Biochemistry & Analytical Biochemistry

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

Global Congress on Biochemistry, Glycomics & Amino Acids

December 08-09, 2016 San Antonio, USA

Uta Kossatz-Boehlert, Benita Wolf, Kanthrin Krieg, Christine Falk, Kai Breuhahn, Hildegard Keppeler, Tilo Biedermann, Evi Schmid, Stefan Warmann, Joerg Fuchs, Silvia Vetter, Dennis Thiele, Maike Nieser, Meltem Avci-Adali, Yulia Skokowa, Ludger Schols, Stefan Hauser, Marc Ringelhahn, Tetyana Yevsa

University Hospital Tuebingen, Germany
Hannover Medical School, Germany
University Hospital Heidelberg, Germany
University of Tuebingen, Germany
Technichal University of Munich, Germany
German Center for Neurodegenerative Diseases (DZNE), Germany
German Cancer Research Center (DKFZ), Germany

Posters & Accepted Abstracts: Biochem Anal Biochem

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 are found in 28-50% 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 the present 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 Interleukin 8, a chemokine which 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 Fig.1: Maintenance of stem cell characteristics by mCXCL1 (KC) via the activation of mTORC1 drives resistance of premalignant tumor-initiating cells. The mechanism induces a G1 arrest of tumor-initiating cells. mTORC1 blockade induces differentiation and sensitivity to doxorubicin.

Biography :

Email: uta.kossatz-boehlert@med.uni-tuebingen.de