Intratumoral heterogeneity of the therapeutical response to gemcitabine and metformin
| Autor: | Maria Schönrogge, Dietmar Zechner, Tobias Radecke, Xianbin Zhang, Brigitte Vollmar, Hao Yu Shih, Florian Bürtin, Ann-Christin Albert, Josefine Graffunder, Robert Jaster, Simone Kumstel, Sarah Müller |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Blood Glucose Male endocrine system diseases medicine.medical_treatment chemotherapy Deoxycytidine Mice 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols Tumor Microenvironment Medicine Pancreatic Stellate Cells Hydrogen-Ion Concentration Cell Hypoxia Metformin Tumor Burden Oncology 030220 oncology & carcinogenesis Adenocarcinoma medicine.drug Research Paper medicine.medical_specialty 03 medical and health sciences Internal medicine Cell Line Tumor Carcinoma pancreatic adenocarcinoma Animals Humans Cell Proliferation Chemotherapy business.industry pH Blot Cancer medicine.disease microenvironment Xenograft Model Antitumor Assays Gemcitabine Coculture Techniques Mice Inbred C57BL Pancreatic Neoplasms 030104 developmental biology Endocrinology Drug Resistance Neoplasm Cancer cell Hepatic stellate cell Cancer research syngeneic orthotopic cancer model business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Dietmar Zechner 1, * , Florian Burtin 1, * , Ann-Christin Albert 1 , Xianbin Zhang 1 , Simone Kumstel 1 , Maria Schonrogge 1 , Josefine Graffunder 1 , Hao-Yu Shih 1 , Sarah Muller 2 , Tobias Radecke 1 , Robert Jaster 2 , Brigitte Vollmar 1 1 Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany 2 Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, 18057 Rostock, Germany * These authors contributed equally to this work Correspondence to: Dietmar Zechner, email: dietmar.zechner@uni-rostock.de Keywords: pancreatic adenocarcinoma, chemotherapy, syngeneic orthotopic cancer model, microenvironment, pH Blot Received: January 18, 2016 Accepted: July 18, 2016 Published: July 28, 2016 ABSTRACT Cancer heterogeneity and microenvironmental aspects within a tumor are considered key factors influencing resistance of carcinoma cells to distinct chemotherapeutical agents. We evaluated a high concentration of metformin in combination with gemcitabine on a syngeneic orthotopic mouse model using 6606PDA cells. We observed reduced tumor size and reduced cancer cell proliferation after three weeks of chemotherapy with either compound and noticed an additive effect between gemcitabine and metformin on tumor weight. Interestingly, distinct areas of the carcinoma responded differently to either compound. Metformin inhibited the proliferation of cancer cells close to the desmoplastic reaction, whereas gemcitabine inhibited the proliferation of cancer cells mainly 360–570 μm distant to the desmoplastic reaction. Indeed, co-culture of pancreatic stellate cells with 6606PDA, 7265PDA or MIA PaCa-2 cells increased gemcitabine resistance. Metformin resistance, however, was increased by high glucose concentration in the medium. Other factors such as hypoxia or the pH of the medium had no influence on gemcitabine or metformin induced inhibition of cancer cell proliferation. These data demonstrate a spatial heterogeneity in drug resistance within pancreatic adenocarcinomas and that microenvironmental aspects such as supply of glucose and the presence of pancreatic stellate cells regulate cancer cell sensitivity towards metformin or gemcitabine. |
| Databáze: | OpenAIRE |
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