Role of vascular remodeling in the accumulation, clearance, and biodistribution of biomolecular factors in melanoma

Abstract

Local inflammation within the tumor microenvironment is implicated in the systemic effects of disease progression, such as immune suppression and metastasis. Soluble factors (SF) produced within the tumor, including cytokines, exosomes, proteases, and microvesicles, mediate pathological signaling and have emerged as putative therapeutic targets. However, SF bioavailability in distributed tissues and the impact of disease progression on their dissemination profiles and exposure to various immune cell subsets is poorly defined. This stymies progress towards therapeutic amelioration of SF signaling activities to improve disease outcomes and is the critical knowledge gap this thesis seeks to fill. The central hypothesis is that tumor vascular remodeling redirects the organism-wide exposure of SF secreted locally within the tumor microenvironment, which may negatively contribute to disease burden by altering the bioavailability of molecules important to systemic disease progression. In this thesis, the effects of local tissue remodeling in melanoma leading to pathological SF accumulation profiles within distributed tissues are elucidated in order to provide insight into the potential for localized disease to exert systemic effects and inform opportunities to develop better preventive and curative treatment options for advanced melanomas.