Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer.
Carcinogenesis
; 41(5): 561-570, 2020 07 10.
Article
en En
| MEDLINE
| ID: mdl-31369062
ABSTRACT
The lack of tools for early detection of pancreatic ductal adenocarcinoma (PDAC) is directly correlated with the abysmal survival rates in patients. In addition to several potential detection tools under active investigation, we tested the gut microbiome and its metabolic complement as one of the earliest detection tools that could be useful in patients at high risk for PDAC. We used a combination of 16s rRNA pyrosequencing and whole-genome sequencing of gut fecal microbiota in a genetically engineered PDAC murine model (KRASG12DTP53R172HPdxCre or KPC). Metabolic reconstruction of microbiome was done using the HUMAnN2 pipeline. Serum polyamine levels were measured from murine and patient samples using chromogenic assay. Our results showed a Proteobacterial and Firmicutes dominance in gut microbiota in early stages of PDAC development. Upon in silico reconstruction of active metabolic pathways within the altered microbial flora, polyamine and nucleotide biosynthetic pathways were significantly elevated. These metabolic products are known to be actively assimilated by the host and eventually utilized by rapidly dividing cells for proliferation validating their importance in the context of tumorigenesis. In KPC mice, as well as PDAC patients, we show significantly elevated serum polyamine concentrations. Therefore, at the early stages of tumorigenesis, there is a strong correlation between microbial changes and release of metabolites that foster host tumorigenesis, thereby fulfilling the 'vicious cycle hypothesis' of the role of microbiome in health and disease states. Our results provide a potential, precise, noninvasive tool for early detection of PDAC, which may result in improved outcomes.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Poliaminas
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Carcinoma Ductal Pancreático
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Detección Precoz del Cáncer
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Disbiosis
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Microbioma Gastrointestinal
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
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Risk_factors_studies
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Screening_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Carcinogenesis
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos