Functions of Thrombospondin-1 in the Tumor Microenvironment.

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.

1990年血小板反应蛋白-1被鉴定为一种血管生成抑制剂，这激发了人们对其在癌症生物学中的作用以及作为治疗靶点的潜力的兴趣。血小板反应蛋白-1的mRNA和蛋白质表达降低与多种癌症的进展相关，而肿瘤微环境中的非恶性细胞的表达以及癌症患者的循环水平可能会升高。THBS1不是肿瘤抑制基因，但是癌基因和肿瘤抑制基因对其在恶性细胞中表达的调控介导了它们对癌症发生、肿瘤进展和转移的一些影响。除了调节肿瘤血管生成和灌注外，血小板反应蛋白-1还通过依赖CD47对先天性和适应性免疫细胞的调节来限制抗肿瘤免疫。相反，血小板反应蛋白-1是免疫细胞释放的介导肿瘤细胞杀伤的颗粒的一种成分。血小板反应蛋白-1对恶性和非恶性细胞对放疗和化疗引起的基因毒性应激的敏感性有差异调节作用。血小板反应蛋白-1调节自噬、衰老、干细胞维持、细胞外囊泡功能以及对缺血和基因毒性应激的代谢反应等多种活动是由几种细胞表面受体介导的，并且是通过调节几种分泌蛋白的功能来实现的。这篇综述强调了在理解血小板反应蛋白-1在癌症中的功能方面的进展以及在利用其治疗潜力方面仍然存在的挑战。