title: Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-β pathways.
abstract: Fibroblasts are rich in the surrounding microenvironment of hepatocellular carcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role of cancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFs promote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone, brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFs secret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5 increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migration and invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh) pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-β (TGF-β) pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs on HCC metastasis and compromised the activation of Hh and TGF-β pathways in HCC cells. In summary, CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activation of Hh and TGF-β pathways in HCC cells.
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Bei-Fang
authors.initials: BF
authors.lastname: Ning
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200433, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Shen
authors.affiliation: The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Wansheng
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Electronic address: weifenxie@medmail.com.cn.
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China; Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Electronic address: zhang68@hotmail.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D054410:Chemokine CCL7 / Q000378:metabolism; D000075743:Chemokine CXCL16; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008297:Male; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D051116:Receptors, Scavenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: C111835:CCL2 protein, human; C483024:CCL5 protein, human; C515450:CCL7 protein, human; C423727:CXCL16 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054410:Chemokine CCL7; D000075743:Chemokine CXCL16; D018925:Chemokines; D019743:Chemokines, CXC; D053823:Hedgehog Proteins; D051116:Receptors, Scavenger; D016212:Transforming Growth Factor beta
keywords: Cancer-associated fibroblasts; Chemokines; Hedgehog pathway; Metastasis; TGF-β pathway