Enrico Giraudo, PhD
Associate Professor University of Torino School of Medicine
Semaphorins: new tools to “normalize” the tumor microenvironment and to halt metastasis formation.
Angiogenesis is required for invasive tumor growth and metastasis. It is well described that tumor vessel normalization represents a remarkably advantageous anti-cancer strategy, reducing tumor hypoxia and also being able to favor chemotherapy delivery and response to radiotherapy. It is critical therefore to identify new “pro-normalizing” modulators to define new anti-angiogenic combinatory regimens to block tumor growth. In these years, several studies have showed that class3 semaphorins (Sema3s) - that act via receptor complexes binding neuropilins 1 and 2 (Nrp1/2) and transducing the signal by plexins (Plxns) - represent new targets to inhibit tumor angiogenesis and cancer growth.
Sema3A has been uncovered as a new vessel normalizing and anti-metastatic agent in mouse models of spontaneous pancreatic neuroendocrine tumors (RIP-Tag2) of cervical carcinomas (HPV16/E2), of pancreatic adenocarcinoma (PDAC) and of breast cancer (4T1). Interestingly, the treatment of mice with adeno-associate virus AAV-8-Sema3A counteracted the resistance to the anti-angiogenic therapies by normalizing the tumor vasculature, inhibiting hypoxia and several hypoxia-induced pro-metastatic signaling pathways. Sema3A was able to recruit into tumors a sub-population of CD11b+, Nrp-1+, GR-1- and Tie-2- monocyte (NEMs) inhibiting tumor progression and to normalize the tumor vasculature. Notably, Sema3A acted directly on tumor cells. In fact, inhibited HGF-induced Met phosphorylation and impaired the chemo-invasion of several met-addicted tumor cell lines, by interfering with Met recycling and internalization. Remarkably, Met phosphorylation was strongly inhibited both in vessels and cancer cells in Sema3A-treated PDAC mouse model. In collaboration with the Laboratories of Cell Adhesion Dynamics of our Institute, we generated a furin-resistant mutant Sema3A* protein that, binding with high affinity with plexin A4, efficiently inhibited metastasis formation and normalized the tumor vasculature in mouse models of pancreatic cancer. We uncovered together a novel Sema that is endowed with an unpredictable in vivo pro-angiogenic activity.
Conclusions and perspectives
Our findings provide evidences that Sema3A, by acting on several tumor cell types and activating the immune-system, blocks tumor growth and metastasis spreading in different tumor types. Based on these findings the main focus of research are the following: (i) investigation of the molecular mechanisms by which Sema3A turns off the HGF/Met pathway in different stroma cell types and cancer cells; (ii) evaluation of new therapeutic combinatorial strategies to enhance with Sema3A (and other Semas) the anti-tumor immune response in several mouse models of cancers; (iii) evaluation of the anti-metastatic and pro-vessel normalizing effects of mutant Sema3A* protein in different human mouse models of pancreatic, breast, cervical, and colon cancer.
Gabriele Sardo, PhD
Arianna Aricò, PhD, MDV
Serena Brundu, PhD