Thrombospondins and remodeling of the tumor microenvironment

Abstract

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.

Keywords: Thrombospondin; angiogenesis; cancer; inflammation.

Figure 1.

Hyperglycemia promotes cancer growth by regulating thrombospondin (TSP)-1- and TSP-4-dependent pathways. Upregulation of TGF-β in response to hyperglycemia leads to upregulation of TSP-4. TSP-4 is a pro-angiogenic protein that also promotes recruitment of macrophages and other leukocytes into tissues and increases local inflammation. Upregulation of miR-467 in a tissue-specific manner blocks TSP-1 production. In the absence of the anti-angiogenic pressure of TSP-1, cancer angiogenesis is increased. In the absence of TSP-1, the resolution of inflammation is impaired. Increased inflammation and angiogenesis promote cancer growth in the absence of TSP-1. TSP-1 and TSP-4 pathways converge and complement each other to promote the tumor growth

Figure 2.

Interaction of hyperglycemia-regulated thrombospondin (TSP) pathways. TSP-4 increases recruitment of macrophages, while TSP-1 is needed for the resolution of inflammation. In response to hyperglycemia, TSP-1 levels are downregulated by increased levels of miR-467. TSP-4 is upregulated as a result of upregulation of TGF-β and activation of SMAD3. Upregulation of TSP-4 result in increased recruitment of macrophages into the tumor. In the absence of TSP-1 and resolution of inflammation, the accumulation of macrophages increases. In a feedback loop, TSP-4 increases the levels of an inhibitory TGF-β receptor beta-glycan. TGF-β further decreases the production of TSP-1. In a feedback loop, TSP-1 is an activator of TGF-β. Green arrow and text = upregulation in response to hyperglycemia; red arrow and text = downregulation in response to hyperglycemia. TGF-β: transforming growth factor beta