Functions of Thrombospondin-1 in the Tumor Microenvironment

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.

Keywords: CD36; CD47; angiogenesis; autophagy; cytotoxic T cells; integrins; natural killer cells; nitric oxide; transforming growth factor-β1; tumor-initiating cells.

Figure 1

TSP1 subunit domains and their cell surface receptors or extracellular ligands. TSP1 is a ~450 kDa homotrimer of subunits linked by disulfide bonds near the N-terminal pentraxin-like domain. Type 1 TSP1 repeats (TSR), EGF-like, and calcium-binding repeats form the central stalk region of TSP1, connecting the N- and C-terminal globular domains.

Figure 2

Redundant regulation of NO signaling by TSP1–CD47 interaction. Endogenous NO synthesis is stimulated via Akt-mediated phosphorylation of endothelial nitric oxide synthase (eNOS) downstream of the VEGF receptor VEGFR2. Ligation of CD47 by TSP1 also inhibits activation of soluble guanylyl cyclase (sGC) mediated by endogenous or exogenous NO. TSP1 also inhibits calcium-dependent activation of eNOS and NO signaling downstream of cGMP by inhibiting cGMP-dependent protein kinase (cGK-1).

Figure 3

Innate and adaptive immune checkpoint functions of CD47 and TSP1. In the “don’t eat me” model (a), CD47 on tumor cells interacts with SIRPα on macrophages to induce inhibitory signaling, preventing the phagocytic killing of tumor cells. CD47 is also expressed by immune cells and mediates TSP1 signaling in immune cells. TSP1 interaction with CD47 on NK cells and cytotoxic T cells inhibits their activation and limits granzyme B production that mediates antigen-dependent lysis of tumor cells (b). Inhibitory TSP1 signaling mediated by CD47 on macrophages and dendritic cells limits their presentation of antigens to T cells and limits macrophage production of IL-1β.

Figure 4

Differential effects of CD47 signaling in normal versus cancer stem/tumor-initiating cells [183]. TSP1 signaling via CD47 limits the maintenance of stem cells in nonmalignant tissues (a). Blocking CD47 signaling has opposing effects on asymmetric cell division in normal versus cancer cells (b). A function-blocking CD47 antibody forces the differentiation of breast cancer stem cells, in part by decreasing expression of the stem cell transcription factor KLF4 and decreasing epidermal growth factor receptor (EGFR) signaling (c).

Figure 5

Roles of TSP1 and CD47 in the intercellular communication mediated by EVs in the tumor microenvironment. EVs derived from T cells (a) modulate angiogenic signaling in endothelial cells and activate other T cells in a CD47-dependent manner. EVs produced by cancer cells and cancer stem cells (b) have TSP1- and CD47-dependent effects on endothelial cells and other tumor cells that CD47 antibodies can modulate. EVs enriched with TSP1 from myeloid-derived suppressor cells (MDSCs, (c)) stimulate chemotaxis, blocked by a CD47 antibody. EVs produced by cancer-associated fibroblasts (d) containing TSP1 associated with LRP1 are circulating poor survival markers.