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Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer

Key Points

  • Members of the transforming growth factor-β (TGF-β) family maintain homeostasis in many organ systems under normal physiological conditions.

  • Antiproliferative and apoptotic responses to TGF-β in epithelial, endothelial, neuronal and haematopoietic cells effectively limit the growth of these cell lineages.

  • The importance of TGF-β as a growth suppressor is demonstrated by the disruption of TGF-β signalling components in human cancers.

  • Certain tumours develop resistance to TGF-β growth-suppressive effects in the absence of mutations that disrupt the core TGF-β pathway.

  • TGF-β induces epithelial–mesenchymal transitions (EMT) in cancer cells, and pro-angiogenic and immunosuppressive effects on the tumour microenvironment, all of which promote cancer progression.

  • TGF-β acts as an important mediator of metastasis to specific organ sites — such as breast cancer metastasis to the bone — by increasing the expression of tissue-specific metastasis genes.

Abstract

The cytostatic and apoptotic functions of transforming growth factor-β (TGF-β) help restrain the growth of mammalian tissues; loss of these effects leads to hyperproliferative disorders and is common in cancer. However, tumour cells that are relieved from TGF-β growth constraints might then overproduce this cytokine to create a local immunosuppressive environment that fosters tumour growth and exacerbates the invasive and metastatic behaviour of the tumour cells themselves. For these reasons, there is a growing interest in understanding and therapeutically targeting TGF-β-mediated processes in cancer progression.

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Figure 1: TGF-β targets and its actions in mature tissues.
Figure 2: A schematic diagram of the TGF-β signalling pathway.
Figure 3: Gene responses of the TGF-β cytostatic programme that are shared by skin, lung and mammary epithelial cells.
Figure 4: A schematic diagram illustrating signalling intermediates and transcriptional targets involved in TGF-β induced apoptosis.
Figure 5: Points of TGF-β action during cancer progression.

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Acknowledgements

We apologize to those colleagues whose publications could not be cited because of space limitations. Work from the authors' laboratory is supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute.

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Correspondence to Joan Massagué.

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Glossary

NUCLEOPORINS

Proteins that form pores in the nuclear envelope that facilitate the movement of molecules into and out of the nucleus.

E3 UBIQUITIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for the binding of E2 enzymes and their specific substrates, thereby coordinating ubiquitylation of the selected substrates.

CAVEOLIN-RICH VESICLES

Invaginations in the plasma membrane or closed vesicles that are enriched for proteins called caveolins. These vesicles are believed to participate in endocytic processes.

ERK1/2

Extracellular-signal-regulated kinases are constituents in a kinase cascade that lie downstream of RAS.

p38

A member of the mitogen-activated protein kinase family that is activated by inflammatory cytokines and cellular responses to environmental stress.

JNK

(c-JUN amino-terminal kinase). A stress-induced protein kinase that has been implicated in cell death or cell viability — depending on the cellular context — and that is activated by XIAP.

LOBULO-ALVEOLAR

Differentiation of the mammary epithelium into functional secretory units during pregnancy that can produce milk proteins during lactation.

EXTRACELLULAR MATRIX

(ECM). A complex, three-dimensional network of very large macromolecules that provides contextual information and an architectural scaffold for cellular adhesion and migration.

IL-2

A cytokine that belongs to the interleukin family that is produced by leukocytes and is important for inducing T-cell proliferation.

CTLs

T lymphocytes that exert a cytolytic function following engagement of their T-cell antigen receptor on target cells.

TH1

A T-helper-1-cell-mediated immune response is mediated by pro-inflammatory cytokines such as interferon-γ, interleukin-1β and tumour necrosis factor-α. It promotes cellular immune responses against intracellular infections and malignancy.

TH2

A T-helper-2 response involves production of cytokines, such as interleukin-4, which stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions.

RESTRICTION POINT

The point at which cells become committed to enter into S phase of the cell cycle.

BASIC HELIX–LOOP–HELIX TRANSCRIPTION FACTORS

A diverse family of general transcriptional regulators that dimerize through the basic helix–loop–helix motif and that bind DNA via the basic domain.

BCL2 FAMILY

A family of proteins that inhibit or activate apoptosis through modification of mitochondrial function.

CASPASES

A family of cysteine-containing aspartic-acid-specific proteases that are involved in the initiation/execution phases of apoptosis.

MICROSATELLITE INSTABILITY

(MSI). Describes diploid tumours in which genetic instability is due to a high mutation rate, primarily in short nucleotide repeats. Cancers with the MSI phenotype are associated with defects in DNA mismatch-repair genes.

DOMINANT-NEGATIVE

A defective protein that inhibits wild-type function by retaining interaction capabilities that result in distortion or competition with normal proteins.

FAMILIAL JUVENILE POLYPOSIS

An inherited disease that is characterized by the development of benign polyps, usually in the colon.

ORTHOTOPIC

Occurring in the normal or usual position (for example, the orthotopic site for breast cancer cells is in the mammary gland).

CD8+

T cell bearing the CD8 cell-surface glycoprotein, which recognizes major histocompatibility complex class I molecules on target cells. CD8+ T cells are usually cytotoxic T cells.

CD4+

Helper T lymphocytes that express the co-receptor CD4, which recognizes antigenic peptides (or helper epitopes) that are presented by human leukocyte antigen class II molecules. They exert regulatory and helper functions for B cells, cytotoxic T lymphocytes and other immune effector cells.

T-CELL ANERGY

A state of T-cell unresponsiveness to various stimuli, including antigen presentation.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). Locus of genes that encode products essential to immune function. Class I and class II MHC genes encode proteins that are involved in antigen presentation to T cells.

NEUTROPHILS

Leukocytes of the polymorphonuclear leukocyte subgroup that form the primary defence against bacterial function.

MATRIX METALLOPROTEINASES

A family of proteolytic enzymes that degrade the extracellular matrix and that have important roles in tissue remodelling and tumour metastasis.

DESMOSOMES

An adhesive junction that anchors intermediate filaments between adjoining cells.

BIGENIC MICE

Transgenic mice that have been engineered to simultaneously express two different transgenes in the same target organ.

EXTRAVASATION

Passage from the blood or lymph vessel into tissue.

OSTEOLYSIS

Destruction of bone that is mediated by bone-resorbing cells, usually osteoclasts.

AUTOIMMUNE INFLAMMATORY DISEASE

A condition that is characterized by infiltration of inflammatory cells into several organ systems accompanied by the production of circulating autoimmune antibodies.

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Siegel, P., Massagué, J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev Cancer 3, 807–820 (2003). https://doi.org/10.1038/nrc1208

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