American Association for Cancer Research
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Effects of doxorubicin and hCXCL8 on stem associated markers in hHCC cell lines from Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma

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posted on 2023-03-31, 00:13 authored by Benita Wolf, Kathrin Krieg, Christine Falk, Kai Breuhahn, Hildegard Keppeler, Tilo Biedermann, Evi Schmid, Steven Warmann, Joerg Fuchs, Silvia Vetter, Dennis Thiele, Maike Nieser, Meltem Avci-Adali, Yulia Skokowa, Ludger Schöls, Stefan Hauser, Marc Ringelhan, Tetyana Yevsa, Mathias Heikenwalder, Uta Kossatz-Boehlert

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German Research Foundation


Hofschneider foundation




Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related deaths and is reported to be resistant to chemotherapy caused by tumor-initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1–mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550–61. ©2016 AACR.

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