Understanding the interaction of human cancer cells with the surrounding microenvironment: the new challenge in modern oncology

Cancer cells are able to shape the surrounding environment, altering the behavior of the neighbouring normal cells and de-arranging their inter-relationship inducing a pro-tumor activity. The communication between tumor and stromal cells may be mediated by: 1) cell-cell direct interaction; 2) soluble factors like chemokines and growth factors; 3) extracellular microvesicles and/or exosomes (EVs) containing mRNAs, miRNA and proteins that can be delivered to the target cells. We used a peculiar example of niche-dependent tumor, multiple myeloma (MM), to investigate these different mechanisms of crosstalk. With the final goal to provide the rationale for an innovative molecular therapy, we also investigated how one of the key oncogenic signaling in MM, the Notch pathway, affects the interplay between tumor cells and the bone marrow (BM) niche. Our evidences indicate that MM cells promotes the development of bone lesions boosting osteoclast differentiation both through the secretion of the soluble factor RANKL and through the direct activation of Notch in osteoclast precursors. Interestingly, EVs have a crucial role in this interaction and are able to boost osteoclastogenesis in a Notch-dependent manner. Moreover, MM cells interact with BM stromal cells and, through the activation of Notch, stimulate the secretion of anti-apoptotic and growth stimulating factor such as IL6 and SDF1, that may represent part of the EVs-cargo. Altogether our data provides new insights in the pathophysiology of the BM niche and represents the rationale for a Notch-tailored therapy in MM, in order to interrupt the vicious cycle between tumor cells and the surrounding microenvironment. This provides a further understanding in the role of this oncogenic pathway in the BM niche and will strength the rationale for the development of a Notch-tailored therapy in relapsing MM patient.