The Microbiome as a Potential Target for Therapeutic Manipulation in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the second most common cause of cancer-related death by 2030, with an overall 5-year survival rate between 7% and 9%. Despite recent advances in surgical, chemotherapy, and radiotherapy techniques, the outcome for patients with PDAC remains poor. Poor prognosis is multifactorial, including the likelihood of sub-clinical metastatic disease at presentation, late-stage at presentation, absence of early and reliable diagnostic biomarkers, and complex biology surrounding the extensive desmoplastic PDAC tumour micro-environment. Microbiota refers to all the microorganisms found in an environment, whereas microbiome is the collection of microbiota and their genome within an environment. These organisms reside on body surfaces and within mucosal layers, but are most abundantly found within the gut. The commensal microbiome resides in symbiosis in healthy individuals and contributes to nutritive, metabolic and immune-modulation to maintain normal health. Dysbiosis is the perturbation of the microbiome that can lead to a diseased state, including inflammatory bowel conditions and aetiology of cancer, such as colorectal and PDAC. Microbes have been linked to approximately 10% to 20% of human cancers, and they can induce carcinogenesis by affecting a number of the cancer hallmarks, such as promoting inflammation, avoiding immune destruction, and microbial metabolites can deregulate host genome stability preceding cancer development. Significant advances have been made in cancer treatment since the advent of immunotherapy. The microbiome signature has been linked to response to immunotherapy and survival in many solid tumours. However, progress with immunotherapy in PDAC has been challenging. Therefore, this review will focus on the available published evidence of the microbiome association with PDAC and explore its potential as a target for therapeutic manipulation.

Gut Dysbiosis in Pancreatic Diseases: A Causative Factor and a Novel Therapeutic Target

“…Patients with PDAC had an increased phylum Proteobacteria (such as Gammaproteobacteria) and a decreased phylum Firmicutes (such as butyrate-producing bacteria, including Eubacterium rectale, Faecalibacterium prausnitzii , and Roseburia intestinalis ) when compared with healthy controls ( 139 ). Additionally, several recent review articles have underscored the importance of the gut microbiome in the development and progression of PDAC ( 140 – 142 ).…”

Neoadjuvant Treatment for Pancreatic Adenocarcinoma: A False Promise or an Opportunity to Improve Outcome?

“…The study of the microbiome and its role as a possible prognostic biomarker, along with the potential for its modulation to improve the efficacy and toxicity of existing treatments, has gained significant interest in oncology. In PDAC, it has been suggested that the relatively disappointing results seen with immunotherapy may in some part be attributable to the patient microbiome [96].…”

Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities

“…Emerging evidence shows that gut microbiome, an abundant source of TLR ligands, has a critical role in inflammation and treatment resistance in PDAC [68]. A comprehensive study on 1526 PDAC tumors with matched adjacent normal tissues showed that PDAC tumors are dominated by Proteobacteria including the Enterobacteriales and Pseudomonadales species, which are naturally abundant in normal duodenum [69].…”