The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma.

Glioblastoma (GBM), a high-grade glioma (WHO grade IV), is the most aggressive form of brain cancer. Available treatment options for GBM involve a combination of surgery, radiation and chemotherapy but result in a poor survival outcome. GBM is a high-vascularized tumor and antiangiogenic drugs are widely used in GBM therapy as adjuvants to control abnormal vasculature. Vasculogenic mimicry occurs in GBM as an alternative vascularization mechanism, providing a means whereby GBM can escape anti-angiogenic therapies. Here, using an in vitro tube formation assay on Matrigel^®, we evaluated the ability of different histone deacetylase inhibitors (HDACis) to interfere with vasculogenic mimicry. We found that vorinostat (SAHA) and MC1568 inhibit tube formation by rat glioma C6 cells. Moreover, at sublethal doses for GBM cells, SAHA, trichostatin A (TSA), entinostat (MS275), and MC1568 significantly decrease tube formation by U87MG and by patient-derived human GBM cancer stem cells (CSCs). The reduced migration and invasion of HDACis-treated U87 cells, at least in part, may account for the inhibition of tube formation. In conclusion, our results indicate that HDACis are promising candidates for blocking vascular mimicry in GBM.

Experimental evidence implicates reactive oxygen species (ROS) generation in the hypoxic stabilization of hypoxia-inducible factor (HIF)-1α and in the subsequent expression of promoters of tumor invasiveness and metastatic spread. However, the role played by mitochondrial ROS in hypoxia-induced Epithelial-Mesenchymal Transition (EMT) activation is still unclear. This study was aimed at testing the hypothesis that the inhibition of hypoxia-induced mitochondrial ROS production, mainly at the mitochondrial Complex III UQCRB site, could result in the reversion of EMT, in addition to decreased HIF-1α stabilization. The role of hypoxia-induced ROS increase in HIF-1α stabilization and the ability of antioxidants, some of which directly targeting mitochondrial Complex III, to block ROS production and HIF-1α stabilization and prevent changes in EMT markers were assessed by evaluating ROS, HIF-1α and EMT markers on breast cancer cells, following 48 h treatment with the antioxidants. The specific role of UQCRB in hypoxia-induced EMT was also evaluated by silencing its expression through RNA interference and by assessing the effects of its downregulation on ROS production, HIF-1α levels, and EMT markers. Our results confirm the pivotal role of UQCRB in hypoxic signaling inducing EMT. Thus, UQCRB might be a new therapeutic target for the development of drugs able to reverse EMT by blocking mitochondrial ROS production.