{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThrombospondin‑2 (THBS2) has emerged as a promising secreted biomarker in various human diseases, particularly malignancies. Elevated plasma THBS2 levels have demonstrated potential for the early detection of pancreatic ductal adenocarcinoma, especially when combined with CA19‑9 to distinguish cancer from benign pancreatic disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Aberrant regulation of THBS2 is also associated with colorectal cancer progression and, through splicing‐altering polymorphisms, with lumbar disc herniation via impaired interactions with matrix metalloproteinases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In lung cancer, particularly adenocarcinoma and squamous cell carcinoma, THBS2 overexpression correlates with enhanced invasion and poor prognosis through mechanisms that involve integrin‑mediated signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " In head and neck as well as cervical and oral cavity cancers, dysregulation of THBS2—often mediated by microRNAs—has been linked to tumor invasion and adverse clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": " Moreover, studies in Ewing’s sarcoma and malignant mesothelioma underscore a tumor‐suppressive function for THBS2."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": " Recent clinical investigations have suggested that circulating THBS2 is a promising biomarker in non‑small‑cell lung cancer and heart failure, while genetic variants in THBS2 have been linked to metabolic and cardiovascular conditions, including type 2 diabetes mellitus."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Large‑scale genetic association studies of coronary heart disease provide additional context"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", and elevated THBS2 has also been implicated in promoting invasion in gastric cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In malignant pleural mesothelioma, increased THBS2 expression correlates with reduced overall survival"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", and early diagnostic utility has been demonstrated in non‑small‑cell lung cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In the prostate cancer microenvironment, stromal estrogen receptor signaling upregulates THBS2 to attenuate metastatic potential"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", and in salivary gland carcinomas, loss‐of‐heterozygosity in the THBS2 gene is associated with increased angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its biomarker role, THBS2 is a key regulator of angiogenesis, extracellular matrix remodeling, and cell‐matrix interactions. Experimental studies in human microvascular endothelial cells show that THBS2 inhibits endothelial cell proliferation and modulates angiogenic responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " Detailed structural analyses have defined the modular architecture of THBS2, highlighting its type III repeats and lectin‑like domain that mediate interactions with integrins such as α6β1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " THBS2 expression is further regulated by nitric oxide and reactive oxygen species, which influence its promoter activity and subsequent effects on angiogenic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " Its binding to fibroblast growth factor‑2 (FGF2) via conserved type III repeats can reduce FGF2 receptor interactions, thereby tempering pro‑angiogenic signals"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": ", and THBS2 has been shown to enhance Notch pathway activation through interactions with low‑density lipoprotein receptor–related protein‑1 (LRP1)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": " The delicate balance of THBS2 is further underscored in conditions like uterine fibroids, where altered expression contributes to fibrosis, and in calcific aortic valve disease, where its modulation may affect pathological angiogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its vascular and matrix‑modulating functions, THBS2 plays pivotal roles in cellular differentiation, migration, and tissue repair. Autocrine secretion of THBS2 in mesenchymal stem cells enhances chondrogenic differentiation through modulation of Notch and MAPK signaling pathways while attenuating hypertrophy during cartilage regeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Increased THBS2 expression in the human cerebral cortex relative to nonhuman primates suggests a contribution to synaptic organization and possibly cognitive evolution."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": " Moreover, in models of myocardial injury and in pancreatic tumor microenvironments, THBS2 modulates inflammation and extracellular matrix remodeling, thereby affecting tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": " Recent investigations in cervical cancer have revealed that microRNA‑mediated downregulation of THBS2 diminishes cell proliferation and autophagy, highlighting its therapeutic potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "39", "end_ref": "41"}]}, {"type": "t", "text": " In osteosarcoma, THBS2 promotes cell migration via activation of MMP‑9 signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "42"}]}, {"type": "t", "text": ", while studies in gastric cancer further implicate THBS2 in tumor invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "43"}]}, {"type": "t", "text": " Finally, emerging evidence in acute cardiac injury points to roles for THBS2 in myocyte survival and matrix integrity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "44"}]}, {"type": "t", "text": ", and circulating THBS2 is now under evaluation as a non‑invasive biomarker for advanced fibrosis in nonalcoholic fatty liver disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jungsun Kim, William R Bamlet, Ann L Oberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.aah5583"}], "href": "https://doi.org/10.1126/scitranslmed.aah5583"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28701476"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28701476"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xue Wang, Lei Zhang, Hui Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "THBS2 is a Potential Prognostic Biomarker in Colorectal Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep33366"}], "href": "https://doi.org/10.1038/srep33366"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27632935"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27632935"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yuichiro Hirose, Kazuhiro Chiba, Tatsuki Karasugi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2008.03.013"}], "href": "https://doi.org/10.1016/j.ajhg.2008.03.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18455130"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18455130"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Ju-Fang Liu, Chiang-Wen Lee, Ming-Horng Tsai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin 2 promotes tumor metastasis by inducing matrix metalloproteinase-13 production in lung cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Pharmacol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bcp.2018.07.024"}], "href": "https://doi.org/10.1016/j.bcp.2018.07.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30031810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30031810"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Tzu-Yang Weng, Chih-Yang Wang, Yu-Hsuan Hung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential Expression Pattern of THBS1 and THBS2 in Lung Cancer: Clinical Outcome and a Systematic-Analysis of Microarray Databases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0161007"}], "href": "https://doi.org/10.1371/journal.pone.0161007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27513329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27513329"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Maofeng Wang, Chia-Chia Chao, Po-Chun Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Pharmacol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bcp.2019.05.005"}], "href": "https://doi.org/10.1016/j.bcp.2019.05.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31075265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31075265"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Chia-Wei Hsu, Jau-Song Yu, Pei-Hua Peng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Secretome profiling of primary cells reveals that THBS2 is a salivary biomarker of oral cavity squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteome Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/pr500038k"}], "href": "https://doi.org/10.1021/pr500038k"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24708169"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24708169"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Y Nezu, K Hagiwara, Y Yamamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-135b, a key regulator of malignancy, is linked to poor prognosis in human myxoid liposarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2016.157"}], "href": "https://doi.org/10.1038/onc.2016.157"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27157622"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27157622"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Qinghong Zhou, Jinju Dong, Ruoyu Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-20a regulates cell proliferation, apoptosis and autophagy by targeting thrombospondin 2 in cervical cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pharmacol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejphar.2018.11.043"}], "href": "https://doi.org/10.1016/j.ejphar.2018.11.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30513279"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30513279"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Qinggang Tian, Yun Liu, Yuguo Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "THBS2 is a biomarker for AJCC stages and a strong prognostic indicator in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J BUON (2018)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30570855"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30570855"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Gary Potikyan, Rupert O V Savene, Julie M Gaulden, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-06-4140"}], "href": "https://doi.org/10.1158/0008-5472.CAN-06-4140"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17638877"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17638877"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Rob Noorlag, Petra van der Groep, Frank K J Leusink, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal metastasis and survival in oral cancer: Association with protein expression of SLPI, not with LCN2, TACSTD2, or THBS2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Head Neck (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hed.23716"}], "href": "https://doi.org/10.1002/hed.23716"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24764155"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24764155"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Hsuan-Yu Peng, Ming-Chu Chang, Chun-Mei Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin-2 is a Highly Specific Diagnostic Marker and is Associated with Prognosis in Pancreatic Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Surg Oncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1245/s10434-018-07109-6"}], "href": "https://doi.org/10.1245/s10434-018-07109-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30569296"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30569296"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Kimihiko Kato, Mitsutoshi Oguri, Noriyuki Kato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Assessment of genetic risk factors for thoracic aortic aneurysm in hypertensive patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hypertens (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ajh.2008.229"}], "href": "https://doi.org/10.1038/ajh.2008.229"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18600213"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18600213"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Werner Koch, Petra Hoppmann, Antoinette de Waha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in thrombospondin genes and myocardial infarction: a case-control study and a meta-analysis of available evidence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddn001"}], "href": "https://doi.org/10.1093/hmg/ddn001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18178577"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18178577"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Shinsuke Hanatani, Yasuhiro Izumiya, Seiji Takashio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circulating thrombospondin-2 reflects disease severity and predicts outcome of heart failure with reduced ejection fraction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1253/circj.cj-13-1221"}], "href": "https://doi.org/10.1253/circj.cj-13-1221"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24500070"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24500070"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Sachiyo Yamaguchi, Yoshiji Yamada, Hitoshi Matsuo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gender differences in the association of gene polymorphisms with type 2 diabetes mellitus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17334638"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17334638"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "J J McCarthy, A Parker, R Salem, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2003.016584"}], "href": "https://doi.org/10.1136/jmg.2003.016584"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15121769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15121769"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Chuanjun Zhuo, Xubin Li, Hongqing Zhuang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated THBS2, COL1A2, and SPP1 Expression Levels as Predictors of Gastric Cancer Prognosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000453184"}], "href": "https://doi.org/10.1159/000453184"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27997896"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27997896"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Ombretta Melaiu, Erika Melissari, Luciano Mutti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression status of candidate genes in mesothelioma tissues and cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mutat Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mrfmmm.2014.11.002"}], "href": "https://doi.org/10.1016/j.mrfmmm.2014.11.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25771974"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25771974"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Yi-Ming Jiang, Dan-Lu Yu, Guo-Xin Hou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum thrombospondin-2 is a candidate diagnosis biomarker for early non-small-cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biosci Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BSR20190476"}], "href": "https://doi.org/10.1042/BSR20190476"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31296790"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31296790"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Spencer Slavin, Chiuan-Ren Yeh, Jun Da, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Estrogen receptor α in cancer-associated fibroblasts suppresses prostate cancer invasion via modulation of thrombospondin 2 and matrix metalloproteinase 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgt488"}], "href": "https://doi.org/10.1093/carcin/bgt488"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24374826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24374826"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Munehiro Kishi, Mitsutoshi Nakamura, Masayoshi Nishimine, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of heterozygosity on chromosome 6q correlates with decreased thrombospondin-2 expression in human salivary gland carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1349-7006.2003.tb01478.x"}], "href": "https://doi.org/10.1111/j.1349-7006.2003.tb01478.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12824879"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12824879"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Lucas C Armstrong, Benny Björkblom, Kurt D Hankenson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin 2 inhibits microvascular endothelial cell proliferation by a caspase-independent mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e01-09-0066"}], "href": "https://doi.org/10.1091/mbc.e01-09-0066"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12058057"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12058057"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "C Britt Carlson, Douglas A Bernstein, Douglas S Annis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of the calcium-rich signature domain of human thrombospondin-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb997"}], "href": "https://doi.org/10.1038/nsmb997"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16186819"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16186819"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Maria J Calzada, John M Sipes, Henry C Krutzsch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Recognition of the N-terminal modules of thrombospondin-1 and thrombospondin-2 by alpha6beta1 integrin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M302014200"}], "href": "https://doi.org/10.1074/jbc.M302014200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12909644"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12909644"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Susan MacLauchlan, Jun Yu, Marcus Parrish, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1104357108"}], "href": "https://doi.org/10.1073/pnas.1104357108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21949402"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21949402"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Neuza Lopes, David Gregg, Sanjay Vasudevan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.23.15.5401-5408.2003"}], "href": "https://doi.org/10.1128/MCB.23.15.5401-5408.2003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12861025"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12861025"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Marco Rusnati, Patrizia Borsotti, Elisabetta Moroni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The calcium-binding type III repeats domain of thrombospondin-2 binds to fibroblast growth factor 2 (FGF2)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Angiogenesis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10456-018-9644-3"}], "href": "https://doi.org/10.1007/s10456-018-9644-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30168023"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30168023"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "He Meng, Xiaojie Zhang, Soo Jung Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.144634"}], "href": "https://doi.org/10.1074/jbc.M110.144634"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20472562"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20472562"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Anush Oganesian, Lucas C Armstrong, Mary M Migliorini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondins use the VLDL receptor and a nonapoptotic pathway to inhibit cell division in microvascular endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-07-0649"}], "href": "https://doi.org/10.1091/mbc.e07-07-0649"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18032585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18032585"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Virva Pohjolainen, Erja Mustonen, Panu Taskinen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased thrombospondin-2 in human fibrosclerotic and stenotic aortic valves."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Atherosclerosis (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.atherosclerosis.2011.10.003"}], "href": "https://doi.org/10.1016/j.atherosclerosis.2011.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22035575"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22035575"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Millie A Behera, Liping Feng, Bryan Yonish, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin-1 and thrombospondin-2 mRNA and TSP-1 and TSP-2 protein expression in uterine fibroids and correlation to the genes COL1A1 and COL3A1 and to the collagen cross-link hydroxyproline."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1933719107309591"}], "href": "https://doi.org/10.1177/1933719107309591"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18089612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18089612"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Sang Young Jeong, Dong Hyun Kim, Jueun Ha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin-2 secreted by human umbilical cord blood-derived mesenchymal stem cells promotes chondrogenic differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/stem.1471"}], "href": "https://doi.org/10.1002/stem.1471"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23843355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23843355"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Sang Young Jeong, Jueun Ha, Miyoung Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autocrine Action of Thrombospondin-2 Determines the Chondrogenic Differentiation Potential and Suppresses Hypertrophic Maturation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/stem.2120"}], "href": "https://doi.org/10.1002/stem.2120"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26235673"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26235673"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Mario Cáceres, Carolyn Suwyn, Marcelia Maddox, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased cortical expression of two synaptogenic thrombospondins in human brain evolution."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cereb Cortex (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cercor/bhl140"}], "href": "https://doi.org/10.1093/cercor/bhl140"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17182969"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17182969"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Anna-Pia Papageorgiou, Melissa Swinnen, Davy Vanhoutte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin-2 prevents cardiac injury and dysfunction in viral myocarditis through the activation of regulatory T-cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvs077"}], "href": "https://doi.org/10.1093/cvr/cvs077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22308237"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22308237"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Ahmed M Abu El-Asrar, Mohd I Nawaz, Mohammad S Ola, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of thrombospondin-2 as a marker in proliferative diabetic retinopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Ophthalmol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/aos.12035"}], "href": "https://doi.org/10.1111/aos.12035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23387388"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23387388"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "X-Y Sun, X-M Han, X-L Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-93-5p promotes cervical cancer progression by targeting THBS2/MMPS signal pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_201906_18175"}], "href": "https://doi.org/10.26355/eurrev_201906_18175"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31298364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31298364"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Chi-Ho Lee, Wai-Kay Seto, David Tak-Wai Lui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circulating Thrombospondin-2 as a Novel Fibrosis Biomarker of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes Care (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/dc21-0131"}], "href": "https://doi.org/10.2337/dc21-0131"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34183428"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34183428"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Takefumi Kimura, Naoki Tanaka, Naoyuki Fujimori, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Liver Int (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/liv.14776"}], "href": "https://doi.org/10.1111/liv.14776"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33386676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33386676"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Ju-Fang Liu, Po-Chun Chen, Tsung-Ming Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin-2 stimulates MMP-9 production and promotes osteosarcoma metastasis via the PLC, PKC, c-Src and NF-κB activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.15874"}], "href": "https://doi.org/10.1111/jcmm.15874"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33021341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33021341"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Ruochuan Sun, Jifeng Wu, Yuanyuan Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down regulation of Thrombospondin2 predicts poor prognosis in patients with gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1476-4598-13-225"}], "href": "https://doi.org/10.1186/1476-4598-13-225"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25262009"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25262009"}]}, {"type": "r", "ref": 44, "children": [{"type": "t", "text": "Po-Chun Chen, Chih-Hsin Tang, Liang-Wei Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hematol Oncol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13045-017-0390-6"}], "href": "https://doi.org/10.1186/s13045-017-0390-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28122633"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28122633"}]}, {"type": "r", "ref": 45, "children": [{"type": "t", "text": "Kazuhiro Kozumi, Takahiro Kodama, Hiroki Murai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptomics Identify Thrombospondin-2 as a Biomarker for NASH and Advanced Liver Fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep.31995"}], "href": "https://doi.org/10.1002/hep.31995"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34105780"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34105780"}]}]}]}