Thbs2, also known as thrombospondin 2, is a secreted extracellular matrix protein. It plays crucial roles in various biological processes such as angiogenesis, tissue remodeling, and inflammation. It is involved in multiple signaling pathways, including the MAPK, Notch, Wnt/β -catenin, and PI3K/AKT pathways [1,4,5,6]. Genetic models, like KO/CKO mouse models, can be valuable in studying Thbs2's functions.

In pancreatic ductal adenocarcinoma (PDAC), RNA in situ hybridization in genetically engineered mouse models showed that cancer-associated fibroblasts (CAFs) expressed Thbs2, and its levels increased with disease progression. Cancer cell-secreted TGF-β1 activated CAFs to induce Thbs2 expression, which then bound to integrin αvβ3/CD36 in PDAC cells, activating the MAPK pathway to promote tumor growth [1]. In early-stage lung adenocarcinoma, THBS2+ CAFs identified by scRNA-seq promoted tumor aggressiveness. THBS2 was preferentially secreted via exosomes, suppressed ex vivo T cells proliferation, and promoted in vivo tumor growth and distant micro-metastasis [2]. In colorectal cancer, THBS2+ CAFs promoted oxaliplatin resistance by activating EMT through the COL8A1-mediated PI3K/AKT activation [3].

In conclusion, Thbs2 is involved in important biological processes and plays a significant role in multiple cancer types, such as PDAC, lung adenocarcinoma, and colorectal cancer. The use of mouse models has revealed its role in cancer-stroma interactions, tumor growth, metastasis, and drug resistance, providing insights into potential therapeutic strategies targeting Thbs2 in these diseases [1,2,3].

References:

1. Nan, Peng, Dong, Xiu, Bai, Xiaofeng, Sun, Yulin, Zhao, Xiaohang. 2021. Tumor-stroma TGF-β1-THBS2 feedback circuit drives pancreatic ductal adenocarcinoma progression via integrin αvβ3/CD36-mediated activation of the MAPK pathway. In Cancer letters, 528, 59-75. doi:10.1016/j.canlet.2021.12.025. https://pubmed.ncbi.nlm.nih.gov/34958892/

2. Yang, Haitang, Sun, Beibei, Fan, Liwen, Yang, Weiwei, Yao, Feng. 2022. Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. In Theranostics, 12, 3104-3130. doi:10.7150/thno.69590. https://pubmed.ncbi.nlm.nih.gov/35547750/

3. Zhou, Xing, Han, Jiashu, Zuo, Anning, Deng, Jinhai, Liu, Zaoqu. 2024. THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer. In Molecular cancer, 23, 282. doi:10.1186/s12943-024-02180-y. https://pubmed.ncbi.nlm.nih.gov/39732719/

4. Chang, Zhengyao, Gao, Yunhe, Chen, Peng, Chen, Lin, Xi, Hongqing. 2024. THBS2 promotes gastric cancer progression and stemness via the Notch signaling pathway. In American journal of cancer research, 14, 3433-3450. doi:10.62347/UXWK4038. https://pubmed.ncbi.nlm.nih.gov/39113869/

5. Liu, Yunze, Lv, Heng, Liu, Xin, Lin, Changwei, Zhang, Yi. 2024. The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization. In Journal of experimental & clinical cancer research : CR, 43, 195. doi:10.1186/s13046-024-03107-7. https://pubmed.ncbi.nlm.nih.gov/39020380/

6. Qu, Hong-Lan, Hasen, Gao-Wa, Hou, Yan-Yan, Zhang, Chun-Xia. 2022. THBS2 promotes cell migration and invasion in colorectal cancer via modulating Wnt/β-catenin signaling pathway. In The Kaohsiung journal of medical sciences, 38, 469-478. doi:10.1002/kjm2.12528. https://pubmed.ncbi.nlm.nih.gov/35315209/