Multidisciplinary Approach to Neurofibromatosis Type 1

Abstract

The mechanical properties of the microenvironment have been increasingly accepted as potent modulators of cell behavior and function in physiological and pathological conditions. In tumors, tissue rigidity has been recognized as a potent driver of both neoplastic initiation from healthy tissue and progression toward malignancy. Several benign or malignant tumors are fibrotic and characterized by increased deposition, turnover, and posttranslational modifications of the extracellular matrix (ECM) that progressively stiffens the stroma. Likewise, neurofibromas are complex tumors composed of transformed Schwann cells, immersed in a heterogeneous fibrotic matrix. The molecular crosstalks that govern neurofibroma onset, growth, invasiveness, and progression toward malignancy remain poorly understood. In this chapter we propose that neurofibroma development requires the integration of potent pro-tumorigenic circuitries, such as those mastered by hyperactive Ras, and altered mechanosignaling axes conveyed by a stiff ECM, and that these pathways could be orchestrated by a pro-inflammatory extracellular milieu.