簡易檢索 / 詳目顯示

研究生: 林弦
Lin, Husan
論文名稱: 胰腺星形細胞釋出之CD248對胰臟癌細胞功能的影響
CD248 Released from Pancreatic Stellate Cells promotes the progression of Pancreatic Cancer
指導教授: 吳華林
Wu, Hua-Lin
學位類別: 碩士
Master
系所名稱: 醫學院 - 生物化學暨分子生物學研究所
Department of Biochemistry and Molecular Biology
論文出版年: 2020
畢業學年度: 108
語文別: 中文
論文頁數: 37
中文關鍵詞: 腫瘤內皮標誌一胰臟癌胰腺星形細胞
外文關鍵詞: CD248, pancreatic stellate cells, pancreatic cancer cells
相關次數: 點閱:87下載:5
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 腫瘤內皮標誌一(CD248)表現於纖維母細胞和周細胞,為第一型穿膜醣蛋白。先前的報導指出CD248會促進腫瘤的發展。胰腺星形細胞是胰臟中一種類纖維母細胞,在胰臟癌中扮演著重要角色。然而CD248是否參與胰腺星形細胞與胰臟癌細胞間的訊號溝通仍未明。由生物資訊得知CD248表現量較少的胰臟癌病患,有比較好的預後。我們還發現CD248表現於胰腺星形細胞而不是胰臟癌細胞。弱化CD248基因(CD248 Knockdown)後的纖維母細胞,其細胞培養液可以減少其促進惡性胰臟癌細胞增生與爬行的能力。直接給予重組CD248蛋白,會增強胰臟癌細胞的增生、爬行及侵襲的能力。此外我們發現重組CD248蛋白和血小板衍生生長因子受體β(Platelet-derived growth factor receptors beta,PDGFRβ)有交互作用,並且增強其下游的ERK的訊號傳遞。另外我們證明原位胰臟癌動物實驗中,給予重組CD248蛋白會增強胰臟癌細胞的轉移程度。總結我們認為腫瘤內皮標誌一蛋白會參與在胰腺星形細胞與胰臟癌細胞間的訊號溝通裡,抑制腫瘤內皮標誌一有助於減少胰臟癌的惡性轉移。

    Tumor endothelial marker 1 (TEM1), also called endosialin or CD248, is correlated with cancer-associated fibroblasts. Pancreatic stellate cells (PSCs), the fibroblast-like cells in the pancreas, are critical to tumor microenvironment, which stimulates local tumor growth and distant metastasis. Whether soluble CD248 participates in PSCs and pancreatic cancer cells is still elusive. Here we used MTT assay and transwell migration assay to observe the tumor biological functions of CD248. We showed that CD248 could promotes proliferation and migration via binding to Platelet-derived growth factor receptors beta (PDGFRβ). Moreover, intraperitoneal injection of rCD248 could enhance the growth and metastasis of pancreatic cancer in orthotopic pancreatic tumor mouse model. These results suggest that CD248 is essential for pancreatic cancer progression.

    中文摘要 I Abstract II 致謝 IV 目錄 V 介紹 P1 特定研究目標 P3 材料與方法 P4 實驗結果 P12 結論 P15 討論 P15 參考文獻 P18

    1. Christian, S., et al., Molecular cloning and characterization of endosialin, a C-type lectin-like cell surface receptor of tumor endothelium. J Biol Chem, 2001. 276(10): p. 7408-14.
    2. Rettig, W.J., et al., Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer. Proc Natl Acad Sci U S A, 1992. 89(22): p. 10832-6.
    3. Bagley, R.G., et al., Endosialin/TEM 1/CD248 is a pericyte marker of embryonic and tumor neovascularization. Microvasc Res, 2008. 76(3): p. 180-8.
    4. MacFadyen, J.R., et al., Endosialin (TEM1, CD248) is a marker of stromal fibroblasts and is not selectively expressed on tumour endothelium. FEBS Lett, 2005. 579(12): p. 2569-75.
    5. Rouleau, C., et al., Endosialin protein expression and therapeutic target potential in human solid tumors: sarcoma versus carcinoma. Clin Cancer Res, 2008. 14(22): p. 7223-36.
    6. Thway, K., et al., Endosialin expression in soft tissue sarcoma as a potential marker of undifferentiated mesenchymal cells. Br J Cancer, 2016. 115(4): p. 473-9.
    7. Maia, M., et al., CD248 facilitates tumor growth via its cytoplasmic domain. BMC Cancer, 2011. 11: p. 162.
    8. Tomkowicz, B., et al., Interaction of endosialin/TEM1 with extracellular matrix proteins mediates cell adhesion and migration. Proc Natl Acad Sci U S A, 2007. 104(46): p. 17965-70.
    9. Brady, J., et al., Human endosialin (tumor endothelial marker 1) is abundantly expressed in highly malignant and invasive brain tumors. J Neuropathol Exp Neurol, 2004. 63(12): p. 1274-83.
    10. Fujii, S., et al., TEM1 expression in cancer-associated fibroblasts is correlated with a poor prognosis in patients with gastric cancer. Cancer Med, 2015. 4(11): p. 1667-78.
    11. Nanda, A., et al., Tumor endothelial marker 1 (Tem1) functions in the growth and progression of abdominal tumors. Proc Natl Acad Sci U S A, 2006. 103(9): p. 3351-6.
    12. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA Cancer J Clin, 2016. 66(1): p. 7-30.
    13. Sohn, T.A., et al., Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg, 2000. 4(6): p. 567-79.
    14. Rahib, L., et al., Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res, 2014. 74(11): p. 2913-21.
    15. Pishvaian, M.J. and J.R. Brody, Therapeutic Implications of Molecular Subtyping for Pancreatic Cancer. Oncology (Williston Park), 2017. 31(3): p. 159-66, 168.
    16. Wood, L.D. and R.H. Hruban, Pathology and molecular genetics of pancreatic neoplasms. Cancer J, 2012. 18(6): p. 492-501.
    17. Erkan, M., et al., StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut, 2012. 61(2): p. 172-8.
    18. Bachem, M.G., et al., Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology, 2005. 128(4): p. 907-21.
    19. Masamune, A., et al., Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis. Clin Gastroenterol Hepatol, 2009. 7(11 Suppl): p. S48-54.
    20. Wang, H.C., et al., Pancreatic stellate cells activated by mutant KRAS-mediated PAI-1 upregulation foster pancreatic cancer progression via IL-8. Theranostics, 2019. 9(24): p. 7168-7183.
    21. Kikuta, K., et al., Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun, 2010. 403(3-4): p. 380-4.
    22. Apte, M.V. and J.S. Wilson, Stellate cell activation in alcoholic pancreatitis. Pancreas, 2003. 27(4): p. 316-20.
    23. Braganza, J.M., et al., Chronic pancreatitis. Lancet, 2011. 377(9772): p. 1184-97.
    24. Cheng, T.L., et al., Functions of rhomboid family protease RHBDL2 and thrombomodulin in wound healing. J Invest Dermatol, 2011. 131(12): p. 2486-94.
    25. Hong, Y.K., et al., Tumor Endothelial Marker 1 (TEM1/Endosialin/CD248) Enhances Wound Healing by Interacting with Platelet-Derived Growth Factor Receptors. J Invest Dermatol, 2019. 139(10): p. 2204-2214 e7.
    26. Tomkowicz, B., et al., Endosialin/TEM-1/CD248 regulates pericyte proliferation through PDGF receptor signaling. Cancer Biol Ther, 2010. 9(11): p. 908-15.
    27. Naylor, A.J., et al., A differential role for CD248 (Endosialin) in PDGF-mediated skeletal muscle angiogenesis. PLoS One, 2014. 9(9): p. e107146.
    28. Weissmueller, S., et al., Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling. Cell, 2014. 157(2): p. 382-394.
    29. Di Benedetto, P., et al., Blocking CD248 molecules in perivascular stromal cells of patients with systemic sclerosis strongly inhibits their differentiation toward myofibroblasts and proliferation: a new potential target for antifibrotic therapy. Arthritis Res Ther, 2018. 20(1): p. 223.
    30. Teicher, B.A., CD248: A therapeutic target in cancer and fibrotic diseases. Oncotarget, 2019. 10(9): p. 993-1009.
    31. Kiyohara, E., et al., Endosialin Expression in Metastatic Melanoma Tumor Microenvironment Vasculature: Potential Therapeutic Implications. Cancer Microenviron, 2015. 8(2): p. 111-8.

    下載圖示 校內:2022-02-02公開
    校外:2022-02-02公開
    QR CODE