Human High Molecular Weight-Melanoma-Associated Antigen (HMW-MAA): A Melanoma Cell Surface Chondroitin Sulfate Proteoglycan (MSCP) with Biological and Clinical Significance

Abstract

The lack of effective conventional therapies for the treatment of advanced stage melanoma has stimulated interest in the application of novel strategies for the treatment of patients with malignant melanoma. Because of its expression in a large percentage of melanoma lesions and its restricted distribution in normal tissues, the high molecular weight-melanoma-associated antigen (HMW-MAA), also known as the melanoma chondroitin sulfate proteoglycan (MCSP), has been used to implement immunotherapy of melanoma. The potential clinical relevance of HMW-MAA/MCSP has stimulated investigations to characterize its structural properties and biological function in melanoma cells. Over the last 10 years, the field of HMW-MAA/MCSP research has seen tremendous growth. Specifically, a significant amount of information has been accumulated regarding (1) the structural characteristics of the HMW-MAA/MCSP, (2) its role in the biology of melanoma cells, and (3) the potential molecular mechanisms underlying the association between HMW-MAA/MCSP-specific immunity and survival prolongation in melanoma patients immunized with HMW-MAA/MCSP mimics. In this review, we summarize the characteristics of the HMW-MAA/MCSP in terms of its structure, antigenic profile, tissue distribution, and similarities with its counterparts in other animal species. Additionally, we discuss the role the HMW-MAA/MCSP plays in melanoma cell biology with emphasis on the recently identified signal transduction pathways triggered by the HMW-MAA/MCSP. Finally, we discuss the potential molecular mechanisms underlying the beneficial effect of anti-HMW-MAA/MCSP antibodies on the clinical course of the disease in patients with melanoma.

Eradication of melanomas by targeted elimination of a minor subset of tumor cells

“…1A). Melanotransferrin (mtf) was expressed by nearly all melanoma cells and HMW-MAA, also referred to as melanoma-associated chondroitin sulfate proteoglycan (MCSP), by a substantial number of melanoma cells; this is in accordance with published data (10). Moreover, we detected small islets of CD20 + cells that coexpressed HMW-MAA (Fig.…”

Melanoma‐associated chondroitin sulphate proteoglycan as a new target antigen for CD4+ T cells in melanoma patients

“…On our search for suitable target antigens for the active-specific immunotherapy of melanoma, we focused on the human melanoma-associated chondroitin sulfate proteoglycan (MCSP), also known as high molecular weight-melanoma-associated antigen, which has been shown to be expressed in the majority of human melanoma lesions and cultured cells with a limited expression in normal tissues. 5,6 In addition, MCSP expression was found in uveal melanoma, which is refractory to standard chemotherapy. 7 MCSP represents an unique glycoprotein-proteoglycan complex, with a 250 kDa core glycoprotein to which, via serine residues, the larger than 450 kDa proteoglycan component is attached.…”

“…21 Discussion MCSP is strongly expressed in a high percentage of melanoma lesions with low intralesional and interlesional heterogeneity and appears to be functionally relevant for adhesion, migration, invasion and proliferation of melanoma cells. 6 These properties and the availability of MCSP-specific mAb have provided the rationale to use MCSP as a target of passive antibody-based as well as active-specific immunotherapy. Several in vitro as well as animal studies have demonstrated that targeting MCSP with antibodies alone or conjugated to toxins effectively inhibits tumor growth.…”

“…6 These findings obviously raise concerns about the induction of autoimmunity when immunizing with this antigen.…”

Immunoaffinity‐based isolation of melanoma cell‐derived exosomes from plasma of patients with melanoma

“…As a result, this mAb can differentiate malignant from normal cells. The CSPG4 epitope recognized by the 763.74 mAb is present on >80% of melanomas [11], and it is carried by exosomes produced by melanoma cells (Supplementary Figure 1). Using this unique CSPG4-specific mAb, we have developed a novel and highly effective method for the isolation of a subset of CSPG4+ exosomes produced by melanoma cells (MTEX) from a pool of plasma-derived exosomes.…”