Thrombospondins and remodeling of the tumor microenvironment

Vascular remodeling defines cancer growth and aggressiveness. Although cancer cells produce pro-angiogenic signals, the fate of angiogenesis critically depends on the cancer microenvironment. Composition of the extracellular matrix (ECM) and tumor inflammation determine whether a cancer will remain dormant, will be recognized by the immune system and eliminated, or whether the tumor will develop and lead to the spread and metastasis of cancer cells. Thrombospondins (TSPs), a family of ECM proteins that has long been associated with the regulation of angiogenesis and cancer, regulate multiple physiological processes that determine cancer growth and spreading, from angiogenesis to inflammation, metabolic changes, and properties of ECM. Here, we sought to review publications that describe various functions of TSPs that link these proteins to regulation of cancer growth by modulating multiple physiological and pathological events that prevent or support tumor development. In addition to its direct effects on angiogenesis, TSPs have important roles in regulation of inflammation, immunity, ECM properties and composition, and glucose and insulin metabolism. Furthermore, TSPs have distinct roles as regulators of remodeling in tissues and tumors, such that the pathways activated by a single TSP can interact and influence each other. The complex nature of TSP interactions and functions, including their different cell- and tissue-specific effects, may lead to confusing results and controversial conclusions when taken out of the context of interdisciplinary and holistic approaches. However, studies of TSP functions and roles in different systems of the organism offer an integrative view of tumor remodeling and a potential for finding therapeutic targets that would modulate multiple complementary processes associated with cancer growth.