition of extracellular matrix proteins that results in an exaggerated wound healing response that impairs the architecture and function of the normal organ or tissue.

Fibrillar ECM

A loosely assembled form of extracellular matrix (ECM), constituted by abundant fibronectin and type I collagen, which serves as a scaffold for other ECM components.

Desmoplastic reaction

The collective response of various stromal cells that is secondary to an initial tissue injury and usually causes dense fibrosis or scar tissue in malignant neoplasms.

Matrix metalloproteinases

(MMPs). Calcium-dependent zinc-containing endoproteases that belong to a larger family of proteases known as the metzincin superfamily and are able to degrade various matrix molecules such as collagens.

Stellate cells

Particular fibroblast-like cells in the pancreas and liver that are characterized by their vitamin A storage and can become activated fibroblasts.

Epithelial-to-mesenchymal transition

(EMT). A cellular programme wherein epithelial cells lose cell–cell contact and acquire mesenchymal-like characteristics.

Endothelial-to-mesenchymal transition

(EndMT). A cellular programme wherein endothelial cells lose some of their features and gain mesenchymal phenotypes.

Transdifferentiation

A process of lineage reprogramming whereby one mature somatic cell directly transforms into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type.

Pericytes

Mesenchymal cells with contractility that wrap around endothelial cells to stabilize the capillaries and venules throughout the body.

M2 polarization

A process of macrophage polarization wherein macrophages are polarized and acquire a specific M2 (alternatively activated macrophage) phenotype.

T helper 17 (TH17) cells

TH cells that produce interleukin-17.

Regulatory T (Treg) cells

Suppressor T cells that maintain immune tolerance to self-antigens and restrain the expansion of effector T cells.

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Chen, X., Song, E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov 18, 99–115 (2019). https://doi.org/10.1038/s41573-018-0004-1

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