Abstract
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.
Highlights
Chondroitin sulphate proteoglycan 4 (CSPG4), alternatively known as melanoma-associated chondroitin-sulphate proteoglycan (MCSP) or high molecular weight melanoma-associated antigen (HMW MAA), is a membrane-integral chondroitin sulphate (CS)-modified glycoprotein-proteoglycan (Figure 1)
TRAIL is expressed as a type II transmembrane protein on immune effector cells, whereas proteolytic or alternative may yield soluble of TRAILeffector in vivo.cells, Soluble forms
Disease-specific apoptosis induction by scFv:sTRAIL fusion proteins has been demonstrated for various malignancies, including αMCSP:sTRAIL which targets melanoma featuring over-expression of CSPG4 [45]
Summary
Chondroitin sulphate proteoglycan 4 (CSPG4), alternatively known as melanoma-associated chondroitin-sulphate proteoglycan (MCSP) or high molecular weight melanoma-associated antigen (HMW MAA), is a membrane-integral chondroitin sulphate (CS)-modified glycoprotein-proteoglycan (Figure 1). The extracellular region of CSPG4 consists of three domains (D1–3), with D1 most distal from structural and functional properties, including binding domains for growth factors and other ligands the membrane and D3 most proximal to the cell membrane. Each of these domains has distinct that constitutively activate mitogenic pathways and transcription [3,4]. The extracellular part of CSPG4 and is exclusively subject to N-linked glycosylation This modification is seemingly not required for signal transduction functionalities of the CSPG4, The cytoplasmic tail includes ERK and PKCα phosphorylation sites For the purposes of this review, we recognize CSPG4 as a marker for aggressive, therapy-resistant cancers and are interested in its potential as target for tumor-selective oncolytic agents such as antibody-drug conjugates (ADCs), immunotoxins (ITs) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) fusion proteins, described later in this review
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