Abstract
Thrombospondins (TSPs) are multifaceted proteins that contribute to physiologic as well as pathologic conditions. Due to their multiple receptor-binding domains, TSPs display both oncogenic and tumor-suppressive qualities and are thus essential components of the extracellular matrix. Known for their antiangiogenic capacity, TSPs are an important component of the tumor microenvironment. The N- and C-terminal domains of TSP are, respectively, involved in cell adhesion and spreading, an important feature of wound healing as well as cancer cell migration. Previously known for the activation of TGF-β to promote tumor growth and inflammation, TSP-1 has recently been found to be transcriptionally induced by TGF-β, implying the presence of a possible feedback loop. TSP-1 is an endogenous inhibitor of T cells and also mediates its immunosuppressive effects via induction of Tregs. Given the diverse roles of TSPs in the tumor microenvironment, many therapeutic strategies have utilized TSP-mimetic peptides or antibody blockade as anti-metastatic approaches. This chapter discusses the diverse structural domains, functional implications, and anti-metastatic therapies in the context of the role of TSP in the tumor microenvironment.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Lawler J, Hynes RO (1986) The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins. J Cell Biol 103(5):1635–1648
Stenina-Adognravi O (2014) Invoking the power of thrombospondins: regulation of thrombospondins expression. Matrix Biol 37:69–82
Finlin BS et al (2013) Regulation of thrombospondin-1 expression in alternatively activated macrophages and adipocytes: role of cellular cross talk and omega-3 fatty acids. J Nutr Biochem 24(9):1571–1579
Raugi GJ, Olerud JE, Gown AM (1987) Thrombospondin in early human wound tissue. J Invest Dermatol 89(6):551–554
Frolova EG et al (2010) Thrombospondin-4 regulates vascular inflammation and atherogenesis. Circ Res 107(11):1313–1325
Agah A et al (2002) The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Am J Pathol 161(3):831–839
Liang Y et al (2005) Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci U S A 102(16):5814–5819
Ma XJ et al (2009) Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res 11(1):R7
Miao WM et al (2001) Thrombospondin-1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res 61(21):7830–7839
Dalla-Torre CA et al (2006) Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma. BMC Cancer 6:237
Greco SA et al (2010) Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation. BMC Cancer 10:494
McCart Reed AE et al (2013) Thrombospondin-4 expression is activated during the stromal response to invasive breast cancer. Virchows Arch 463(4):535–545
Chen PC et al (2017) Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression. J Hematol Oncol 10(1):33
Liu JF et al (2018) Thrombospondin 2 promotes tumor metastasis by inducing matrix metalloproteinase-13 production in lung cancer cells. Biochem Pharmacol 155:537–546
Streit M et al (1999) Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis. Proc Natl Acad Sci U S A 96(26):14888–14893
Kazerounian S, Yee KO, Lawler J (2008) Thrombospondins in cancer. Cell Mol Life Sci 65(5):700–712
Huang T et al (2017) Thrombospondin-1 is a multifaceted player in tumor progression. Oncotarget 8(48):84546–84558
Lawler J, Detmar M (2004) Tumor progression: the effects of thrombospondin-1 and -2. Int J Biochem Cell Biol 36(6):1038–1045
Chandrasekaran S et al (1999) Pro-adhesive and chemotactic activities of thrombospondin-1 for breast carcinoma cells are mediated by alpha3beta1 integrin and regulated by insulin-like growth factor-1 and CD98. J Biol Chem 274(16):11408–11416
Gomes N, Legrand C, Fauvel-Lafeve F (2005) Shear stress induced release of von Willebrand factor and thrombospondin-1 in HUVEC extracellular matrix enhances breast tumour cell adhesion. Clin Exp Metastasis 22(3):215–223
John AS, Rothman VL, Tuszynski GP (2010) Thrombospondin-1 (TSP-1) stimulates expression of integrin alpha6 in human breast carcinoma cells: a downstream modulator of TSP-1-induced cellular adhesion. J Oncol 2010:645376
Guo N et al (2000) Thrombospondin-1 promotes alpha3beta1 integrin-mediated adhesion and neurite-like outgrowth and inhibits proliferation of small cell lung carcinoma cells. Cancer Res 60(2):457–466
Streit M et al (1999) Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas. Am J Pathol 155(2):441–452
Albo D et al (2000) Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor. Br J Cancer 83(3):298–306
Pal SK et al (2016) THBS1 is induced by TGFB1 in the cancer stroma and promotes invasion of oral squamous cell carcinoma. J Oral Pathol Med 45(10):730–739
Seliger C et al (2013) Lactate-modulated induction of THBS-1 activates transforming growth factor (TGF)-beta2 and migration of glioma cells in vitro. PLoS One 8(11):e78935
Motegi K et al (2008) Differential involvement of TGF-beta1 in mediating the motogenic effects of TSP-1 on endothelial cells, fibroblasts and oral tumour cells. Exp Cell Res 314(13):2323–2333
Guo N et al (1997) Thrombospondin 1 and type I repeat peptides of thrombospondin 1 specifically induce apoptosis of endothelial cells. Cancer Res 57(9):1735–1742
Dawson DW et al (1997) CD36 mediates the in vitro inhibitory effects of thrombospondin-1 on endothelial cells. J Cell Biol 138(3):707–717
Kanda S et al (1999) Role of thrombospondin-1-derived peptide, 4N1K, in FGF-2-induced angiogenesis. Exp Cell Res 252(2):262–272
Taraboletti G et al (1997) The 140-kilodalton antiangiogenic fragment of thrombospondin-1 binds to basic fibroblast growth factor. Cell Growth Differ 8(4):471–479
Kawahara N et al (1998) Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma. Hepatology 28(6):1512–1517
Fontanini G et al (1999) Thrombospondins I and II messenger RNA expression in lung carcinoma: relationship with p53 alterations, angiogenic growth factors, and vascular density. Clin Cancer Res 5(1):155–161
Li Z et al (2001) Thrombospondin-1 inhibits TCR-mediated T lymphocyte early activation. J Immunol 166(4):2427–2436
Miller TW et al (2013) Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation. Matrix Biol 32(6):316–324
Li SS et al (2002) T lymphocyte expression of thrombospondin-1 and adhesion to extracellular matrix components. Eur J Immunol 32(4):1069–1079
Kudo-Saito C et al (2009) Cancer metastasis is accelerated through immunosuppression during snail-induced EMT of cancer cells. Cancer Cell 15(3):195–206
Li Y et al (2013) Thrombospondin 1 activates the macrophage toll-like receptor 4 pathway. Cell Mol Immunol 10(6):506–512
Martin-Manso G et al (2008) Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells. Cancer Res 68(17):7090–7099
Kirsch T et al (2010) Endothelial-derived thrombospondin-1 promotes macrophage recruitment and apoptotic cell clearance. J Cell Mol Med 14(7):1922–1934
Pierson BA et al (1996) Human natural killer cell expansion is regulated by thrombospondin-mediated activation of transforming growth factor-beta 1 and independent accessory cell-derived contact and soluble factors. Blood 87(1):180–189
Van VQ et al (2006) Expression of the self-marker CD47 on dendritic cells governs their trafficking to secondary lymphoid organs. EMBO J 25(23):5560–5568
Doyen V et al (2003) Thrombospondin 1 is an autocrine negative regulator of human dendritic cell activation. J Exp Med 198(8):1277–1283
Bandyopadhyay G et al (2014) Elevated postinjury thrombospondin 1-CD47 triggering aids differentiation of patients' defective inflammatory CD1a+dendritic cells. J Leukoc Biol 96(5):797–807
Weng TY et al (2014) A novel cancer therapeutic using thrombospondin 1 in dendritic cells. Mol Ther 22(2):292–302
Adams JC, Lawler J (2011) The thrombospondins. Cold Spring Harb Perspect Biol 3(10):a009712
Adams JC, Tucker RP (2000) The thrombospondin type 1 repeat (TSR) superfamily: diverse proteins with related roles in neuronal development. Dev Dyn 218(2):280–299
Tolsma SS et al (1993) Peptides derived from two separate domains of the matrix protein thrombospondin-1 have anti-angiogenic activity. J Cell Biol 122(2):497–511
Guo NH et al (1997) Antiproliferative and antitumor activities of D-reverse peptides derived from the second type-1 repeat of thrombospondin-1. J Pept Res 50(3):210–221
Iruela-Arispe ML et al (1999) Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats. Circulation 100(13):1423–1431
Mikhailenko I et al (1997) Cellular internalization and degradation of thrombospondin-1 is mediated by the amino-terminal heparin binding domain (HBD). High affinity interaction of dimeric HBD with the low density lipoprotein receptor-related protein. J Biol Chem 272(10):6784–6791
Wang S et al (2004) Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans. J Cell Biochem 91(4):766–776
Roberts DD et al (1985) The platelet glycoprotein thrombospondin binds specifically to sulfated glycolipids. J Biol Chem 260(16):9405–9411
Roberts DD, Sherwood JA, Ginsburg V (1987) Platelet thrombospondin mediates attachment and spreading of human melanoma cells. J Cell Biol 104(1):131–139
Roberts DD (1988) Interactions of thrombospondin with sulfated glycolipids and proteoglycans of human melanoma cells. Cancer Res 48(23):6785–6793
Jimenez B et al (2001) C-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1. Oncogene 20(26):3443–3448
Jimenez B et al (2000) Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 6(1):41–48
Yehualaeshet T et al (1999) Activation of rat alveolar macrophage-derived latent transforming growth factor beta-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol 155(3):841–851
Leung LL (1984) Role of thrombospondin in platelet aggregation. J Clin Invest 74(5):1764–1772
Silverstein RL et al (1992) Sense and antisense cDNA transfection of CD36 (glycoprotein IV) in melanoma cells. Role of CD36 as a thrombospondin receptor. J Biol Chem 267(23):16607–16612
Volpert OV et al (2002) Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Nat Med 8(4):349–357
Chen H, Herndon ME, Lawler J (2000) The cell biology of thrombospondin-1. Matrix Biol 19(7):597–614
Zheng B, Clemmons DR (1998) Blocking ligand occupancy of the alphaVbeta3 integrin inhibits insulin-like growth factor I signaling in vascular smooth muscle cells. Proc Natl Acad Sci U S A 95(19):11217–11222
Neugebauer KM et al (1991) Vitronectin and thrombospondin promote retinal neurite outgrowth: developmental regulation and role of integrins. Neuron 6(3):345–358
Stern M, Savill J, Haslett C (1996) Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis. Mediation by alpha v beta 3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am J Pathol 149(3):911–921
Kosfeld MD, Frazier WA (1992) Identification of active peptide sequences in the carboxyl-terminal cell binding domain of human thrombospondin-1. J Biol Chem 267(23):16230–16236
Kosfeld MD, Frazier WA (1993) Identification of a new cell adhesion motif in two homologous peptides from the COOH-terminal cell binding domain of human thrombospondin. J Biol Chem 268(12):8808–8814
Gao AG, Frazier WA (1994) Identification of a receptor candidate for the carboxyl-terminal cell binding domain of thrombospondins. J Biol Chem 269(47):29650–29657
Moralez AM et al (2005) Insulin-like growth factor binding protein-5 (IGFBP-5) interacts with thrombospondin-1 to induce negative regulatory effects on IGF-I actions. J Cell Physiol 203(2):328–334
Chung J, Gao AG, Frazier WA (1997) Thrombospondin acts via integrin-associated protein to activate the platelet integrin alphaIIbbeta3. J Biol Chem 272(23):14740–14746
Wang XQ, Lindberg FP, Frazier WA (1999) Integrin-associated protein stimulates alpha2beta1-dependent chemotaxis via Gi-mediated inhibition of adenylate cyclase and extracellular-regulated kinases. J Cell Biol 147(2):389–400
Lamy L et al (2007) Interactions between CD47 and thrombospondin reduce inflammation. J Immunol 178(9):5930–5939
Yabkowitz R, Dixit VM (1991) Human carcinoma cells bind thrombospondin through a Mr 80,000/105,000 receptor. Cancer Res 51(14):3648–3656
Vogel T et al (1993) Modulation of endothelial cell proliferation, adhesion, and motility by recombinant heparin-binding domain and synthetic peptides from the type I repeats of thrombospondin. J Cell Biochem 53(1):74–84
Sipes JM et al (1999) Cooperation between thrombospondin-1 type 1 repeat peptides and alpha(v)beta(3) integrin ligands to promote melanoma cell spreading and focal adhesion kinase phosphorylation. J Biol Chem 274(32):22755–22762
Short SM et al (2005) Inhibition of endothelial cell migration by thrombospondin-1 type-1 repeats is mediated by beta1 integrins. J Cell Biol 168(4):643–653
Bagavandoss P, Wilks JW (1990) Specific inhibition of endothelial cell proliferation by thrombospondin. Biochem Biophys Res Commun 170(2):867–872
Cursiefen C et al (2011) Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med 208(5):1083–1092
Sheibani N, Newman PJ, Frazier WA (1997) Thrombospondin-1, a natural inhibitor of angiogenesis, regulates platelet-endothelial cell adhesion molecule-1 expression and endothelial cell morphogenesis. Mol Biol Cell 8(7):1329–1341
Bougnaud S et al (2016) Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma. Oncotarget 7(22):31955–31971
Isenberg JS et al (2005) Thrombospondin-1 inhibits endothelial cell responses to nitric oxide in a cGMP-dependent manner. Proc Natl Acad Sci U S A 102(37):13141–13146
Isenberg JS et al (2008) Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling. Blood 111(2):613–623
Isenberg JS, Wink DA, Roberts DD (2006) Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses. Cardiovasc Res 71(4):785–793
Isenberg JS et al (2006) CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1. J Biol Chem 281(36):26069–26080
Isenberg JS et al (2009) Thrombospondin-1 and CD47 regulate blood pressure and cardiac responses to vasoactive stress. Matrix Biol 28(2):110–119
Zhang X et al (2007) Continuous administration of the three thrombospondin-1 type 1 repeats recombinant protein improves the potency of therapy in an orthotopic human pancreatic cancer model. Cancer Lett 247(1):143–149
Isenberg JS et al (2008) Thrombospondin 1 and vasoactive agents indirectly alter tumor blood flow. Neoplasia 10(8):886–896
Csanyi G et al (2012) Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1. Arterioscler Thromb Vasc Biol 32(12):2966–2973
Ribeiro SM et al (1999) The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem 274(19):13586–13593
Schultz-Cherry S et al (1995) Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1. J Biol Chem 270(13):7304–7310
Young GD, Murphy-Ullrich JE (2004) Molecular interactions that confer latency to transforming growth factor-beta. J Biol Chem 279(36):38032–38039
Daubon T et al (2019) Deciphering the complex role of thrombospondin-1 in glioblastoma development. Nat Commun 10(1):1146
Guo N et al (1998) Differential roles of protein kinase C and pertussis toxin-sensitive G-binding proteins in modulation of melanoma cell proliferation and motility by thrombospondin 1. Cancer Res 58(14):3154–3162
Takahashi K et al (2012) Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc Natl Acad Sci U S A 109(6):1985–1990
Lawler J et al (2001) Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice. Am J Pathol 159(5):1949–1956
Fontana A et al (2005) Human breast tumors override the antiangiogenic effect of stromal thrombospondin-1 in vivo. Int J Cancer 116(5):686–691
Yee KO et al (2009) The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat 114(1):85–96
Riser BL et al (1989) Monocyte killing of human squamous epithelial cells: role for thrombospondin. Cancer Res 49(21):6123–6129
Hawighorst T et al (2002) Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice. Oncogene 21(52):7945–7956
Streit M et al (2002) Systemic inhibition of tumor growth and angiogenesis by thrombospondin-2 using cell-based antiangiogenic gene therapy. Cancer Res 62(7):2004–2012
Noh YH et al (2003) An N-terminal 80 kDa recombinant fragment of human thrombospondin-2 inhibits vascular endothelial growth factor induced endothelial cell migration in vitro and tumor growth and angiogenesis in vivo. J Invest Dermatol 121(6):1536–1543
Rodriguez-Manzaneque JC et al (2001) Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A 98(22):12485–12490
Hamano Y et al (2004) Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 64(5):1570–1574
Geranmayeh MH, Rahbarghazi R, Farhoudi M (2019) Targeting pericytes for neurovascular regeneration. Cell Commun Signal 17(1):26
Seymour K et al (2010) Differential effect of nitric oxide on thrombospondin-1-, PDGF- and fibronectin-induced migration of vascular smooth muscle cells. Am J Surg 200(5):615–619
Scheef EA, Sorenson CM, Sheibani N (2009) Attenuation of proliferation and migration of retinal pericytes in the absence of thrombospondin-1. Am J Physiol Cell Physiol 296(4):C724–C734
Birbrair A et al (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307(1):C25–C38
Kalas W et al (2005) Oncogenes and angiogenesis: down-regulation of thrombospondin-1 in normal fibroblasts exposed to factors from cancer cells harboring mutant ras. Cancer Res 65(19):8878–8886
Volpert OV, Dameron KM, Bouck N (1997) Sequential development of an angiogenic phenotype by human fibroblasts progressing to tumorigenicity. Oncogene 14(12):1495–1502
Gautam A et al (2002) Aerosol delivery of PEI-p53 complexes inhibits B16-F10 lung metastases through regulation of angiogenesis. Cancer Gene Ther 9(1):28–36
Giuriato S et al (2006) Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc Natl Acad Sci U S A 103(44):16266–16271
Isenberg JS et al (2009) Regulation of nitric oxide signalling by thrombospondin 1: implications for anti-angiogenic therapies. Nat Rev Cancer 9(3):182–194
Wang S et al (2016) Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. Sci Transl Med 8(329):329ra34
Tuszynski GP et al (1989) The GPIIB-IIIa-like complex may function as a human melanoma cell adhesion receptor for thrombospondin. Exp Cell Res 182(2):473–481
Tuszynski GP et al (1987) Thrombospondin, a potentiator of tumor cell metastasis. Cancer Res 47(15):4130–4133
Murphy-Ullrich JE, Mosher DF (1987) Interactions of thrombospondin with endothelial cells: receptor-mediated binding and degradation. J Cell Biol 105(4):1603–1611
Lawler J, Weinstein R, Hynes RO (1988) Cell attachment to thrombospondin: the role of ARG-GLY-ASP, calcium, and integrin receptors. J Cell Biol 107(6 Pt 1):2351–2361
Tuszynski GP et al (1993) Identification and characterization of a tumor cell receptor for CSVTCG, a thrombospondin adhesive domain. J Cell Biol 120(2):513–521
Albo D, Shinohara T, Tuszynski GP (2002) Up-regulation of matrix metalloproteinase 9 by thrombospondin 1 in gastric cancer. J Surg Res 108(1):51–60
Giehl K, Graness A, Goppelt-Struebe M (2008) The small GTPase Rac-1 is a regulator of mesangial cell morphology and thrombospondin-1 expression. Am J Physiol Renal Physiol 294(2):F407–F413
Wang TN et al (1996) Thrombospondin-1 (TSP-1) promotes the invasive properties of human breast cancer. J Surg Res 63(1):39–43
Wang TN et al (1996) Inhibition of breast cancer progression by an antibody to a thrombospondin-1 receptor. Surgery 120(2):449–454
Qian X et al (1997) Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in endothelial cells. Exp Cell Res 235(2):403–412
Arnoletti JP et al (1995) Thrombospondin and transforming growth factor-beta 1 increase expression of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in human MDA-MB-231 breast cancer cells. Cancer 76(6):998–1005
Albo D et al (1999) Thrombospondin-1 and transforming growth factor beta-1 upregulate plasminogen activator inhibitor type 1 in pancreatic cancer. J Gastrointest Surg 3(4):411–417
Albo D et al (1997) Thrombospondin-1 and transforming growth factor-beta l promote breast tumor cell invasion through up-regulation of the plasminogen/plasmin system. Surgery 122(2):493–499; discussion 499–500
Guo NH et al (1992) Heparin- and sulfatide-binding peptides from the type I repeats of human thrombospondin promote melanoma cell adhesion. Proc Natl Acad Sci U S A 89(7):3040–3044
Taraboletti G, Roberts DD, Liotta LA (1987) Thrombospondin-induced tumor cell migration: haptotaxis and chemotaxis are mediated by different molecular domains. J Cell Biol 105(5):2409–2415
Xing T et al (2017) Thrombospondin-1 production regulates the inflammatory cytokine secretion in THP-1 cells through NF-kappaB signaling pathway. Inflammation 40(5):1606–1621
Pettersen RD et al (1999) CD47 signals T cell death. J Immunol 162(12):7031–7040
Mateo V et al (1999) CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia. Nat Med 5(11):1277–1284
Lamy L et al (2003) CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis. J Biol Chem 278(26):23915–23921
Grimbert P et al (2006) Thrombospondin/CD47 interaction: a pathway to generate regulatory T cells from human CD4+ CD25- T cells in response to inflammation. J Immunol 177(6):3534–3541
Fang LL et al (2015) Thrombospondin 1 modulates monocyte properties to suppress intestinal mucosal inflammation. J Innate Immun 7(6):601–611
Lopez-Dee ZP et al (2015) Thrombospondin-1 in a murine model of colorectal carcinogenesis. PLoS One 10(10):e0139918
Peinado H et al (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17(5):302–317
Liu Y, Cao X (2016) Characteristics and significance of the pre-metastatic niche. Cancer Cell 30(5):668–681
Kang SA et al (2015) Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis. Mol Ther 23(6):1044–1054
Wan L, Pantel K, Kang Y (2013) Tumor metastasis: moving new biological insights into the clinic. Nat Med 19:1450
Rofstad EK, Graff BA (2001) Thrombospondin-1-mediated metastasis suppression by the primary tumor in human melanoma xenografts. J Invest Dermatol 117(5):1042–1049
Catena R et al (2013) Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1. Cancer Discov 3(5):578–589
El Rayes T et al (2015) Lung inflammation promotes metastasis through neutrophil protease-mediated degradation of tsp-1. Proc Natl Acad Sci U S A 112(52):16000–16005
Aguirre-Ghiso JA, Sosa MS (2018) Emerging topics on disseminated cancer cell dormancy and the paradigm of metastasis. Annual Review of Cancer Biology 2(1):377–393
Ghajar CM et al (2013) The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 15(7):807–817
Armant M et al (1999) CD47 ligation selectively downregulates human interleukin 12 production. J Exp Med 190(8):1175–1182
Stein EV et al (2016) Secreted Thrombospondin-1 regulates macrophage interleukin-1beta production and activation through CD47. Sci Rep 6:19684
Zhao Y et al (2014) Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury. Mucosal Immunol 7(2):440–448
Csanyi G et al (2017) CD47 and Nox1 mediate dynamic fluid-phase macropinocytosis of native LDL. Antioxid Redox Signal 26(16):886–901
Lawler J et al (1998) Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 101(5):982–992
Li Y et al (2011) Thrombospondin1 deficiency reduces obesity-associated inflammation and improves insulin sensitivity in a diet-induced obese mouse model. PLoS One 6(10):e26656
Futagami Y et al (2007) Role of thrombospondin-1 in T cell response to ocular pigment epithelial cells. J Immunol 178(11):6994–7005
Crawford SE et al (1998) Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93(7):1159–1170
Mir FA, Contreras-Ruiz L, Masli S (2015) Thrombospondin-1-dependent immune regulation by transforming growth factor-beta2-exposed antigen-presenting cells. Immunology 146(4):547–556
Molckovsky A, Siu LL (2008) First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American Society of Clinical Oncology meeting. J Hematol Oncol 1(1):20
Kang SY et al (2009) Prosaposin inhibits tumor metastasis via paracrine and endocrine stimulation of stromal p53 and tsp-1. Proc Natl Acad Sci U S A 106(29):12115–12120
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Ramchandani, D., Mittal, V. (2020). Thrombospondin in Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment . Advances in Experimental Medicine and Biology, vol 1272. Springer, Cham. https://doi.org/10.1007/978-3-030-48457-6_8
Download citation
DOI: https://doi.org/10.1007/978-3-030-48457-6_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-48456-9
Online ISBN: 978-3-030-48457-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)