Atorvastatin (Lipitor) attenuates the effects of aspirin on pancreatic cancerogenesis and the chemotherapeutic efficacy of gemcitabine on pancreatic cancer by promoting M2 polarized tumor associated macrophages

Abstract

BackgroundInteractions of inflammatory cells with pancreatic cancer cells play crucial roles in pancreatic cancer, however the dynamic changes of inflammatory cell populations in pancreatic cancerogensis and after chemotherapy have not been well eclucidated. The combinational use of aspirin and atrovastatin (Lipitor) have been widely prescribled for cardio-cerebral vascular diseases mainly by regulation of inflammations, and they have been also reported to have plausible anti-tumor effects, however their potential roles in pancreatic cancerogenesis and chemotherapeutic effects have been seldom investigated. We scanned the dynamic changes of pan-inflammatory cell populations in pancreatic cancerogensis and after chemotherapy and found the potential target cell populations. Then we tested the roles of aspirin and Lipitor to regulate these inflammatory cell populations and their effects on pancreatic cancerogenesis and chemotherapeutic effects.MethodsCancerogen, dimethylbenzanthracene (DMBA), was used to induce pancreatic cancerogenesis and subcatunous implantation of syngenic murine Panc02 pancreatic cancer cells was adopted as well. Gemcitabine was used for chemotherapy. The peripheral blood, pancreatic lesions and tumor samples were harvested and analyzed to search for the potential target cell populations. The roles of aspirin and Lipitor to regulate these cell populations and their potential effects on pancreatic cancerogenesis and chemotherapeutic efficacy were investigated both in vitro and in vivo.ResultsWe found progressive accumulations of myeloid-derived suppressor cells (MDSC) and M2-polarzied tumor associated macrophages(M2) in pancreatic lesions accompanied with dynamic reducations of cytotoxic T cells(CTL) and helper T cells(Th) in the progression of pancreatic cancerogenesis. After gemcitabine treatment, the MDSC significantly reduced, however M2 soared up unexpectedly. Aspirin could significantly inhibit the MDSC and M2 to prevent pancreatic cancerogenesis and improve chemotherapeutic effects of gemcitabine, however Lipitor did not significantly affect MDSC, instead it could promote M2 to attenuate the postive effects of aspirin and gemcitabine.ConclusionsMDSC and M2 accumulate in progression of pancreatic cancerogenesis and gemcitabine can induce M2. Aspirin could prevent pancreatic cancerogenesis and improve efficacy of gemcitabine partially by inhibiting MDSC and M2, however when used in combination, Lipitor could weaken the efficacy of aspirin and gemcitabine partially by promoting M2.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0304-4) contains supplementary material, which is available to authorized users.

Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma

“…Our results showed that the expression of CCL18 level in pancreatic cancer was significantly higher than that in corresponding normal pancreatic tissues (Supplementary Figure S1A ). It was recently reported that pancreatic TAMs are primarily polarized M2 macrophages that are associated with cancer progression and metastasis 10 , 11 . Hence, we utilized an experimental model of monocyte-derived macrophage polarization as described in the Supplementary Methods 12 .…”

Statins and pancreatic cancer risk in patients with chronic pancreatitis: A Danish nationwide population‐based cohort study

“…Although our findings agree with a previous meta-analysis that found no association between statin use and pancreatic cancer risk in healthy individuals, 6 they contrast with the substantial experimental evidence suggesting that statins inhibit pancreatic carcinogenesis. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] An explanation for this discrepancy may be that poor lifestyle choice such as excessive alcohol consumption, tobacco smoking or a high level of comorbidity, which is frequently seen in chronic pancreatitis patients, 40,41 may mitigate any potentially beneficial effect of statins. Furthermore, the potential anticancer effect of statins may differ according to statin solubility (i.e., lipophilic or hydrophilic), 42 which our study was not large enough to examine.…”

“…5 Furthermore, experimental studies suggest that statins can decrease pancreatic cancer risk by interfering with vital intracellular signaling pathways. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] A recently published Danish case-cohort study of approximately 4,800 chronic pancreatitis patients suggested that statin use was associated with an 80% reduction in pancreatic cancer risk. 24 Although a compelling finding, the study reported a crude null finding and the beneficial effect of statins was only evident in a propensity-score matched analysis of 339 statin users (7% of the total population).…”

Statin use and mortality among ovarian cancer patients: A population‐based cohort study

“…Although caution should be exercised for these findings, one potential explanation could be that a potential prognostic effect of statins is attenuated when used in combination with low-dose aspirin. 33,34 Alternatively, the different effect of post-diagnostic statin use by use of low-dose aspirin may reflect differences in population characteristics as the majority of users of low-dose aspirin have cardiovascular disease or risk. 35 On the other hand, statin use among non-users of low-dose aspirin is predominantly prescribed for indications other than cardiovascular prophylaxis, and mainly hyperlipidaemia.…”