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.

Nucleoside-catabolizing Enzymes in Mycoplasma-infected Tumor Cell Cultures Compromise the Cytostatic Activity of the Anticancer Drug Gemcitabine

“…The activity of such antitumor molecules could be counteracted by co-administration of THU (40). More recently, decreased chemosensitivity of pancreatic adenocarcinoma to gemcitabine was attributed to macrophage-induced up-regulation of Cyd deaminase (43,44) indicating the high relevance of Cyd deaminase expression in the tumor microenvironment. We confirmed pronounced mycoplasma-associated conversion of dFdC to dFdU when exposing the radiolabeled drug to the spent culture medium (containing free-living mycoplasmas) or tumor cell extracts (containing enzymes of adherent/ intracellular mycoplasmas) of mycoplasma-infected but not uninfected MCF-7 cells.…”

Pancreatic Cancer Fostered Immunosuppression Privileges Tumor Growth and Progression

“…M2 and M1 macrophages may concur in favoring PDAC progression and metastases, also because they induce EMT as well as metalloproteinase (MMP)2 and MMP9 proteolytic activity in PDAC cells [87,88]. As recently demonstrated, the adverse effects of M2 TAMs on PDAC prognosis also depend on their ability to induce in cancer cells the expression of cytidine deaminase involved in the metabolism of gemcitabine thus preventing apoptosis during gemcitabine treatment [89]. Informations on the molecular pathways underlying M2 polarization in PDAC are scarse.…”

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

“…96 In vitro, macrophage-induced CDA upregulation in human Panc-1 pancreatic tumor cell line has been shown to confer gemcitabine resistance. 111 Data from ample studies have indicated that CDA polymorphisms alter CDA enzyme activity and the pharmacokinetics of gemcitabine, [135][136][137][138] and three functional polymorphisms of CDA (rs2072671, CDA 79A  C; rs60369023, CDA 208G  A; and rs1048977, CDA 435C  T) could predict the clinical outcomes of gemcitabine-based tumor chemotherapy. 33,135,136 …”