Impact of Surgery-Induced Myeloid-derived Suppressor Cells and the NOX2/ROS Axis on Postoperative Survival in Human Pancreatic Cancer.

Preclinical studies imply that surgery triggers inflammation that may entail tumor outgrowth and metastasis. The potential impact of surgery-induced inflammation in human pancreatic cancer is insufficiently explored. This study included 17 patients with periampullary cancer [pancreatic ductal adenocarcinoma (PDAC) n = 14, ampullary carcinoma n = 2, cholangiocarcinoma n = 1] undergoing major pancreatic cancer surgery with curative intent. We analyzed the potential impact of preoperative and postoperative immune phenotypes and function on postoperative survival with >30 months follow-up. The surgery entailed prompt expansion of monocytic myeloid-derived suppressor cells (M-MDSC) that generated NOX2-derived reactive oxygen species (ROS). Strong induction of immunosuppressive M-MDSC after surgery predicted poor postoperative survival and coincided with reduced functionality of circulating natural killer (NK) cells. The negative impact of surgery-induced M-MDSC on survival remained significant in separate analysis of patients with PDAC. M-MDSC-like cells isolated from patients after surgery significantly suppressed NK cell function ex vivo, which was reversed by inhibition of NOX2-derived ROS. High NOX2 subunit expression within resected tumors from patients with PDAC correlated with poor survival whereas high expression of markers of cytotoxic cells associated with longer survival. The surgery-induced myeloid inflammation was recapitulated in vivo in a murine model of NK cell-dependent metastasis. Surgical stress thus induced systemic accumulation of M-MDSC-like cells and promoted metastasis of NK cell-sensitive tumor cells. Genetic or pharmacologic suppression of NOX2 reduced surgery-induced inflammation and distant metastasis in this model. We propose that NOX2-derived ROS generated by surgery-induced M-MDSC may be targeted for improved outcome after pancreatic cancer surgery. SIGNIFICANCE: Pancreatic cancer surgery triggered pronounced accumulation of NOX2+ myeloid-derived suppressor cells that inhibited NK cell function and negatively prognosticated postoperative patient survival. We propose the targeting of M-MDSC as a conceivable strategy to reduce postoperative immunosuppression in pancreatic cancer.

High expression of p62/SQSTM1 predicts shorter survival for patients with pancreatic cancer.

BACKGROUND: Accumulation of the signal adaptor protein p62 has been demonstrated in many forms of cancer, including pancreatic ductal adenocarcinoma (PDAC). Although data from experimental studies suggest that p62 accumulation accelerates the development of PDAC, the association between p62 protein expression and survival in PDAC patients is unclear. METHODS: Thirty-three tumor specimens from PDAC patients treated by primary surgery were obtained. Immunohistochemical expression of p62, microtubule-associated protein 1A/1B-light chain 3 (LC3), and nuclear factor-erythroid factor 2-related factor 2 (NRF2) in tumor tissue was examined for associations with clinicopathological characteristics and disease-specific survival (DSS). RESULTS: There was no association between p62 expression and any of the clinicopathological variables. However, high p62 protein expression in tumor cells was significantly associated with shorter DSS (7 months vs. 29 months, p = 0.017). The hazard ratio for death in patients with high p62 protein expression in tumor cells was 2.88 (95% confidence interval: 1.17-7.11, p = 0.022). In multivariable analysis, high p62 expression was an independent prognostic factor for shorter DSS (p = 0.020) when follow up time was more than 5 years. LC3 and NRF2 staining was not associated with survival or other clinicopathological parameters. CONCLUSION: Our results show that high p62 protein expression in tumor cells is associated with shorter survival following pancreatic tumor resection. This association supports a role for p62 as a prognostic marker in patients with PDAC treated by primary surgery.

Fractional uptake of circulating tumor cells into liver-lung compartments during curative resection of periampullary cancer.

Circulating tumor cells (CTCs) are able to predict outcome in patients with breast, colon and prostate cancer and appear to be promising biomarkers of pancreatic carcinoma. The aim of the present study was to demonstrate a statistically significant portal-arterial difference of CTCs during curative resection of periampullary cancer. A commercially available instrument (IsofluxR) was used to quantify blood content of CTC in 10 patients with periampullary cancer according to preoperative diagnostics. Portal and arterial blood samples (~8 ml each) were simultaneously collected intra-operatively following surgical dissection prior to division of the pancreas for tumor removal. Quantitative CTC analyses were performed according to standardized protocols for immune-magnetic enrichment of CTC. Flow cytometry was applied for qualitative evaluations of various CTC markers in 7 patients. There was a statistically significant difference in the number of CTCs collected in the portal blood [58±14 cells per 100 ml; mean ± standard error (SE)] vs. arterial blood [24±7 cells per 100 ml (SE), P<0.025]. A fractional uptake of ≥40% across liver and lung compartments of assumed malignant CTC was estimated to correspond to the appearance of ~410 tumor cells per minute during pancreatic resections based on estimated hepatic blood flow, measured tumor cell mass and tumor cell proliferation activity. Complications in the collection of portal blood were not observed. A significant uptake across liver or lung compartments of potentially malignant tumor CTCs from periampullary carcinoma may represent a model to capture, define and characterize cell clones with metastatic potential in liver and lung tissues following surgical resection.

Catechol-O-methyltransferase is dispensable for vascular protection by estradiol in mouse models of atherosclerosis and neointima formation.

Estradiol is converted to the biologically active metabolite 2-methoxyestradiol via the activity of the enzyme catechol-O-methyltransferase (COMT). Exogenous administration of both estradiol and 2-methoxyestradiol reduces experimental atherosclerosis and neointima formation, and COMT-dependent formation of 2-methoxyestradiol likely mediates the antimitogenic effect of estradiol on smooth muscle cells in vitro. This study evaluated whether 2-methoxyestradiol mediates the vasculoprotective actions of estradiol in vivo. Wild-type (WT) and COMT knockout (COMTKO) mice on an apolipoprotein E-deficient background were gonadectomized and treated with estradiol or placebo. Exogenous estradiol reduced atherosclerotic lesion formation in both females (WT, -78%; COMTKO, -82%) and males (WT, -48%; COMTKO, -53%) and was equally effective in both genotypes. We further evaluated how exogenous estradiol affected neointima formation after ligation of the carotid artery in ovariectomized female mice; estradiol reduced intimal hyperplasia to a similar extent in both WT (-80%) and COMTKO (-77%) mice. In ovarian-intact female COMTKO mice, atherosclerosis was decreased (-25%) compared with WT controls. In conclusion, the COMT enzyme is dispensable for vascular protection by exogenous estradiol in experimental atherosclerosis and neointima formation in vivo. Instead, COMT deficiency in virgin female mice with intact endogenous production of estradiol results in relative protection against atherosclerosis.