CSPG4 as a potential target of antibody-based immunotherapy for malignant mesothelioma

Abstract

Malignant Mesothelioma (MM) is an aggressive tumor associated with asbestos exposure: [1]. Chemotherapy is the mainstay of MM treatment; however it only extends survival by 11 weeks. The high mortality rate and the distinctive chemoresistance of MM underscore the need for novel targeted therapies for this deadly disease. Chondroitin Sulfate Proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is highly expressed and involved in cell proliferation and migration of many tumor cell types [2]. Through binding this antigen with extracellular matrix components (ECM) components (such as Collagens and Fibronectin) and integrins, it modulates cellular activities such as polarization, adhesion and spreading via activation of signaling cascades leading to FAK, Src and ERK1/ERK2 activation [3]. Highly over-expressed in most melanoma cells, CSPG4 is associated with expression and activation of membrane type matrix metalloproteinases (MT-MMPs) at the site of contact between cells and the underlying ECM, indicating a role in cell invasion [4]. To date, no study has examined the role, if any, of CSPG4 in the progression of MM. The lack of effective therapies for MM prompts the search to identify targets to implement antibody-based immunotherapy. We report here the expression of the membrane bound Chondroitin Sulphate Proteoglycan 4 (CSPG4) in 6 out of 8 MM cell lines and in 24 out of 40 MM biopsies, with minimal expression in surrounding normal cells. CSPG4 is involved in the onset and progression of several tumors, as well as in angiogenesis. CSPG4 expression in MM cells was induced upon engagement of ECM, especially fibronectin, and increased percentage of viable MM cells. CSPG4-specific monoclonal antibody (mAb) TP41.2 inhibited MM cell attachment to the ECM, the resulting intracellular signaling and induced apoptosis. Moreover, in vitro, CSPG4-specific mAb TP41.2 significantly reduced MM cell motility, invasiveness, wound healing and inhibited MM growth in soft agar. In vivo, mAb TP41.2 prevented human MM tumor establishment in SCID mice and significantly inhibited the growth of established MM xenografts. These results suggest that CSPG4 mAb-based immunotherapy may represent a possible novel valid approach for the treatment of MM.