Role of neoangiogenic pericytes in tumour dissemination

Role of neoangiogenic pericytes in tumour dissemination

This line of research aims at clarifying the role of neoangiogenic pericytes in the control of tumour dissemination through the haematic circuit, with particular attention to the contribution that pericyte may make in the entrance of pro-metastatic cells into vascular circuits (intravasation) and their exit from the blood stream (extravasation). Recent data are raising the awareness that variations in pericyte maturation, coverage of neovascular structures and endothelial interplays may modulate the intravasation of disseminating cancer cells, but the cellular and molecular mechanisms involved in this process are still controversial and largely unknown.

Our current observations that pericytes affect the migration of distinct tumour cell types in vitro and in vivo support the hypothesis of an active role of pericytes in tumour spreading. Concurrently, we are evaluating the topographical arrangement and phenotypic traits of pericytes lesions of a wide range of tumour classes. Preliminary observations purport tumour grade-related and type-related differences in pericyte phenotype and coverage of the tumour neovasculature, suggesting that more targeted and effective anti-metastatic therapeutic approaches may be based upon the specific characteristics of pericytes in the target tumour.

Some membrane-associated proteoglycans (PGs) are already known to be abundantly expressed by both pericytes and tumour cells and hypothesized to be actively engaged in the neovasculature/tumour cell cross-talk. NG2 is a well-established primary surface component of sprouting pericytes and is known to regulate the microenvironmental interactions of these cells. However, recent findings of collaborating groups reveal that melanoma and soft-tissue sarcomas share with pericytes the expression of other cell surface PGs. We aim to establish the precise function of these molecules in the context of the participation of pericytes in the control of tumour spreading and how these may dictate their pro- or anti-metastatic effects. In parallel, a particular effort is devoted to understanding how the extracellular matrix elaborated by the pericytes themselves, or the adjacent endothelium may affect the pericyte behaviour and the intra- and extravasation phenomena. For addressing the above issues we have designed multi-disciplinary and multi-functional in vitro and in vivo research strategies, spanning from gene and protein profilings to transgenic animal models.

The outcome of these studies is channelled into research efforts striving at defining the potential of a dual immune-therapeutic targeting of pericytes and highly aggressive tumour cell subsets such as to allow for the combined therapeutic ablation of neovascular elements and spreading tumour cells.