Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma

Joachim C. Mertens, Christian D. Fingas, John D. Christensen, Rory L. Smoot, Steven F. Bronk, Nathan W. Werneburg, Michael P. Gustafson, Allan B. Dietz, Lewis R. Roberts, Alphonse E. Sirica, Gregory J. Gores

Research output: Contribution to journalArticle

93 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)897-907
Number of pages11
JournalCancer research
Volume73
Issue number2
DOIs
StatePublished - Jan 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma'. Together they form a unique fingerprint.

  • Cite this

    Mertens, J. C., Fingas, C. D., Christensen, J. D., Smoot, R. L., Bronk, S. F., Werneburg, N. W., Gustafson, M. P., Dietz, A. B., Roberts, L. R., Sirica, A. E., & Gores, G. J. (2013). Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer research, 73(2), 897-907. https://doi.org/10.1158/0008-5472.CAN-12-2130