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The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma

Nature Reviews Gastroenterology & Hepatology volume 9, pages 44–54 (2012)Cite this article

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Abstract

Intrahepatic cholangiocarcinoma is typically characterized by a dense desmoplastic stroma, of which cancer-associated myofibroblasts (which express α-smooth muscle actin), are a major cellular component. These stromal myofibroblasts have a crucial role in accelerating the progression of intrahepatic cholangiocarcinoma and in promoting resistance to therapy through interactive autocrine and paracrine signaling pathways that promote malignant cell proliferation, migration, invasiveness, apoptosis resistance and/or epithelial–mesenchymal transition. These changes correlate with aggressive tumor behavior. Hypoxic desmoplasia and aberrant Hedgehog signaling between stromal myofibroblastic cells and cholangiocarcinoma cells are also critical modulators of intrahepatic cholangiocarcinoma progression and therapy resistance. A novel strategy has been developed to achieve improved therapeutic outcomes in patients with advanced intrahepatic cholangiocarcinoma, based on targeting of multiple interactive pathways between cancer-associated myofibroblasts and intrahepatic cholangiocarcinoma cells that are associated with disease progression and poor survival. Unique organotypic cell culture and orthotopic rat models of cholangiocarcinoma progression are well suited to the rapid preclinical testing of this potentially paradigm-shifting strategy.

Key Points

  • Increasing, albeit largely anecdotal, evidence indicates that the desmoplastic stroma has a prominent role in promoting intrahepatic cholangiocarcinoma (ICC) progression

  • Cancer-associated myofibroblasts, which express α-smooth muscle actin, mediate proliferation, migration, invasion, apoptosis resistance and epithelial–mesenchymal transition of ICC cells, through autocrine and paracrine signaling pathways

  • Hypoxia and aberrant Hedgehog signaling associated with interactions between tumor stromal myofibroblasts and cholangiocarcinoma cells probably act as important modulators of ICC progression and resistance to therapy

  • Targeting of both stromal and ICC cell components could translate into therapies for advanced ICC, which are likely to be more effective than single agents against carcinoma cells alone

  • Unique organotypic culture and orthotopic rat models of human ICC are being established to identify and test therapeutic strategies that target stromal cell–cancer cell interactions

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Figure 1: Photomicrograph of a typical tissue section of an experimentally induced intrahepatic cholangiocarcinoma in rat showing numerous stromal CAFs that express α-SMA (arrows).
Figure 2: Selected interactive molecular pathways that promote increased cholangiocarcinoma cell invasion, metastasis and apoptosis resistance.
Figure 3: Combined targeting of α-SMA+CAF and cholangiocarcinoma cell molecular pathways as a new strategy for ICC therapy.

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Acknowledgements

A. E. Sirica's research work is supported by NIH grants R01 CA 83650 and R01 CA 39225.

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  1. Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, 23298-0297, Virginia, VA, USA

    Alphonse E. Sirica

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Sirica, A. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 9, 44–54 (2012). https://doi.org/10.1038/nrgastro.2011.222

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