Remodeling at the intersection of time and tissue: Aging, obesity, and the MT1-MMP proteolytic driver in ovarian cancer.

Ovarian cancer is the leading cause of gynecological cancer death for women in the United States. Aging and obesity are known risk factors that increase incidence rate, severity, and metastatic progression of ovarian cancer. With aging and obesity, physiological changes occur including increased inflammation, altered metabolism, and, most notably, extracellular matrix (ECM) remodeling. Remodeling of the ECM is critical for accommodating adipocyte expansion in obesity and arises from accumulated modifications with aging. The already remodeled collagen under these host factors is driven by remodeling enzymes such as matrix metalloproteinases (MMPs). Of particular interest is membrane-bound MT1-MMP, which is required for invasion in metastatic ovarian cancer. MT1-MMP is responsible for the directed collagenolysis of the ECM, which is a barrier to metastatic growth. Because of metastatic dependence on MT1-MMP, there have been many attempts to inhibit this enzyme, but current therapies lack specificity and cause significant adverse side effects. Nonetheless, novel therapeutic interventions targeting MT1-MMP are promising to improve selectivity. In this chapter, we will highlight key pathways regulating MT1-MMP expression, impact on oncogenic phenotypes, and the mechanisms that aging and obesity use to further promote ECM remodeling and accelerate disease progression, while assessing past and future challenges to study and targeting MMPs for cancer treatment.