Chondroitin-sulfate proteoglycan 4 (CSPG4) is a transmembrane
glycoprotein overexpressed on malignant cells in several
cancer types with only limited expression on normal cells. CSPG4 is implicated in several signaling pathways believed to drive
cancer progression, particularly proliferation, motility and metastatic spread. Expression may serve as a prognostic marker for survival and risk of relapse in treatment-resistant
malignancies including
melanoma,
triple negative breast cancer,
rhabdomyosarcoma and
acute lymphoblastic leukemia. This
tumor-associated overexpression of CSPG4 points towards a highly promising therapeutic target for antibody-guided
cancer therapy. Monoclonal αCSPG4
antibodies have been shown to inhibit
cancer progression by blocking
ligand access to the CSPG4 extracellular binding sites. Moreover, CSPG4-directed antibody conjugates have been shown to be selectively internalized by CSPG4-expressing
cancer cells via endocytosis. CSPG4-directed
immunotherapy may be approached in several ways, including: (1) antibody-based fusion
proteins for the selective delivery of a pro-apoptotic factors such as
tumor necrosis factor-related apoptosis-inducing
ligand to agonistic
death receptors 4 and 5 on the cell surface; and (2) CSPG4-specific
immunotoxins which bind selectively to diseased cells expressing CSPG4, are internalized by them and induce arrest of biosynthesis, closely followed by initiation of apoptotic signaling. Here we review various methods of exploiting
tumor-associated CSPG4 expression to improve targeted
cancer therapy.