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.
Highlights
Multiple chemotherapies for the treatment of pancreatic cancer have been evaluated, the 5-year survival rate of pancreatic cancer patients is still only 7% [1]
The presented in vivo data demonstrate that gemcitabine inhibits cancer cell proliferation primarily in cancer cells that are situated distant to the desmoplastic reaction in a more central position of cyst like carcinomas (Figure 3)
The function of the desmoplastic reaction is described as barrier, which blocks access of gemcitabine to cancer cells and thereby causes resistance to this drug [13,14,15]
Summary
Multiple chemotherapies for the treatment of pancreatic cancer have been evaluated, the 5-year survival rate of pancreatic cancer patients is still only 7% [1]. For the treatment of advanced or metastatic pancreatic cancer gemcitabine in combination with nab-paclitaxel or a combination known as FOLFIRINOX (5-fluoruracil, leucovorin, oxaliplatin, irinotecan) can be used [3, 4]. The benefit of metformin, a traditional diabetes type II medication, has been evaluated in clinical studies. These studies demonstrated that metformin at a low dose typical for glycemic control is unlikely to benefit patients with pancreatic cancer when used in combination with traditional cytostatic agents [7, 8]. A subgroup of patients with high metformin concentration (> 1 mg/L) in the blood seemed to have an improved survival [7]
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