Inducing differentiation of premalignant hepatic cells as a novel therapeutic strategy in hepatocarcinoma

• Verfasst von: Wolf, Benita [VerfasserIn]
• Verfasst von: Breuhahn, Kai [VerfasserIn]
• Titel: Inducing differentiation of premalignant hepatic cells as a novel therapeutic strategy in hepatocarcinoma
• Verf.angabe: 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
• Umfang: 12 S.
• Fussnoten: Gesehen am 21.12.2017
• Titel Quelle: Enthalten in: Cancer research
• Jahr Quelle: 2016
• Band/Heft Quelle: 76(2016), 18, S. 5550-5561
• ISSN Quelle: 1538-7445
• DOI: doi:10.1158/0008-5472.CAN-15-3453
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1566636035

Abstract

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.