Role of stromal Caveolin-1 in breast cancer angiogenesis

Abstract

Tumors have been described as “wounds that never heal”; and non-tumoral surrounding cell populations involved in angiogenesis and response to injury, such as endothelial cells, immune cells and fibroblasts are actively engaged to support the aberrant growth and remodeling of the tumor mass, which conversely determine tumor architecture and behavior. These cells, along with extracellular matrix (ECM) components, define the tumor microenvironment or tumor stroma. While breast cancer progression was conceived for a long time to be largely dependent on aberrant mutations in tumor cells, stromal Cancer-Associated Fibroblasts (CAFs) have been demonstrated to modulate breast cancer growth, invasion, metastasis and therapeutic resistance. Caveolin-1 (CAV1), a prominent organizer of plasma membrane properties and function, exhibits extensive ties with many events defining tumor onset and progression. Although previous studies have shown CAV1 expression levels in CAFs to influence breast cancer growth and metastasis, the underlying driving mechanisms remain incompletely characterized. In this regard, ECM modification and metabolic reprogramming have been proposed as key aspects of a stromal CAV1-dependent role in tumor biology. This thesis research report aims to contribute to our understanding as to how CAV1 expression in stromal CAFs impact tumor angiogenesis, and thus tumor hypoxia, cancer aggressiveness and metastasis. The present work showcases evidence supporting a positive reciprocal feedback relationship between stromal CAV1 downregulation and endoplasmic reticulum (ER) stress, which can drive exacerbated proangiogenic signaling, causative of the generation of an aberrant and dysfunctional tumor vasculature. This report proposes defective angiogenesis and consequent hypoxia as major driving causes for increased aggressiveness of breast cancer in low stromal CAV1 tumors.