The tetraspanin CD9 inhibits the proliferation and tumorigenicity of human colon carcinoma cells

Abstract

The implication of the tetraspanin CD9 in cancer has received much recent attention and an inverse correlation between CD9 expression and the metastatic potential and cancer survival rate has been established for different tumor types. In contrast to the well-established role of CD9 in metastasis, very little is known about the involvement of this tetraspanin in the process of development of primary tumors. In the present study, we present evidence on the implication of CD9 in colon carcinoma tumorigenesis. We report here that ectopic expression of CD9 in colon carcinoma cells results in enhanced integrin-dependent adhesion and inhibition of cell growth. Consistently with these effects, treatment of these cells with anti-CD9-specific antibodies resulted in (i) increased b1 integrin-mediated cell adhesion through a mechanism involving clustering of integrin molecules rather than altered affinity; (ii) induction of morphological changes characterized by the acquisition of an elongated cell phenotype; (iii) inhibition of cell proliferation with no significant effect on cell survival; (iv) increased expression of membrane TNF-a, and finally (v) inhibition of the in vivo tumorigenic capacity in nude mice. In addition, through the use of selective blockers of TNF-a, we have demonstrated that this cytokine partly mediates the antiproliferative effects of CD9. These results clearly establish for the first time a role for CD9 in the tumorigenic process. ' 2007 Wiley-Liss, Inc.Key words: CD9; TNF-a; proliferation; tumorigenicity; tetraspanin The tetraspanin CD9 is a widely distributed surface molecule implicated in diverse functions, including cell signaling, growth, adhesion and motility, metastasis and sperm-egg fusion. Like other members of the tetraspanin protein family, CD9 participates in the organization of cell surface protein microdomains, termed ''the tetraspanin web,'' through association with other transmembrane proteins including members of the integrin family of adhesion receptors. [1][2][3] The implication of CD9 in cancer has received much attention. An inverse correlation between its expression in primary tumors and the metastatic potential and patient survival rate has been established for melanomas and colon, lung and breast carcinomas. 1,4-8 The involvement of this tetraspanin in tumor progression has been inferred from the effects of CD9 antibodies or CD9 overexpression on tumor cell motility and migration. In this regard, it has been shown that overexpression of this tetraspanin in melanoma and breast, lung, pancreas and colon carcinoma cells suppresses the motility and metastatic potential of these cells. 5,7,9,10 mAbs directed to the CD9 molecule have also been shown to inhibit the migration of different types of carcinoma tumor cells and the transendothelial migration of melanoma cells. 11-13 Therefore, the inverse correlation observed between CD9 expression and the metastatic potential could be explained, at least in part, by the effects mediated by CD9 on cell adhesion and migration through the ...

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

“…These results indicate that CD9 disruption could accelerate GSC differentiation. As CD9 has been demonstrated to regulate tumor cell viability, 26,27 we investigated the impact of CD9 on GSC proliferation and apoptosis, and found that CD9 disruption apparently inhibited GSC proliferation and significantly induced GSC apoptosis (Supplementary Figure S2h and Figure 1f). Collectively, these data demonstrate that CD9 is essential for maintaining the self-renewal and proliferation of GSCs.…”

The tetraspanin CD9 regulates migration, adhesion, and homing of human cord blood CD34+ hematopoietic stem and progenitor cells

“…Our results are in agreement with studies on some cancer cells. Pretreatment of pre-B-cell acute lymphoblastic leukemia, 35 melanoma, 50 or colon carcinoma 51 with CD9 mAb enhanced their adhesion to fibronectin, endothelial, and bone marrow stromal cells, suggesting that CD9 is a negative regulator of cellular adhesion. Our observations, together with those in metastatic tumors, suggest that the presence of CD9 on CD34 ϩ cells might inhibit SDF-1-mediated cell motility to a certain extent, but that such activities could be modulated by adhesion to endothelial cells.…”

Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer

“…ALB6 treatment of mice bearing CD9-expressing human gastric cancer cells has been recently shown to successfully inhibit tumor progression via not only antiproliferative and proapoptotic effects on malignant cells but also antiangiogenic effects on tumor vessels reducing microvessel density (42). Inhibitory effects of anti-CD9 mAb on in vivo tumorigenicity as well as in vitro proliferation of human colon carcinoma cells has also been reported (43). Regulation of tumor angiogenesis by ALB6 in vivo is likely and acceptable because another anti-CD9 mAb (ALMA.1) inhibited human vascular endothelial cell migration toward ECM proteins at wound lesion and impaired its repair (44).…”

“…Furthermore, antibody-dependent cellular cytotoxicity might have participated in antitumor activity by anti-CD9 antibodies in vivo (42,43), although the authors did not refer to the matter. IgG 1 subclass antibodies such as trastuzumab, rituximab, and cetuximab are well known to preferentially induce this immune reaction because they have longer half-lives and could bind to all subtypes of FcγR on effector cells (45)(46)(47)(48).…”