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

Oncogene volume 34, pages 2052–2060 (2015)Cite this article

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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.

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Acknowledgements

We are grateful to Dr Patrick C Swanson, Creighton University, Omaha, for suggestions. We appreciate the UNMC Cell Analysis Facility for analysis and graduate students and technician Erik Moore from Dr Batra’s lab for help in sample preparation. This work was supported in part by the grant from National Institute of Health (R01CA78590, EDRN U01 CA111294, R01 CA133774, R01 CA131944, SPORE P50 CA127297, T32 CA009476, P20 GM103480, R21 CA156037 and U54 TMEN CA163120).

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  1. S Kumar and M P Torres: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    S Kumar, M P Torres, S Kaur, S Rachagani, S Joshi, N Momi, M J Baine, M Jain & S K Batra

  2. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    M P Torres & S K Batra

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    S L Johansson

  4. Department of Biology, University of Nebraska at Omaha, Omaha, NE, USA

    C E Gilling

  5. Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA

    L M Smith

  6. Division of Pulmonary, Critical Care, Sleep & Allergy, University of Nebraska Medical Center, Omaha, NE, USA

    T A Wyatt

  7. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical center, Omaha, NE, USA

    M Jain & S K Batra

  8. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

    S S Joshi

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Kumar, S., Torres, M., Kaur, S. et al. Smoking accelerates pancreatic cancer progression by promoting differentiation of MDSCs and inducing HB-EGF expression in macrophages. Oncogene 34, 2052–2060 (2015). https://doi.org/10.1038/onc.2014.154

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