Hao-Xiang Tan1,2, Wei-Zhi Gong3, Kai Zhou4, Zhi-Gang Xiao1, Fu-Tao Hou1, Tao Huang1, Ling Zhang1, Hong-Yu Dong1, Wei-Lin Zhang1, Yu Liu1, Zhong-Cheng Huang1. 1. Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China. 2. Department of General Surgery, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, P.R.China. 3. Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China. 4. Department of Emergency, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, P.R.China.
Abstract
Background: Liver metastasis of colon cancer is strongly affected by the tumor microenvironment (TME), with interactions between tumor cells and cancer-associated fibroblasts (CAFs) in particular. TGF-β is well known for its ability to mediate the CAF phenotype, and CXCR4 expression is closely correlated to poor prognosis in CRC. The relationship between these two signaling pathways remains to be delineated in liver metastasis of colon cancer. Methods: Immunohistochemistry was employed to investigate CXCR4 expression in 45 human specimens of primary colorectal cancer (CRC) and liver metastasis. The functions of SDF-1 released by hepatic stellate cells (HSCs) on CXCR4 and TGF-β1 in CRC cells were investigated in vitro. The effects of CRC on HSCs differentiation into CAFs were confirmed using co-culture technology and expression analysis of CAFs markers by qPCR, western blot and immunofluorescence. The involvement of CXCR4 and TGF-β1 was verified with addition of CXCR4 inhibitor AMD3100 and TGF-β1 inhibitor cyclophosphamide (Cy) both in vitro and in vivo. Results: There were more CXCR4-positive cells at the liver metastatic tissues compared to the primary sites. CRC cells activated and transformed HSCs to CAFs after co-cultivating with HSCs. Activated HSCs stimulated TGF-β1 secretion from CRC cells after co-culture with CRC cells in vitro. Moreover, the expression of CAFs markers was increasing in the activated HSCs. In a mouse hepatic metastasis model, treated with AMD3100 or Cy blocked the metastatic potential of HCT116 cells and the hepatic CAFs differentiation.Conclusions: These results indicated that CXCR4/TGF-β1 axis plays an important role in CRC liver metastasis through mediating HSCs differentiation into CAFs, providing preclinical evidences that blockade of the axis might be beneficial for anti-metastasis therapy in CRC.
Background: Liver metastasis of colon cancer is strongly affected by the tumor microenvironment (TME), with interactions between tumor cells and cancer-associated fibroblasts (CAFs) in particular. TGF-β is well known for its ability to mediate the CAF phenotype, and CXCR4 expression is closely correlated to poor prognosis in CRC. The relationship between these two signaling pathways remains to be delineated in liver metastasis of colon cancer. Methods: Immunohistochemistry was employed to investigate CXCR4 expression in 45 human specimens of primary colorectal cancer (CRC) and liver metastasis. The functions of SDF-1 released by hepatic stellate cells (HSCs) on CXCR4 and TGF-β1 in CRC cells were investigated in vitro. The effects of CRC on HSCs differentiation into CAFs were confirmed using co-culture technology and expression analysis of CAFs markers by qPCR, western blot and immunofluorescence. The involvement of CXCR4 and TGF-β1 was verified with addition of CXCR4 inhibitor AMD3100 and TGF-β1 inhibitor cyclophosphamide (Cy) both in vitro and in vivo. Results: There were more CXCR4-positive cells at the liver metastatic tissues compared to the primary sites. CRC cells activated and transformed HSCs to CAFs after co-cultivating with HSCs. Activated HSCs stimulated TGF-β1 secretion from CRC cells after co-culture with CRC cells in vitro. Moreover, the expression of CAFs markers was increasing in the activated HSCs. In a mouse hepatic metastasis model, treated with AMD3100 or Cy blocked the metastatic potential of HCT116 cells and the hepatic CAFs differentiation.Conclusions: These results indicated that CXCR4/TGF-β1 axis plays an important role in CRCliver metastasis through mediating HSCs differentiation into CAFs, providing preclinical evidences that blockade of the axis might be beneficial for anti-metastasis therapy in CRC.
Authors: Yasushi Kojima; Ahmet Acar; Elinor Ng Eaton; Kieran T Mellody; Christina Scheel; Ittai Ben-Porath; Tamer T Onder; Zhigang C Wang; Andrea L Richardson; Robert A Weinberg; Akira Orimo Journal: Proc Natl Acad Sci U S A Date: 2010-11-01 Impact factor: 11.205
Authors: Mercedes Herrera; Abul B M M K Islam; Alberto Herrera; Paloma Martín; Vanesa García; Javier Silva; Jose M Garcia; Clara Salas; Ignacio Casal; Antonio García de Herreros; Félix Bonilla; Cristina Peña Journal: Clin Cancer Res Date: 2013-09-19 Impact factor: 12.531
Authors: Akira Orimo; Piyush B Gupta; Dennis C Sgroi; Fernando Arenzana-Seisdedos; Thierry Delaunay; Rizwan Naeem; Vincent J Carey; Andrea L Richardson; Robert A Weinberg Journal: Cell Date: 2005-05-06 Impact factor: 41.582
Authors: Mingfang Ao; Omar E Franco; Dean Park; Dayanidhi Raman; Karin Williams; Simon W Hayward Journal: Cancer Res Date: 2007-05-01 Impact factor: 12.701
Authors: Minna Allinen; Rameen Beroukhim; Li Cai; Cameron Brennan; Jaana Lahti-Domenici; Haiyan Huang; Dale Porter; Min Hu; Lynda Chin; Andrea Richardson; Stuart Schnitt; William R Sellers; Kornelia Polyak Journal: Cancer Cell Date: 2004-07 Impact factor: 31.743
Authors: Megan M Harper; Miranda Lin; Michael J Cavnar; Prakash K Pandalai; Reema A Patel; Mei Gao; Joseph Kim Journal: PLoS One Date: 2022-07-07 Impact factor: 3.752