Tetraspanins and Cancer Metastasis
Metastasis formation is the final result of a cascade of events that primary tumor cells pass through by changing their phenotype and the crosstalk with the tumor environment. Molecules involved in this process are besides others tetraspanins, which surprisingly can either inhibit or promote metastasis formation. These opposing activities are supposed to rely on the special feature of tetraspanins that mostly act via modulating the activity of a multitude of associating molecules. Tetraspanins assemble a web between themselves and other associating molecules in special glycolipid-enriched membrane microdomains, which function as signaling platform, but are also prone for internalization. Internalization of tetraspanins and associated molecules by itself can contribute to promotion or inhibition of tumor progression. Notably, the internalized tetraspanin web is abundantly recovered in exosomes, small vesicles that derive from internalized membrane microdomains. Thus, it appears reasonable to assume that exosomal tetraspanins are of major importance for the crosstalk between the metastasizing tumor cell, the tumor stroma, the vessel endothelium, and the premetastatic organ. I will briefly introduce the structure of tetraspanins and their presently known main functional activities as a starting point to appreciate the contribution of selective tetraspanins in metastasis promotion and inhibition.
KeywordsEpidermal Growth Factor Receptor Focal Adhesion Kinase Metastasis Formation Epidermal Growth Factor Receptor Activation Membrane Microdomains
This work was supported by the Deutsche Forschungsgemeinschaft (grant ZO 40/12-1), the Deutsche Krebshilfe, and the Tumorzentrum Heidelberg/Mannheim.
- André F, Schartz NE, Chaput N et al (2002) Tumor-derived exosomes: a new source of tumor rejection antigens. Vaccine 20 Suppl 4:A28–A31Google Scholar
- Ardón-Alonso M, Yañez-Mó M, Barreiro O et al (2006) Tetraspanins CD9 and CD81 modulate HIV-1-induced membrane fusion. J Immunol 177:5129–5137Google Scholar
- Belting M, Wittrup A (2008) J Nanotubes, exosomes, and nucleic acid-binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease. Cell Biol 183:1187–1191Google Scholar
- Fang Y, Wu N, Gan X et al (2007) Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol 5:e158Google Scholar
- Gesierich S (2006) Das Tetraspanin CO-029/D6.1A in Membrankomplexen und Exosomen: Einfluss auf Tumorprogression und Angiogenese. Dissertation, University of Karlsruhe, GermanyGoogle Scholar
- Hotta H, Ross AH, Huebner K et al (1998) Molecular cloning and characterization of an antigen associated with early stages of melanoma tumor progression. Cancer Res 48:2955–2962Google Scholar
- Imai T, Yoshie O (1993) C33 antigen and M38 antigen recognized by monoclonal antibodies inhibitory to syncytium formation by human T cell leukemia virus type 1 are both members of the transmembrane 4 superfamily and associate with each other and with CD4 or CD8 in T cells. J Immunol 151:6470–6481PubMedGoogle Scholar
- Kusukawa J, Ryu F, Kameyama T et al (2001) Reduced expression of CD9 in oral squamous cell carcinoma: CD9 expression inversely related to high prevalence of lymph node metastasis. J Oral Pathol 30:73–79Google Scholar
- Levy S, Shoham T (2005a) Protein-protein interactions in the tetraspanin web. Physiology (Bethesda) 20:218–224Google Scholar
- Todeschini RA, Hakomori SI (2008) Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta 1780:421–433Google Scholar