Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment
| Autor: | Bingji Li, Wei Yin, Ying-Hong Shi, Yuli Lin, Yan Song, Qian Cai, Haoyang Luo, Xuguang Yang, Wei-Ren Liu, Rui He, Meng-Xin Tian |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cancer Research Angiogenesis Lymphocyte Apoptosis Cholangiocarcinoma Mice 0302 clinical medicine Cell Movement Tumor Microenvironment Antigens Ly Gene knockdown ICC intrahepatic cholangiocarcinoma medicine.diagnostic_test Chemistry Serine Endopeptidases MVD microvessel density lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.anatomical_structure Gelatinases Gene Knockdown Techniques 030220 oncology & carcinogenesis Heterografts MDSCs myeloid derived suppression cells medicine.symptom EMT epithelial–mesenchymal transition STAT3 Transcription Factor Original article congenital hereditary and neonatal diseases and abnormalities lcsh:RC254-282 Flow cytometry 03 medical and health sciences Stroma Cell Line Tumor TAMs tumor-associated macrophages Endopeptidases medicine Animals Humans FAP fibroblast activation protein neoplasms Cell Proliferation Cell growth Myeloid-Derived Suppressor Cells Membrane Proteins Fibroblasts Fbs fibroblasts digestive system diseases Desmoplasia Disease Models Animal 030104 developmental biology Bile Duct Neoplasms Cancer research Tumor promotion CAFs cancer-associated fibroblasts |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 21, Iss 12, Pp 1133-1142 (2019) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| DOI: | 10.1016/j.neo.2019.10.005 |
| Popis: | Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAFs were the primary source of CCL2 in human ICC microenvironment by using ICC-Fbs from six ICC patients. Fibroblastic knockdown of FAP significantly impaired the ability of ICC-CAFs to promote ICC growth, MDSCs infiltration and angiogenesis, which was restored by adding exogenous CCL2. Furthermore, interestingly, the tumor-promoting effect of fibroblastic FAP is dependent on MDSCs via secretion of CCL2, as depletion of Gr-1+ cells reversed the restoring effects of exogenous CCL2 on tumor growth and angiogenesis. In vitro migration assay confirmed that exogenous CCL2 could rescue the impaired ability of ICC-Fbs to attract Gr-1+ cells caused by fibroblastic FAP knockdown. In contrast, fibroblastic FAP knockdown had no effect on ICC cell proliferation and apoptotic resistance. Depletion MDSCs by anti-Gr-1 monoclonal antibody in subcutaneous transplanted tumor model abrogated tumor promotion by ICC-CAFs suggested that the pro-tumor function of Fibroblastic FAP relied on MDSCs. Mechanical, flow cytometry and chamber migration assay were conducted to find Fibroblastic FAP was required by the ability of ICC-CAFs to promote MDSC migration directly. Moreover, fibroblastic FAP knockdown had no effect on cell proliferation and apoptotic resistance. Here, we revealed the T-cell independent mechanisms underlying the ICC-promoting effect of fibroblastic FAP by attracting MDSCs via CCL2, which was mainly attributed to the ability of FAP to attract MDSCs and suggests that specific targeting fibroblastic FAP may represent a promising therapeutic strategy against ICC. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|