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Fibroblasts in cancer

Key Points

  • Fibroblasts are a key cellular component of tumours.

  • Activated fibroblasts (which are sometimes referred to as myofibroblasts) that are found in association with cancer cells are known as carcinoma-associated fibroblasts (CAFs).

  • The role of fibroblasts in the origin and initiation of cancer invasion is poorly understood, but recent evidence indicates that they can provide oncogenic signals to the transformed epithelia in a paracrine fashion.

  • Some studies indicate that myofibroblasts might facilitate angiogenesis and cancer progression.

  • Epithelial-to-mesenchymal transition is a source for converting epithelial cells into fibroblast-like cells in various tissues.

  • Fibroblasts might also have a role in metastasis.

  • Therapies against CAFs are being considered as a way to control cancer.

Abstract

Tumours are known as wounds that do not heal — this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

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Figure 1: Activated fibroblasts.
Figure 2: Tumour–stroma interactions during different stages of mammary ductal carcinoma progression.
Figure 3: Functions of activated fibroblasts in the tumour stroma.
Figure 4: Regulation of epithelial-to-mesenchymal transition by the microenvironment.

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Acknowledgements

The work from the author's laboratories was supported by the National Institutes of Health (NIH) and the Center for Matrix Biology (R.K.). M.Z. is funded by a NIH training grant to BIDMC. We would like to extend our special thanks to H. Dvorak and M. A. Grant for critical reading of this manuscript.

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Correspondence to Raghu Kalluri.

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DATABASES

National Cancer Institute

bladder cancer

breast cancer

melanoma

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Glossary

Stroma

Extracellular matrix, mesenchymal cells and a scaffold consisting of blood and lymphoid vessels, nerves and inflammatory cells.

Cancer-associated fibroblast

Activated fibroblasts within desmoplastic lesions that are associated with malignant tumours and often express α-smooth-muscle actin.

Extracellular matrix

A network of fibrous proteins such as collagens and fibronectins, which are embedded in a visco-elastic gel of glycosaminoglycans, proteoglycans and glycoproteins. These filamentous proteins provide tensile strength and channels for communication by and movement of cells.

Fibrillar ECM

Unorganized, loosely assembled form of ECM. The most important constituents of fibrillar ECM are fibronectin and type I collagen, which are thought to serve as a scaffold for other ECM components.

Basement membrane

A specialized extracellular matrix present at the baso-lateral side of cells. It appears as an amorphous, dense and proteinaceous structure. This term is used interchangeably with basal lamina.

Matrix metalloproteinases

Endopeptidases that belong to a family of zinc-dependent proteases with more than 21 human forms. Their main substrates are matrix molecules such as collagen, but many non-matrix substrates have also been identified recently.

Fibrosis

An excessive deposition of extracellular matrix, which leads to the destruction of organ structure and the impairment of organ function. The main mediators of tissue fibrosis are activated fibroblasts.

Co-culture experiment

In vitro experiment in which cancer cells are either exposed to conditioned media from CAFs or directly cultured in the presence of CAFs.

Reconstitution experiment

Study in which a suspension of CAFs and tumour cells (often in a ratio that favours the CAFs) are injected into mice. Such studies demonstrated that the presence of CAFs enhanced tumour progression.

Hox genes

The Hox genes encode a family of homeodomain transcription factors that determine positional identity along the anterior–posterior and secondary axis in animals.

Myofibroblasts

The myofibroblast was initially identified by means of electron microscopy as a fibroblast with features that are more typical of smooth muscle cells, such as possessing bundles of microfilaments and maintaining gap junctions. Myofibroblasts are commonly detected by their expression of α-smooth-muscle actin.

NOD/SCID mice

Mice with multiple defects in innate immunity, including a largely reduced natural-killer-cell activity and a twofold-reduced bone-marrow cellularity.

Cleared-fat-pad transplantation system

A cleared fat pad, devoid of any epithelium, into which mouse mammary epithelial cells are engrafted before puberty, causing an anatomically normal mammary gland to develop. However, human mammary epithelial cells injected into the cleared mouse fat pad do not form a mammary gland.

Senescence

A programme that is activated by normal cells in various situations of stress to prevent further proliferation. Senescence occurs in response to telomere capping, DNA damage, oxidative stress or activation of oncogenes.

Epithelial-to-mesenchymal transition

A process that is necessary for embryonic development, tumour progression and organ fibrosis. During EMT epithelial characteristics are lost and the mesenchymal phenotype is acquired.

Pericyte

Mesenchymal cells that wrap around endothelial cells in microvessels. They share the common basement membrane with the vascular endothelial cells.

Stellate cells

Fibroblast-like cells in the liver that express glial fibrillary acidic protein and nestin, and are thought to be neural-crest-derived.

Scleroderma

Fibrosis involving the skin.

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Kalluri, R., Zeisberg, M. Fibroblasts in cancer. Nat Rev Cancer 6, 392–401 (2006). https://doi.org/10.1038/nrc1877

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