Microbiota Regulates Pancreatic Cancer Carcinogenesis through Altered Immune Response

Abstract

The microbiota is present in many parts of the human body and plays essential roles. The most typical case is the occurrence and development of cancer. Pancreatic cancer (PC), one of the most aggressive and lethal types of cancer, has recently attracted the attention of researchers. Recent research has revealed that the microbiota regulates PC carcinogenesis via an altered immune response. Specifically, the microbiota, in several sites, including the oral cavity, gastrointestinal tract, and pancreatic tissue, along with the numerous small molecules and metabolites it produces, influences cancer progression and treatment by activating oncogenic signaling, enhancing oncogenic metabolic pathways, altering cancer cell proliferation, and triggering chronic inflammation that suppresses tumor immunity. Diagnostics and treatments based on or in combination with the microbiota offer novel insights to improve efficiency compared with existing therapies.

Strengthening the Evidence for a Causal Link between Type 2 Diabetes Mellitus and Pancreatic Cancer: Insights from Two-Sample and Multivariable Mendelian Randomization

“…The pathophysiological mechanisms linking T2DM to PaCa are complex and multifaceted, encompassing insulin resistance and hyperinsulinemia [16,[36][37][38], persistent hyperglycemia [39][40][41][42], chronic inflammation [16,43,44], alterations in gut microbiota [45][46][47][48][49], and dysregulated adipokine secretion [16,[50][51][52][53][54]. Insulin resistance in T2DM leads to hyperinsulinemia, potentially promoting tumor growth directly by acting on insulin receptors or indirectly by increasing levels of insulin-like growth factor-1 (IGF-1), both of which can stimulate cell proliferation and inhibit apoptosis to enhance cell proliferation pathways [36][37][38].…”

“…Some inflammatory mediators or cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), can promote tumor growth and metastasis [43,44]. Changes in the gut microbiota related to T2DM may influence systemic inflammation and metabolic profiles, which may affect cancer development through alterations in bile acid metabolism and the release of metabolites that may have carcinogenic properties [45][46][47][48][49]. Moreover, altered adipokine secretion, characterized by increased leptin and decreased adiponectin levels due to adiposity in T2DM, may facilitate cancer progression through pro-inflammatory and anti-apoptotic effects [50][51][52][53][54].…”

Impact of gut microbiome in the development and treatment of pancreatic cancer: Newer insights

“…Butyrate, which is a SCFA produced by certain bacteria of gut possesses anti-inflammatory and anti-neoplastic properties in regard to PC by the means of “pro-differentiation, anti-proliferation, anti-invasion, pro-apoptosis” and chemo-sensitization effects[ 91 ]. Another SCFA from the gastrointestinal (GI) microbiota, acetate, induces insulin secretion via the microbiome-brain β-cell axis controlling pancreatic bacterial overgrowth[ 92 , 93 ]. Tryptophan metabolism can serve as an immunomodulatory factor by overexpression of indoleamine2,3-dioxygenase1 which inhibits the maturation of CD11c and dendritic cells, and T-cell proliferation and by high expression of Kyn which leads to induction and activation of the aryl hydrocarbon receptor, leading to upregulation of programmed cell death protein 1 expression; enhancing the efficacy of antitumor adoptive T-cell therapy and reducing the rate of migration and invasion in both tumor-bearing mice and patients with PC[ 94 - 96 ].…”

A Simple Overview of Pancreatic Cancer Treatment for Clinical Oncologists

“…Different types of Claudin proteins play an important role in the EMT progression of pancreatic malignant and benign tumors, tumor development, nerve infiltration, tissue infiltration and metastatic implantation, and we await the results from clinical trials enrolling Claudin-18.2-positive PDAC patients [109]. Interestingly, recent studies have described that microbiota also contributes to cancer onset and progression by activating oncogenic signaling, enhancing oncogenic metabolic pathways, altering cancer cell proliferation and triggering chronic inflammation that suppresses tumor immunity [110]. However, ongoing research into the understanding of the complex interplay between the tumor, stroma and tumor microenvironment is needed to better select agents targeting these compartments.…”