Abstract
The identification of thrombospondin-1 as an angiogenesis inhibitor in 1990 prompted interest in its role in cancer biology and potential as a therapeutic target. Decreased thrombospondin-1 mRNA and protein expression are associated with progression in several cancers, while expression by nonmalignant cells in the tumor microenvironment and circulating levels in cancer patients can be elevated. THBS1 is not a tumor suppressor gene, but the regulation of its expression in malignant cells by oncogenes and tumor suppressor genes mediates some of their effects on carcinogenesis, tumor progression, and metastasis. In addition to regulating angiogenesis and perfusion of the tumor vasculature, thrombospondin-1 limits antitumor immunity by CD47-dependent regulation of innate and adaptive immune cells. Conversely, thrombospondin-1 is a component of particles released by immune cells that mediate tumor cell killing. Thrombospondin-1 differentially regulates the sensitivity of malignant and nonmalignant cells to genotoxic stress caused by radiotherapy and chemotherapy. The diverse activities of thrombospondin-1 to regulate autophagy, senescence, stem cell maintenance, extracellular vesicle function, and metabolic responses to ischemic and genotoxic stress are mediated by several cell surface receptors and by regulating the functions of several secreted proteins. This review highlights progress in understanding thrombospondin-1 functions in cancer and the challenges that remain in harnessing its therapeutic potential.
Highlights
Introduction published maps and institutional affilCancer has been described as a wound that does not heal [1]
Our interest in studying the role of the secreted protein thrombospondin-1 (TSP1, encoded by THBS1) in the tumor microenvironment arose from our observation that TSP1 expression decreased during malignant progression in melanoma and breast carcinoma cell lines
The mRNA content in extracellular vesicles (EVs) differed between WT and CD47-deficient cell lines, and uptake of those EVs by target cells led to CD47-dependent changes in gene expression in target cells that regulate angiogenesis and immune cell function (Figure 5a)
Summary
Understanding the divergent functions of TSP1 in cancer requires an appreciation of the multiple TSP1 receptors that are expressed on each cell type in the tumor microenvironment as well as the secreted factors that interact with TSP1 and mediate some of its functions (Figure 1). Domains of TSP1 and specific peptide sequences have been identified that are recognized by some of its receptors. As TSP1 is a substrate for several proteases in the tumor microenvironment, fragments of TSP1 that engage specific subsets of receptors may have biologic activities that differ from those of intact TSP1 [23,24]
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