Tumour promoting function and therapeutic targeting of NG2-CSPG4 transmembrane proteoglycan

Tumour promoting function and therapeutic targeting of NG2-CSPG4 transmembrane proteoglycan

This line of research aims at unfolding the pro-tumorigenic role of the NG2/CSPG4 transmembrane proteoglycan, such as to provide means for a better clinical trasfer of the potential of this cell surface component as a prognostic factor and therapeutic target. Our recent findings demonstrate that NG2 predicts metastasis formation and constitutes a novel independent prognostic factor in soft-tissue sarcomas, while vaccination of advanced melanoma patients with anti-idiotypic antibodies mimicking NG2 has recently been demonstrated to cure >20% of the patients. Two of our recent studies show that NG2 promotes growth and metastasis formation by linking tumour cells to host collagen type VI and by acting as a co-factor for FGF mitogenic responses during neovascularization processes. Since partly through these studies we have observed that NG2 may interact with additional ECM-associated components, one of our primary goals is to identify putative ligands of the NG2 ectodomain through a combined immunochemical and proteomic approach entailing selected proprietary anti-NG2 monoclonal antibodies. Through the use of these antibodies we are in the process of characterizing tumour cell- and pericyte-specific NG2 isoforms and selectively approach their function in vivo, while, in parallel, determining their distribution in a variety of tumour types. A second goal of the study is to further clarify how NG2 controls growth and metastasis formation by conferring to tumour cells a higher resistance to adverse conditions, a lower drug susceptibility, a higher responsiveness to local growth factors, an increased locomotory and invasive capacity and an enhanced perception of mechanotransducing signals from their microenvironment.

Furthermore, since NG2 may confer to tumour cells an overall higher metastatic potential, we are conducting investigations aimed at resolving the role of the proteoglycan in early steps of the metastatic cascade, such as tissue invasion and transvascular movement. Separation of NG2+ and NG2- cell subsets from primary and metastatic lesions with the aid of our antibodies allows us to comparatively define the global gene expression and phospho-proteomic pattern associated with NG2 surface abundance, such as to establish the signals that the proteoglycan may participate in transducing inside cancer cells and the gene transductions resulting from these signals.

Our investigations also corroborate a major role of NG2 as a prognostic and metastatic-predicting factor uniquely highlight a strong diagnostic impact on soft-tissue sarcomas. These studies are being extended to a number of other tumour entities in which we have identified high levels of NG2. The cumulative exploitation of the knowledge progressively accrued about the biological significance of NG2 in tumour progression, its confirmed diagnostic importance, previous information about the effectiveness of its targeting in abrogating growing tumours and the availability of a panel of over 60 proprietary monoclonal antibodies of which several seem to possess function-perturbing properties, now opens for the potential to generate antibody-based drugs for NG2-directed therapeutic targeting of multiple cancer types.