Genetic Ablation of the Tetraspanin CD151 Reduces Spontaneous Metastatic Spread of Prostate Cancer in the TRAMP Model

Abstract

Tetraspanins are integral membrane proteins that associate with motility-related molecules such as integrins. Experimental studies have indicated that they may be important regulators of tumor invasion and metastasis, and high expression of the tetraspanin CD151 has been linked to poor prognosis in a number of cancers. Here, we show for the first time that genetic ablation of CD151 inhibits spontaneous metastasis in a transgenic mouse model of de novo tumorigenesis. To evaluate the effects of CD151 on de novo prostate cancer initiation and metastasis, a Cd151 À/À (KO) murine model was crossed with the Transgenic Adenocarcinoma of MouseProstate (TRAMP) model. Mice were analyzed for initiation of prostate tumor by palpation and primary tumors were analyzed by immunohistochemistry. Liver and lungs were examined for incidence and size of spontaneous metastatic lesions by histopathology. Knocking-out Cd151 had no significant effect on prostate cancer initiation or on expression of markers of proliferation, apoptosis, or angiogenesis in primary tumors. However, it did significantly decrease metastasis in a site-specific fashion, notably to the lungs but not the liver. Thus, CD151 acts principally as promoter of metastasis in this model. Prostate cancer is the second highest cause of cancerrelated deaths in men in most Western countries, with the majority of deaths attributed to late-stage metastatic disease. CD151 may prove to be a valuable prognostic marker for treatment stratification and is a possible antimetastatic target. Mol Cancer Res; 11(1); 95-105. Ó2012 AACR.

Tetraspanin CD81 Promotes Tumor Growth and Metastasis by Modulating the Functions of T Regulatory and Myeloid-Derived Suppressor Cells

“…Indeed, some tetraspanin members have been shown to play a role in cancer progression. A definite role for CD151 was demonstrated in two independently derived CD151KO mice that were challenged with several tumor models (16,19). In the same studies, diminished metastasis in CD151KO hosts was suggested to be due to impaired adhesion and trans-endothelial migration of CD151 expressing tumor cells (19).…”

“…Overexpression of these tetraspanins correlates with tumor progression and metastasis (15). Corroborating the role of CD151 in tumor progression are studies in CD151-deficient mice, which develop fewer metastases than their wild-type (WT) counterparts in carcinogen-induced skin cancer, melanoma (B16F10), Lewis lung carcinoma (LLC), transgenic breast cancer (MMTV-PyVmT), and adenocarcinoma prostate cancer (TRAMP) models (16)(17)(18)(19).…”

Tetraspanin CD37 Regulates β2 Integrin–Mediated Adhesion and Migration in Neutrophils

“…The best characterized of the tetraspanin molecular partners are integrins. Indeed, in nonimmune cells the evidence that tetraspanins can regulate integrin-mediated functions is overwhelming, incorporating roles in wound healing (43), angiogenesis (44), hemostasis (45), epidermal integrity (46), glomerular filtration (47,48), and cancer cell metastasis (49)(50)(51). By comparison, the evidence that tetraspanins regulate adhesion and migration of leukocytes is limited.…”

Tetraspanins at a glance

“…Several tetraspanins gained special attention because they regulate the progression of various types of cancers or the formation of metastasis, perhaps as a consequence of their ability to regulate the migration of cancer cells and their ability to invade the surrounding matrix Hemler, 2014;Zöller, 2009). In particular, several experimental models, including genetic models of cancers (Copeland et al, 2013a;Copeland et al, 2013b;Deng et al, 2012), as well as clinical data, suggest that CD9 and CD82 are suppressors of metastasis, whereas CD151 and TSPAN8 promote metastasis (Hemler, 2014;Romanska and Berditchevski, 2011;Zöller, 2009).…”