Tumours progress through a cascade of events that enable the formation of metastases. Some of the components that are required for this fatal process are well established. Tetraspanins, however, have only recently received attention as both metastasis suppressors and metastasis promoters. This late appreciation is probably due to their capacity to associate with various molecules, which they recruit into special membrane microdomains, and their abundant presence in tumour-derived small vesicles that aid intercellular communication. It is reasonable to assume that differences in the membrane and vesicular web components that associate with individual tetraspanins account for their differing abilities to promote and suppress metastasis.

Tetraspanins: push and pull in suppressing and promoting metastasis

Tumor-derived exosomes containing the tetraspanin Tspan8 can efficiently induce angiogenesis in tumors and tumor-free tissues. However, little information exists on exosome-endothelial cell (EC) interactions or the proangiogenic role of tetraspanins, which are a constitutive component of exosomes. In this study, we used a rat adenocarcinoma model (AS-Tspan8) to explore the effects of exosomal Tspan8 on angiogenesis. Tspan8 contributed to a selective recruitment of proteins and mRNA into exosomes, including CD106 and CD49d, which were implicated in exosome-EC binding and EC internalization. We found that EC internalized Tspan8-CD49d complex-containing exosomes. Exosome uptake induced vascular endothelial growth factor (VEGF)-independent regulation of several angiogenesis-related genes, including von Willebrand factor, Tspan8, chemokines CXCL5 and MIF, chemokine receptor CCR1, and, together with VEGF, VEGF receptor 2. EC uptake of Tspan8-CD49d complex-containing exosomes was accompanied by enhanced EC proliferation, migration, sprouting, and maturation of EC progenitors. Unraveling these new pathways of exosome-initiated EC regulation could provide new options for therapeutic interference with tumor-induced angiogenesis.

https://cancerres.aacrjournals.org/content/canres/70/4/1668.full.pdf

Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation.

Expression of the tetraspanin CO-029 is associated with poor prognosis in patients with gastrointestinal cancer. In a pancreatic tumor line, overexpression of the rat homologue, D6.1A, induces lethally disseminated intravascular coagulation, suggesting D6.1A engagement in angiogenesis. D6.1A-overexpressing tumor cells induce the greatest amount of angiogenesis in vivo, and tumor cells as well as exosomes derived thereof strikingly increase endothelial cell branching in vitro. Tumor cell-derived D6.1A stimulates angiogenic factor transcription, which includes increased matrix metalloproteinase and urokinase-type plasminogen activator secretion, pronounced vascular endothelial growth factor expression in fibroblasts, vascular endothelial growth factor receptor expression, and strong D6.1A up-regulation in sprouting endothelium. Thus, D6.1A initiates an angiogenic loop that, probably due to the abundance of D6.1A in tumor-derived exosomes, reaches organs distant from the tumor. Most importantly, because of the strong D6.1A up-regulation on sprouting capillaries, angiogenesis could be completely inhibited by a D6.1A-specific antibody, irrespective of whether or not the tumor expresses D6.1A. Tetraspanins have been suggested to be involved in morphogenesis. This is the first report that a tetraspanin, CO-029/D6.1A, promotes tumor growth by its capacity to induce systemic angiogenesis that can effectively, and with high selectivity for sprouting endothelium, be blocked by a D6.1A-specific antibody.

https://cancerres.aacrjournals.org/content/canres/66/14/7083.full.pdf

Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029

EpCAM has been described as a therapeutically relevant tumor marker. We noted an interaction between EpCAM and the tight junction protein claudin-7 and here explored the nature of this interaction and its effect on EpCAM-mediated functions. The interaction between EpCAM and claudin-7 was defined in HEK293 cells transfected with rat claudin-7 and EpCAM cDNA. Deletions of the epidermal growth factor-like and the thyroglobin repeat domains of EpCAM or the cytoplasmic domain of EpCAM or claudin-7 did not prevent the EpCAM-claudin-7 association. A chimeric EpCAM molecule with an exchange of the cytoplasmic and transmembrane domains and an EpCAM molecule with point mutations in an AxxxG motif in the transmembrane region do not associate with claudin-7. HEK cells and the rat pancreatic tumor line BSp73AS, transfected with (mutated) EpCAM and claudin-7 cDNA, revealed that the association of both molecules severely alters the functional activity of EpCAM. Claudin-7-associated EpCAM is recruited into tetraspanin-enriched membrane microdomains (TEM). The TEM-located claudin-7-EpCAM complex supports proliferation accompanied by sustained extracellular signal-regulated kinase-1/2 phosphorylation, up-regulation of antiapoptotic proteins, and drug resistance, but not EpCAM-mediated cell-cell adhesion. Enhanced motility may be supported by colocalization of claudin-7 with actin bundles, which is only seen in EpCAM-claudin-7-expressing cells. The EpCAM-claudin-7 complex strongly promotes tumorigenicity, accelerates tumor growth, and supports ascites production and thymic metastasis formation. High expression of the tumor marker EpCAM is frequently associated with poor prognosis, which could well rely on the EpCAM-claudin-7 association that prohibits EpCAM-mediated cell-cell adhesion but promotes migration, proliferation, apoptosis resistance, and tumorigenicity.

https://mcr.aacrjournals.org/content/molcanres/7/3/285.full.pdf

Claudin-7 regulates EpCAM-mediated functions in tumor progression.

Recently, we have described a panel of metastasis-associated antigens in the rat, i.e., of molecules expressed on metastasizing, but not on nonmetastasizing tumor lines. One of these molecules, recognized by the monoclonal antibody D6.1 and named accordingly D6.1A, was found to be abundantly expressed predominantly on mesenchyme-derived cells. The DNA of the antigen has been isolated and cloned. Surprisingly, the gene product proved to interfere strongly with coagulation.

The 1.182-kb cDNA codes for a 235–amino acid long molecule with a 74.2% homology in the nucleotide and a 70% homology in the amino acid sequence to CO-029, a human tumor-associated molecule. According to the distribution of hydrophobic and hydrophilic amino acids, D6.1A belongs to the tetraspanin superfamily. Western blotting of D6.1A-positive metastasizing tumor lines revealed that the D6.1A, like many tetraspanin molecules, is linked to further membrane molecules, one of which could be identified as α6β1 integrin. Transfection of a low-metastasizing tumor cell line with D6.1A cDNA resulted in increased metastatic potential and provided a clue as to the functional role of D6.1A. We noted massive bleeding around the metastases and, possibly as a consequence, local infarctions predominantly in the mesenteric region and all signs of a consumption coagulopathy. By application of the D6.1 antibody the coagulopathy was counterregulated, though not prevented.

It has been known for many years that tumor growth and progression is frequently accompanied by thrombotic disorders. Our data suggest that the phenomenon could well be associated with the expression of tetraspanin molecules.

/pdf/association-between-the-rat-homologue-of-co-029-a-metastasis-ibecr2tfhj.pdf

Association Between the Rat Homologue of CO-029, a Metastasis-associated Tetraspanin Molecule and Consumption Coagulopathy

The specificity of monoclonal antibodies (mABs) obtained after immunization with a metastasizing rat tumor line was evaluated by screening expression in a variety of nonmetastasizing and metastasizing rat tumor lines. mABs, which by immunohistology and Western blotting recognized metastasizing lines, were used to define the physiological expression of the corresponding antigens during ontogeny as well as in adult rats. From a panel of 12 mABs, 2 recognized structures on metastasizing and nonmetastasizing tumor lines, while 10 stained exclusively metastasizing lines. Five of the latter bound to tumor lines metastasizing either hematogenously or via the lymphatic system. All five recognized an epitope on CD44 variant exon v6. The five remaining mABs, recognizing four independent antigenic entities, only stained tumor lines metastasizing via the lymphatics. Surprisingly, these antigens were also detected in normal tissues: three on epithelial cells either widespread or of the upper gastrointestinal tract or the urogenital system, the fourth preferentially on epithelial cells, but also on nerves and hematopoietic precursor cells, and the fifth on many tissues and cells with a predominance of mesenchyme-derived structures. Notably, during ontogeny, expression on these five antigens was induced in different compartments of the developing fetal and/or maternal part of the placenta. The five newly described metastasis-associated antigens share with CD44v the absence of expression on nonmetastasizing tumor lines as well as expression on distinct, nontransformed cells and induction of expression during ontogeny. Thus, tumor progression may rather be initiated by inappropriate expression or up-regulation of genes, which do not display transforming features, than by de novo appearance of "metastasis genes." Accordingly, metastasizing tumor lines may be a valuable tool to identify developmentally regulated gene products.

http://cgd.aacrjournals.org/cgi/reprint/7/5/663.pdf

Developmentally Regulated Expression of Metastasis- associated Antigens in the Rat'

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Developmentally Regulated Expression of Metastasis- associated Antigens in the Rat'