title: Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma.
abstract: Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are "activated" and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells but lacked similar effects in quiescent fibroblasts or cholangiocarcinoma cells. Unlike cholangiocarcinoma cells, neither CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAFs or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAFs appeared to be due, in part, to upregulation of the proapoptotic protein Bax. Short hairpin RNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors, and apoptotic cell death. In a syngeneic rat model of cholangiocarcinoma, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAFs in the tumor microenvironment as a general strategy to attack solid tumors.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Joachim C
authors.initials: JC
authors.lastname: Mertens
authors.forename: Christian D
authors.initials: CD
authors.lastname: Fingas
authors.forename: John D
authors.initials: JD
authors.lastname: Christensen
authors.forename: Rory L
authors.initials: RL
authors.lastname: Smoot
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bronk
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Werneburg
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gustafson
authors.forename: Allan B
authors.initials: AB
authors.lastname: Dietz
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.forename: Alphonse E
authors.initials: AE
authors.lastname: Sirica
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000166:cytology; D058628:Myofibroblasts / Q000187:drug effects*; D009362:Neoplasm Metastasis / Q000628:therapy; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C528561:navitoclax