Functions of Thrombospondin-1 in the Tumor Microenvironment

• Published in: International journal of molecular sciences Vol. 22; no. 9; p. 4570
• Main Authors: Kaur, Sukhbir, Bronson, Steven M, Pal-Nath, Dipasmita, Miller, Thomas W, Soto-Pantoja, David R, Roberts, David D
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.05.2021; MDPI
• Subjects: Adhesion; Angiogenesis; Angiogenesis inhibitors; Animals; Autophagy; Binding sites; Breast cancer; Cancer; Carcinogenesis; Carcinogens; CD36; CD47; Cell Adhesion; Cell Movement; Cell surface; Chemotherapy; cytotoxic T cells; Extracellular vesicles; Fibroblasts; Gene expression; Genotoxicity; Growth factors; Humans; Immune system; integrins; Integrins - metabolism; Ischemia; Life Sciences; Low density lipoprotein receptors; Lymphocytes; Melanoma; Metabolic response; Metastases; Metastasis; Mice; Motility; mRNA; natural killer cells; Neoplasms - blood supply; Neoplasms - immunology; Neoplasms - pathology; Neovascularization, Pathologic - metabolism; Neovascularization, Physiologic - genetics; Peptides; Perfusion; Phagocytosis; Proteins; Radiation therapy; Review; Senescence; Stem cells; T-Lymphocytes - immunology; Therapeutic targets; Thrombospondin; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Thrombospondin 1 - physiology; Tumor microenvironment; Tumor Microenvironment - physiology; Tumor suppressor genes; natural killer cells; integrins; nitric oxide; autophagy; angiogenesis; transforming growth factor-β1; tumor-initiating cells; CD36; CD47; cytotoxic T cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22094570

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. 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.