Inducing differentiation of premalignant hepatic cells as a novel therapeutic strategy in hepatocarcinoma
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...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
3 August 2016
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| In: |
Cancer research
Year: 2016, Volume: 76, Issue: 18, Pages: 5550-5561 |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-15-3453 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1158/0008-5472.CAN-15-3453 Verlag, kostenfrei, Volltext: http://cancerres.aacrjournals.org/content/76/18/5550 
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| Author Notes: | 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 |
| Summary: | 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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| Item Description: | Gesehen am 21.12.2017 |
| Physical Description: | Online Resource |
| ISSN: | 1538-7445 |
| DOI: | 10.1158/0008-5472.CAN-15-3453 |