title: Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase.
abstract: Resistance to pharmacologic agents used in chemotherapy is common in most human carcinomas, including pancreatic ductal adenocarcinoma (PDA), which is resistant to almost all drugs, including gemcitabine, a nucleoside analog used as a first-line treatment. Poor survival rates of PDA patients have, therefore, not changed much over 4 decades. Recent data indicated that tumor-associated macrophages (TAMs), which are abundant in the microenvironment of several tumors, including PDA, secrete pro-tumorigenic factors that contribute to cancer progression and dissemination. In this study, we show for the first time that TAMs can also induce chemoresistance of PDA by reducing gemcitabine-induced apoptosis. Macrophages co-cultured with cancer cells or TAM-conditioned medium significantly reduced apoptosis and activation of the caspase-3 pathway during gemcitabine treatment. In vivo PDA models of mice, which have reduced macrophage recruitment and activation, demonstrated improved response to gemcitabine compared with controls. Similarly, inhibition of monocytes/macrophages trafficking by a CSF1-receptor antagonist GW2580 augmented the effect of gemcitabine in a transgenic mouse PDA model that was resistant to gemcitabine alone. Analysis of multiple proteins involved in gemcitabine delivery and metabolism revealed that TAMs induced upregulation of cytidine deaminase (CDA), the enzyme that metabolizes the drug following its transport into the cell. Decreasing CDA expression by PDA cells blocked the protective effect of TAMs against gemcitabine. These results provide the first evidence of a paracrine effect of TAMs, which mediates acquired resistance of cancer cells to chemotherapy. Modulation of macrophage trafficking or inhibition of CDA may offer a new strategy for augmenting the response of PDA to chemotherapy.
authors.affiliation: The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Weizman
authors.affiliation: The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Krelin
authors.affiliation: The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Shabtay-Orbach
authors.affiliation: 1] The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel [2] Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, The Technion Israel Institute of Technology, Haifa, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Amit
authors.affiliation: The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Binenbaum
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Wong
authors.affiliation: 1] The Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, Haifa, Israel [2] Department of Otolaryngology Head and Neck Surgery, Rambam Medical Center, The Technion Israel Institute of Technology, Haifa, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Gil
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine