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The biology and function of fibroblasts in cancer

Key Points

  • Resting or quiescent adult fibroblasts are indolent and probably remnants of mesenchymal cells during organ development.

  • Resting fibroblasts serve as precursors of activated fibroblasts including myofibroblasts.

  • Resting fibroblasts share some features with adult tissue stem cells and embryonic stem cells.

  • Activated fibroblasts can differentiate into adipocytes and chondrocytes and exhibit the potential to be programmed into induced pluripotent stem cells, in part because of their epigenetic and transcriptomic state, which favours their reprogramming efficiency.

  • Resting fibroblasts can differentiate into active fibroblasts that are synthetically active and can generate growth factors and extracellular matrix.

  • Cancer metabolism is influenced by activated fibroblasts.

  • Activated fibroblasts recruit immune cells and regulate tumour immunity.

  • Activated fibroblasts modulate chemoresistance.

  • Angiogenesis can be stimulated by activated fibroblasts.

  • It is now generally accepted that cancer-associated fibroblasts are a heterogeneous population with distinct functions.

  • Cancer-associated fibroblasts can serve as positive and negative regulators of tumour progression.

Abstract

Among all cells, fibroblasts could be considered the cockroaches of the human body. They survive severe stress that is usually lethal to all other cells, and they are the only normal cell type that can be live-cultured from post-mortem and decaying tissue. Their resilient adaptation may reside in their intrinsic survival programmes and cellular plasticity. Cancer is associated with fibroblasts at all stages of disease progression, including metastasis, and they are a considerable component of the general host response to tissue damage caused by cancer cells. Cancer-associated fibroblasts (CAFs) become synthetic machines that produce many different tumour components. CAFs have a role in creating extracellular matrix (ECM) structure and metabolic and immune reprogramming of the tumour microenvironment with an impact on adaptive resistance to chemotherapy. The pleiotropic actions of CAFs on tumour cells are probably reflective of them being a heterogeneous and plastic population with context-dependent influence on cancer.

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Figure 1: Multi-step activation of fibroblasts.
Figure 2: Fibroblasts are highly plastic and exhibit multipotency.
Figure 3: CAFs and their secretome remodel the tumour stroma.
Figure 4: Fibroblasts are a heterogeneous population of the tumour microenvironment.
Figure 5: A proposed classification of subtypes of fibroblasts on the basis of function.
Figure 6: CAFs and metabolic reprogramming of the tumour microenvironment.

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Acknowledgements

The Kalluri laboratory is supported by Cancer Prevention and Research Institute of Texas and the Metastasis Research Center at the University of Texas MD Anderson Cancer Center, Houston, USA. The author wishes to thank V. S. LeBleu for her help in preparing this manuscript and also for help in generating the schematic figures. He apologizes if some citations are missing owing to space constraints.

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Correspondence to Raghu Kalluri.

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Competing interests

MD Anderson Cancer Center and R.K. hold patents in the area of exosome biology and have licensed them to Codiak Biosciences, Inc. MD Anderson Cancer Center and R.K. are stock equity holders in Codiak Biosciences and R.K. receives research support from Codiak Biosciences, Inc.

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Glossary

Desmoplastic reaction, tumour stroma or tumour microenvironment

All components of the tumour other than cancer cells. These are generally the components of the host response towards cancer cells, including the immune response. The terms are used interchangeably.

Basement membrane

Organized and assembled extracellular matrix that interacts with all epithelial cells and is also associated with all blood vessels and capillaries.

Extracellular matrix

(ECM). A collection of proteins that are present outside and between cells. ECM consists of large networks of glycoproteins that specialize in protein–protein interactions and serve as ligands of cell surface proteins such as integrins. ECM proteins can form insoluble bundles and generate networks using proteins such as collagens, laminins, entactins, fibronectins and many proteoglycans, such as perlecans.

Angiogenesis

Formation of new capillaries and blood vessels from pre-existing capillaries.

Cancer-associated fibroblasts

(CAFs). All fibroblasts associated with tumours.

Mesenchymal stem cells

(MSCs). Multi-potent stromal cells with the ability to generate connective tissue lineages.

Wound healing response

Injury to the functional parenchyma leads to a reversible host repair or regeneration response that involves myofibroblasts, among other components.

Quiescent, resting fibroblasts

Fibroblast-like cells that are in waiting to become activated when the need arises. They can be considered as resting fibroblasts.

Fibroblast activation

The cellular, biochemical and molecular programme that leads to the conversion of a resting fibroblast into an active fibroblast with a myriad of biological functions.

Scars

The pathologist's term for fibrosis. Fibrosis can be visualized by different dyes that histologically stain different tissue structures, including ECM band-like patterns, making them look like a scar.

Post-mortem

The status of a biological body or tissue after the death of an organism. Observations made in a body or tissue after death are considered post-mortem analyses.

Fibrosis-associated fibroblasts

(FAFs). Activated fibroblasts associated with chronic tissue fibrosis.

Interstitial space

This is the space between layers of functional parenchyma of an organ. It is generally where the support system for an organ exists.

Tissue fibrosis

Chronic wound healing response due to unabated injury to the functional parenchyma.

Mesoderm

The third germ layer, which is considered the precursor to all future mesenchymal cells in the mammalian body, including haematopoietic and connective tissues.

Resting mesenchymal cell

Similar to a resting fibroblast, this is a fibroblast-like cell that is ready to be activated when the need arises. This can also be referred to as an adult tissue-resident mesenchymal stem cell (rMSC).

Induced pluripotent stem cells

(iPSCs). The use of differentiated cells such as fibroblasts to induce stem cell-like features by inserting new genes and/or subjecting cells to physical and biochemical pressures to induce a plastic phenotype.

Carcinoma in situ

(CIS). A basement membrane-contained cancerous lesion. This type of lesion is the lesion that forms early in carcinogenesis. A basement membrane, presumably deposited by CAFs, separates such lesions from the outside interstitial environment.

Stellate cells

Particular mesenchymal cells that are characterized by their vitamin A stores and are found in the liver and pancreas, among other organs. Upon stimulation, they can become activated fibroblasts or myofibroblasts.

Normal activated fibroblasts

(NAFs). Fibroblasts cultured from normal organs.

Epithelial to mesenchymal transition

(EMT). Acquisition of mesenchymal expression programme by epithelial cells.

Exosomes

Extracellular vesicles, approximately 40–150 nm in size, released by all cell types and of multivesicular endosomal origin. They carry proteins and nucleic acids.

Cancer stem cell

Conceptually, a cancer cell that is able to give rise to malignant cancer cells indefinitely and generate tumours; operationally, cancer stem cells are a subset of cancer cells that can, in mice, initiate tumour formation in limiting dilution assay.

Warburg effect

The metabolic phenotype of cells operating predominantly on glycolysis and lactate production despite the bioavailability of oxygen to run oxidative phosphorylation. This is a feature of rapidly proliferating cells, including cancer cells.

Reciprocal metabolic symbiosis

Whereby cancer-associated fibroblasts provide metabolic support to cancer cells in tumours, and vice versa.

Immunosuppressive TME

A tumour microenvironment (TME) that contains cells and other components that interfere with tumour immunity and surveillance.

Dendritic cells

(DCs). Also known as accessory cells, they are antigen-presenting cells in the adaptive immune response.

T cell anergy

Following antigen presentation, T cells may become functionally inactivated, in a hyporesponsive state, to induce immune tolerance.

T helper 17 cell

(TH17 cell). Interleukin-17 (IL-17)-producing T helper cells.

Migration

Movement of cells dependent on motility-inducing molecular signals.

Regulatory T cell

(Treg cell). Regulatory T cells or suppressor T cells maintain immune tolerance to self-antigens and prevent unrestricted effector T cell expansion.

Drug resistance

The adaptive or evasive programmes launched by tumours after treatment with a drug.

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Kalluri, R. The biology and function of fibroblasts in cancer. Nat Rev Cancer 16, 582–598 (2016). https://doi.org/10.1038/nrc.2016.73

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