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  • Review Article
  • Published:

Tumour microenvironment

TGFβ: the molecular Jekyll and Hyde of cancer

Nature Reviews Cancer volume 6, pages 506–520 (2006)Cite this article

Key Points

  • TGFβ signalling is tumour suppressive in epithelial cells, whereas it can promote invasion and metastasis during the later stages of carcinoma progression.

  • During tumour progression, tumour cells frequently lose the growth-inhibitory response to TGFβ, and this is associated with an increased expression of TGFβ in the microenvironment.

  • TGFβ-mediated regulation in the tumour microenvironment can be attributed to many factors, including those that involve cell-autonomous signalling, stromal–epithelial interactions, inflammation, immune evasion and angiogenesis.

  • Cell-autonomous TGFβ signalling can cause epithelial–mesenchymal transitions (EMT) in carcinoma cells, which increase invasion and metastasis.

  • Conversely, the abrogation of carcinoma-cell-autonomous TGFβ signalling can increase metastasis in the apparent absence of EMT.

  • Together, the cell-type-dependent and context-dependent effects of TGFβ signalling contribute to the regulation of tumour initiation, progression and metastasis.

  • Despite the complex nature of TGFβ-mediated regulatory signalling in the tumour microenvironment, many aspects of signalling through this pathway have been targeted for therapeutic intervention using systemic and cell-specific strategies, with some indications of efficacy.

Abstract

Transforming growth factor-β (TGFβ) signalling regulates cancer through mechanisms that function either within the tumour cell itself or through host–tumour cell interactions. Studies of tumour-cell-autonomous TGFβ effects show clearly that TGFβ signalling has a mechanistic role in tumour suppression and tumour promotion. In addition, factors in the tumour microenvironment, such as fibroblasts, immune cells and the extracellular matrix, influence the ability of TGFβ to promote or suppress carcinoma progression and metastasis. The complex nature of TGFβ signalling and crosstalk in the tumour microenvironment presents a unique challenge, and an opportunity to develop therapeutic intervention strategies for targeting cancer.

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Figure 1: General overview of the main signalling networks regulated by TGFβ in cancer.
Figure 2: Targets for TGFβ-based therapeutic intervention in the tumour microenvironment.

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Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, 37232, Tennessee, USA

    Brian Bierie

  2. Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University Medical Center, Nashville, 37232, Tennessee, USA

    Harold L. Moses

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DATABASES

National Cancer Institute

pancreatic cancer

Glossary

Loss of heterozygosity

Tumour cells often lose large genomic regions at loci that often contain tumour-suppressor genes. In cells that carry a mutated allele of a tumour-suppressor gene, the loss of a large region from a chromosome that carries the wild-type allele can result in a complete loss of function.

Microsatellite instability

A condition associated with some cancers whereby a tumours associated genetic instability is due to defects in mismatch-repair gene products. The mutations associated with this type of genomic instability often occur in short nucleotide repeats.

Dominant-negative

A defective protein product that effectively inhibits the function of a wild-type counterpart by retaining essential interaction capabilities without a desired effector function.

Lobular-alveolar

Mammary epithelial cells that are able to differentiate into functional secretory units during pregnancy, and that can produce milk proteins during lactation.

Bigenic mice

Transgenic mice that concurrently express two minigene constructs.

Major histocompatibility complex

Genes that encode products that are necessary for the regulation of immune function. Class I and class II MHC genes are involved in antigen presentation and the regulation of self recognition.

Convection-enhanced delivery

A method of delivering compounds to the brain that circumvents the blood–brain barrier. This method enables a compound to be infused directly into a brain tumour under a controlled pressure and rate of release.

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Bierie, B., Moses, H. TGFβ: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6, 506–520 (2006). https://doi.org/10.1038/nrc1926

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