CIGARETTE SMOKE EXPOSURE PROMOTES CANCER PROGRESSION THROUGH GUT MICROBIAL DYSBIOSIS
Prateek Sharma*, Tejeshwar Jain, Vrishketan Sethi, Saba Kurtom, Pooja Roy, Junyi Tao, Anthony ferrantella, Bhuwan Giri, Dujon B. Edwards, Beatriz Gomez, Sundaram Ramakrishnan, Rajinder Dawra, Ashok Saluja, Vikas Dudeja
Surgery, University of Miami - Jackson Memorial Hospital, Miami, FL
Introduction: Smoking is a major risk factor for many cancers. Cigarette smoke contains numerous carcinogenic compounds but the molecular mechanisms involved in cancer progression due to smoking are still being actively investigated. Smoking results in alteration of gut-microbiome and our recent studies have demonstrated the role of gut-microbiome in progression of cancer. In this study, we aim to delineate the role of smoking induced dysbiosis in cancer promotion.
Methods: 6-8 week old C57BL/6 mice were randomized to receive antibiotics (to sterilize the gut) or saline with or without concurrent cigarette smoke exposure (CSE). CSE was given through smoking chamber to achieve total suspended particulate concentration of 200-250 mg/m3. After pre-exposure of 4 weeks, mice were injected subcutaneously with a cancer cell line; KPC (pancreatic cancer cell line); MC38 (colon cancer cell line) or MB49 (bladder cancer cell line). The tumors were measured serially with ongoing CSE. These experiments were repeated in Rag1-/- mice, which lack adaptive immune response. In another experiment, smoking analogue Nicotine-derived nitrosamine ketone (NNK) was used to simulate smoke exposure. Two-month old genetically engineered KC mice (LSL-KrasG12D/+; Pdx-1-Cre) were randomized into four treatment arms (controls, NNK alone, antibiotics alone and NNK + antibiotics). Treatment was given for 2 months and animals were euthanized at 4 months age.
Results: Cigarette smoke exposure (CSE) significantly promoted tumor growth in all cancer cell lines. Depletion of gut-microbiome by antibiotics prevented smoke induced cancer progression. When compared to WT mice, CSE did not increase tumor growth and gut-microbiome depletion did not decrease tumor growth in Rag1-/- mice, suggesting that smoking induced gut-microbiome alteration promote tumor growth in an adaptive immune response dependent fashion. NNK-exposed KC mice had greater mean pancreatic weights than control group, which correlated with more foci of pancreatic intraepithelial neoplasia, invasive carcinoma in the NNK-exposed group. The ‘antibiotics alone’ and ‘NNK+ antibiotics’ groups had similar mean pancreatic weights, which were less than controls. Stool analysis showed significant enrichment of the Bacteriodetes phyla as well as the genera Clostridium and Parabacteriodes in the NNK alone group.
Conclusion: Our study provides novel insights into how smoking/smoking analogs and gut-microbiome interact to influence cancer progression. Smoke exposure facilitates tumor progression but disappearance of the tumor permissive effects in concomitant antibiotic-treated mice highlights the significant role played by the gut-microbiome in mediating these effects. Targeting this dysbiosis through selective antibiotics or probiotics could be harnessed as a potential strategy to neutralize the detrimental effects of smoking on cancer.
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