Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma

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

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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

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Cholangiocarcinoma
Therapeutic Uses
Neoplasms
Apoptosis
Cell Death
Fibroblasts
Tenascin
bcl-2-Associated X Protein
Hepatic Stellate Cells
Tumor Microenvironment
R Factors
Extracellular Matrix Proteins
Protein C
Cytochromes c
navitoclax
Cancer-Associated Fibroblasts
Small Interfering RNA
Mitochondria
Up-Regulation
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mertens, J. C., Fingas, C. D., Christensen, J. D., Smoot, R., Bronk, S. F., Werneburg, N. W., ... 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

Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. / Mertens, Joachim C.; Fingas, Christian D.; Christensen, John D.; Smoot, Rory; Bronk, Steven F.; Werneburg, Nathan W.; Gustafson, Michael; Dietz, Allan B; Roberts, Lewis Rowland; Sirica, Alphonse E.; Gores, Gregory James.

In: Cancer Research, Vol. 73, No. 2, 15.01.2013, p. 897-907.

Research output: Contribution to journalArticle

Mertens, JC, Fingas, CD, Christensen, JD, Smoot, R, Bronk, SF, Werneburg, NW, Gustafson, M, Dietz, AB, Roberts, LR, Sirica, AE & Gores, GJ 2013, 'Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma', Cancer Research, vol. 73, no. 2, pp. 897-907. https://doi.org/10.1158/0008-5472.CAN-12-2130
Mertens JC, Fingas CD, Christensen JD, Smoot R, Bronk SF, Werneburg NW et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Research. 2013 Jan 15;73(2):897-907. https://doi.org/10.1158/0008-5472.CAN-12-2130
Mertens, Joachim C. ; Fingas, Christian D. ; Christensen, John D. ; Smoot, Rory ; Bronk, Steven F. ; Werneburg, Nathan W. ; Gustafson, Michael ; Dietz, Allan B ; Roberts, Lewis Rowland ; Sirica, Alphonse E. ; Gores, Gregory James. / Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. In: Cancer Research. 2013 ; Vol. 73, No. 2. pp. 897-907.
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