title: Intratumoral heterogeneity of the therapeutical response to gemcitabine and metformin.
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.
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Zechner
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Bürtin
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Albert
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Xianbin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Kumstel
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Schönrogge
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Josefine
authors.initials: J
authors.lastname: Graffunder
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Hao-Yu
authors.initials: HY
authors.lastname: Shih
authors.affiliation: Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Radecke
authors.affiliation: Division of Gastroenterology, Department of Medicine II, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Jaster
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D058954:Pancreatic Stellate Cells; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001786:Blood Glucose; D003841:Deoxycytidine; D008687:Metformin; D000093542:Gemcitabine
keywords: chemotherapy; microenvironment; pH Blot; pancreatic adenocarcinoma; syngeneic orthotopic cancer model