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  • Review Article
  • Published:

Tetraspanin proteins promote multiple cancer stages

Nature Reviews Cancer volume 14, pages 49–60 (2014)Cite this article

Subjects

Key Points

  • New evidence from in vivo mouse models confirms that tetraspanin proteins can contribute substantially to tumour initiation, promotion and progression.

  • In vivo evidence also shows that the tetraspanin CD151 makes substantial contributions to metastasis, and tetraspanin 8 (TSPAN8) can also contribute to metastasis.

  • Although the tetraspanin CD9 is primarily known as a tumour suppressor, it sometimes has oncogenic and pro-metastatic functions. The association of CD9 with different partner proteins could explain its diverse functions.

  • A few tetraspanins (including CD151, TSPAN8 and CD9) contribute to tumour angiogenesis, presumably by affecting endothelial cell function. However, the contributions of tetraspanins to angiogenesis have not yet been shown using de novo tumour models.

  • Intact and modified CD37-specific monoclonal antibodies have shown considerable promise in the treatment of B cell malignancies. These reagents can kill malignant B cells by inducing antibody-dependent cell-mediated cytotoxicity, by delivering lethal radiation and by inducing apoptosis.

  • CD151-specific monoclonal antibodies have been developed that can strongly inhibit both metastasis and primary tumour growth in human–mouse xenograft models.

  • Other tetraspanins (TSPAN8, CD9 and TSPAN12) may also be worthy cancer targets in particular circumstances.

  • The targeting of CD151 (and perhaps CD9 and CD81) might increase cancer cell sensitivity to several other types of anticancer drugs.

Abstract

An abundance of evidence shows supporting roles for tetraspanin proteins in human cancer. Many studies show that the expression of tetraspanins correlates with tumour stage, tumour type and patient outcome. In addition, perturbations of tetraspanins in tumour cell lines can considerably affect cell growth, morphology, invasion, tumour engraftment and metastasis. This Review emphasizes new studies that have used de novo mouse cancer models to show that select tetraspanin proteins have key roles in tumour initiation, promotion and metastasis. This Review also emphasizes how tetraspanin proteins can sometimes participate in tumour angiogenesis. These recent data build an increasingly strong case for tetraspanins as therapeutic targets.

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Figure 1: Diagram of typical tetraspanin structure.
Figure 2: CD151 contributions to tumour development.
Figure 3: Strategies for targeting tetraspanin proteins.

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Acknowledgements

The author is supported by US National Institutes of Health (NIH) grant CA42368.

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    Martin E. Hemler

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Glossary

DMBA–TPA mouse skin chemical carcinogenesis model

A two-stage chemical skin carcinogenesis model that uses a single dose of the genotoxic carcinogen 7,12-dimethyl-benz-[α]anthracene (DMBA) followed by multiple doses of a non-genotoxic tumour promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA).

Intermediate filaments

Deformable eukaryotic cytoskeletal structural proteins (including keratins, vimentin and several others), which have an average diameter of ∼10 nm.

Hemidesmosome

An organized asymmetrical adhesive structure on the surface of epithelial cells that links the extracellular basement membrane and α6β4 integrin with intracellular plectin and keratin intermediate filaments.

Transgenic adenocarcinoma of mouse prostate model

(TRAMP model). A mouse prostate cancer model in which mice that express SV40 T/t antigens (T/t-ag) that are under the control of the androgen-sensitive rat probasin promoter develop focal adenocarcinomas with 100% frequency between 10 and 20 weeks of age. Metastasis also typically occurs.

Sheddase

A membrane-bound enzyme (for example, a disintegrin and metalloproteinase 10 (ADAM10) and ADAM17) that cleaves extracellular portions of targeted transmembrane proteins and thus causes the release of their soluble ectodomains.

Endothelial cell docking-structures

Cup-like structures that occur on endothelial cells at sites of leukocyte contact.

Rat hindlimb ischaemia model

A model for peripheral arterial disease in which ligation of the rat femoral artery results in ischaemic tissue. This model can be used to test the effectiveness of pro-angiogenic therapy.

Aortic ring assay

An assay in which a transverse section of the aorta is embedded within a three-dimensional matrix such as collagen or Matrigel. After several days, the appearance of branching vessel-like structures provides an assessment of the extent of ex vivo angiogenesis.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). Cell death that occurs when the Fc fragment of a monoclonal antibody (mAb) that is bound to a target cell interacts with the Fc receptor on monocytes, macrophages or natural killer (NK) cells. In turn, these cells kill the target cell or secrete cytokines.

Complement-dependent cytotoxicity

(CDC). Cell death that occurs when a monoclonal antibody that is bound to a target cell is then bound by complement, which triggers the complement cascade and thereby results in the formation of the membrane-attack complex.

Lutetium 177

(177Lu). A radionuclide that has been conjugated to peptides and antibodies and has been used in anticancer therapy.

CD20

A protein that is present on the surface of B cells. Because it is highly expressed on all B cell neoplasms, CD20-specific antibodies (for example, rituximab) have been frequently used as therapeutic agents. Although CD20 contains four transmembrane domains, it is not a member of the tetraspanin family.

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Hemler, M. Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer 14, 49–60 (2014). https://doi.org/10.1038/nrc3640

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