Tumor Microenvironment
Enrico Giraudo, PhD
Associate Professor University of Torino School of Medicine
E-mail: enrico.giraudo@ircc.it
Phone. +39.011.9933505
Fax. +39.011.9933524
Research topic
Semaphorins: new tools to “normalize” the tumor microenvironment and to halt metastasis formation.
Background
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.
Research achievements
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.
Staff
Gabriele Sardo, PhD
Phone: 011.993.3226
Email: gabriele.sardo@ircc.it
Arianna Aricò, PhD, MDV
Phone: 011.993.3226
Email: arianna.arico@ircc.it
Serena Brundu, PhD
Phone: 011.993.3226
Email: serena.brundu@ircc.it