Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages

Abstract

Smoking is an established risk factor for pancreatic cancer (PC), but late diagnosis limits the evaluation of its mechanistic role in the progression of PC. We used a well-established genetically engineered mouse model (LSL-K-rasG12D) of PC to elucidate the role of smoking during initiation and development of pancreatic intraepithelial neoplasia (PanIN). The 10-week-old floxed mice (K-rasG12D; Pdx-1cre) and their control unfloxed (LSL-K-rasG12D) littermates were exposed to cigarette smoke (total suspended particles: 150 mg/m3) for 20 weeks. Smoke exposure significantly accelerated the development of PanIN lesions in the floxed mice, which correlated with tenfold increase in the expression of cytokeratin19. The systemic accumulation of myeloid-derived suppressor cells (MDSCs) decreased significantly in floxed mice compared with unfloxed controls (P<0.01) after the smoke exposure with the concurrent increase in the macrophage (P<0.05) and dendritic cell (DCs) (P<0.01) population. Further, smoking-induced inflammation (IFN-γ, CXCL2; P<0.05) was accompanied by enhanced activation of pancreatic stellate cells and elevated levels of serum retinoic acid-binding protein 4, indicating increased bioavailability of retinoic acid which contributes to differentiation of MDSCs to tumor-associated macrophages (TAMs) and DCs. TAMs predominantly contribute to the increased expression of heparin-binding epidermal growth factor-like growth factor (EGFR ligand) in pre-neoplastic lesions in smoke-exposed floxed mice that facilitate acinar-to-ductal metaplasia (ADM). Further, smoke exposure also resulted in partial suppression of the immune system early during PC progression. Overall, the present study provides a novel mechanism of smoking-induced increase in ADM in the presence of constitutively active K-ras mutation.

Clinicopathological and prognostic significance of regulatory T cells in patients with non-small cell lung cancer: A systematic review with meta-analysis

“…The mechanism of this phenomenon is not yet clear. One possible explanation revealed that cigarette smoking could promote the mobilization and accumulation of (MDSCs) and increase the level of interferon-γ in TME [29]. Meanwhile, other studies demonstrated that MDSCs could induce Foxp3+ Tregs development and expansion via the production of cytokines, such as IFN-γ, or direct cell-cell interactions [30–32].…”

Bile acids‐mediated overexpression of MUC4 via FAK‐dependent c‐Jun activation in pancreatic cancer

“…PC cells were grown on sterilized cover slips for 24 h, serum starved for 8 h and treated with appropriate vehicle control (media, ethanol or DMSO), DCA, CDCA, and inhibitors for indicated time‐points. After the treatment, immunofluorescence staining with specific primary antibodies was performed as described previously (Kumar et al., 2015b). For immunohistofluorescence, we deparaffinized tissue sections with xylene, rehydrated with decreasing concentrations of ethanol and incubated tissues for 30 min with 3% H 2 O 2 : methanol solution.…”

Tobacco and alcohol as risk factors for pancreatic cancer

“…These studies revealed that that tobacco exerts dramatic effects in the pancreas. Thus, exposure of KC mice to cigarette smoke (for 20 weeks) enhances ADM formation and accelerates PanIN development in conjunction with decreased number of myeloid-derived suppressor cells (MDSCs) and an increase in the number of M2 macrophages and dendritic cells in the pancreas [37], underscoring the deleterious effects of cigarette smoke on the immune system in the pancreatic microenvironment that has already been compromised by the expression of oncogenic Kras .…”