Intestinal microbiota enhances pancreatic carcinogenesis in preclinical models
| Autor: | Mary K. Reinhard, Maria V. Guijarro, Steven J. Hughes, Anthony A. Fodor, Jillian L. Pope, Maria Zajac-Kaye, Christian Jobin, Raad Z. Gharaibeh, Rachel C. Newsome, Qin Yu, Kathryn Winglee, Jose G. Trevino, Ryan M. Thomas, Josee Gauthier, Mark Beveridge, Zhen He, Christina L. Ohland |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Cancer Research endocrine system diseases Carcinogenesis Transgene Mice Transgenic Mice SCID Biology medicine.disease_cause Mice 03 medical and health sciences Mice Inbred NOD Cell Line Tumor RNA Ribosomal 16S Pancreatic cancer medicine Animals Germ-Free Life Humans Colitis Pancreas Aged Innate immune system Bacteria Host Microbial Interactions General Medicine Middle Aged medicine.disease Xenograft Model Antitumor Assays digestive system diseases Anti-Bacterial Agents Gastrointestinal Microbiome Intestines Pancreatic Neoplasms Editor's Choice 030104 developmental biology medicine.anatomical_structure Cell culture Disease Progression Cancer research Immunohistochemistry Female Carcinoma Pancreatic Ductal |
| Zdroj: | Carcinogenesis |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgy073 |
| Popis: | Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States yet data are scant regarding host factors influencing pancreatic carcinogenesis. Increasing evidence support the role of the host microbiota in carcinogenesis but its role in PDAC is not well established. Herein, we report that antibiotic-mediated microbial depletion of KrasG12D/PTENlox/+ mice showed a decreased proportion of poorly differentiated tumors compared to microbiota-intact KrasG12D/PTENlox/+ mice. Subsequent 16S rRNA PCR showed that ~50% of KrasG12D/PTENlox/+ mice with PDAC harbored intrapancreatic bacteria. To determine if a similar observation in humans correlates with presence of PDAC, benign and malignant human pancreatic surgical specimens demonstrated a microbiota by 16S bacterial sequencing and culture confirmation. However, the microbial composition did not differentiate PDAC from non-PDAC tissue. Furthermore, murine pancreas did not naturally acquire a pancreatic microbiota, as germ-free mice transferred to specific pathogen-free housing failed to acquire intrapancreatic bacteria over time, which was not augmented by a murine model of colitis. Finally, antibiotic-mediated microbial depletion of Nod-SCID mice, compared to microbiota-intact, showed increased time to PDAC xenograft formation, smaller tumors, and attenuated growth. Interestingly, both xenograft cohorts were devoid of intratumoral bacteria by 16S rRNA PCR, suggesting that intrapancreatic/intratumoral microbiota is not the sole driver of PDAC acceleration. Xenografts from microbiota-intact mice demonstrated innate immune suppression by immunohistochemistry and differential regulation of oncogenic pathways as determined by RNA sequencing. Our work supports a long-distance role of the intestinal microbiota on PDAC progression and opens new research avenues regarding pancreatic carcinogenesis. The human pancreas possesses a microbiota that does not discriminate adenocarcinoma from normal tissue but the intestinal microbiota does accelerate pancreatic carcinogenesis through a long-distance mechanism. Targeting of intestinal microbes may prove beneficial in curtailing pancreatic cancer development and progression. |
| Databáze: | OpenAIRE |
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