Review Open Access
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2023; 29(25): 3984-3998
Published online Jul 7, 2023. doi: 10.3748/wjg.v29.i25.3984
Impact of gut microbiome in the development and treatment of pancreatic cancer: Newer insights
Ayrton I Bangolo, Chinmay Trivedi, Ishan Jani, Silvanna Pender, Hirra Khalid, Budoor Alqinai, Alina Intisar, Karamvir Randhawa, Joseph Moore, Nicoleta De Deugd, Shaji Faisal, Suchith Boodgere Suresh, Parva Gopani, Vignesh K Nagesh, Simcha Weissman, Department of Internal Medicine, Palisades Medical Center, North Bergen, NJ 07047, United States
Tracy Proverbs-Singh, Department of Gastrointestinal Malignancies, John Theurer Cancer Center, Hackensack, NJ 07601, United States
ORCID number: Ayrton I Bangolo (0000-0002-2133-2480); Simcha Weissman (0000-0002-0796-6217).
Author contributions: Bangolo AI, Trivedi C, and Nagesh VK searched the literature, wrote, and revised the manuscript; Jani I, Pender S, Khalid H, Alqinai B, Intisar A, Randhawa K, Moore J, De Deugd N, Faisal S, Suresh SB, and Gopani P revised and edited the manuscript; Bangolo AI, Proverbs-Singh T and Weissman S revised and approved the final version of the article and are the article’s guarantors; All authors certify that they contributed sufficiently to the intellectual content and data analysis. Each author has reviewed the final version of the manuscript and approved it for publication.
Conflict-of-interest statement: No potential conflict of interest was reported by the authors.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ayrton I Bangolo, MBBS, MD, Doctor, Department of Internal Medicine, Palisades Medical Center, 7600 River Road, North Bergen, NJ 07047, United States. ayrtonbangolo@yahoo.com
Received: May 15, 2023
Peer-review started: May 15, 2023
First decision: May 23, 2023
Revised: May 24, 2023
Accepted: June 12, 2023
Article in press: June 12, 2023
Published online: July 7, 2023

Abstract

The gut microbiome plays an important role in the variation of pharmacologic response. This aspect is especially important in the era of precision medicine, where understanding how and to what extent the gut microbiome interacts with drugs and their actions will be key to individualizing therapy. The impact of the composition of the gut microbiome on the efficacy of newer cancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell treatment has become an active area of research. Pancreatic adenocarcinoma (PAC) has a poor prognosis even in those with potentially resectable disease, and treatment options are very limited. Newer studies have concluded that there is a synergistic effect for immunotherapy in combination with cytotoxic drugs, in the treatment of PAC. A variety of commensal microbiota can affect the efficacy of conventional chemotherapy and immunotherapy by modulating the tumor microenvironment in the treatment of PAC. This review will provide newer insights on the impact that alterations made in the gut microbial system have in the development and treatment of PAC.

Key Words: Pancreatic cancer, Gut microbiome, Chemotherapy, Dysbiosis, Intratumoral microbiome, Gut flora

Core Tip: Pancreatic cancer (PC) remains of on the most dismal in terms of prognosis. Treatment options are limited and even after complete surgical resection, the prognosis remains poor. The gut microbiome has been incriminated in the past for the development of certain cancers. Our review found that observation to be true as well for PC. Furthermore, we also found that it plays a role in efficacy and tolerance of certain regimens used to treat PC.



INTRODUCTION

Pancreatic cancer (PC) usually refers to ductal pancreatic adenocarcinoma (PAC) (including its subtypes), which represents 85 to 90 percent of all pancreatic neoplasms. PC ranks fourth among cancer related mortality in the United States, only behind lung, colorectal, and prostate cancers in males, and lung, breast, and colorectal cancers in females. Although the incidence of PC has been relatively stable over time, the increasing use of imaging techniques such as endoscopic ultrasound and helical (spiral) abdominal computed tomography (CT) scans has revealed an increasing number of incidentally found cases of PC[1,2].

PC can run in some families, and approximately 10 percent of individuals with PC have a family history of the disease[3,4]. There are two broad categories of hereditary risk for PC which are inherited genetic predisposition syndromes associated with PC and familial PC (FPC), which is defined as a family with a pair of affected first-degree relatives who do not meet criteria for a known PC-associated genetic predisposition syndrome[5].

The major gene causing most cases of hereditary PC remains unknown. Pathogenic germline variants (PGVs) in the breast cancer associated (BRCA) 1 and 2 genes are the most commonly associated mutations, occurring in 13 to 19 percent of FPC families[6]. Next generation sequencing helped uncover other genes causing hereditary pancreatic ductal adenocarcinoma: The partner and localizer of BRCA2 (PALB2) gene and the ataxia-telangiectasia mutated (ATM) gene[7,8]. PGVs are especially common in individuals with early onset PC (i.e., developing before age 50)[6]. Cigarette smoking contributes to the risk of PC in patients with hereditary pancreatitis and FPC and is associated with an earlier PC diagnosis by approximately 20 years[9].

In recent years, the role of gut microbiome in the development and treatment of several cancers, including PC, has been an area of active research. Porphyromonas gingivalis (P. gingivalis), Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) and even Helicobacter Pylori (H. Pylori) are linked to an increased risk of PC[10,11]. Probiotics have been shown to be effective in reducing pancreaticoduodenectomy complications, by directly suppressing the growth of cancer cells. Postbiotics have been shown to have selective cytotoxicity against tumor cells. Prior literature revealed that fecal microbiota transplantation led to a reduction in tumor size for PC[12].

Carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM-7), also known as CGM2, is a glycoprotein expressed on the luminal surface of epithelial cells near the mouth of colonic crypts and on pancreatic ductal epithelial cells[13]. Most recently it has been shown that CEACAM7-directed chimeric antigen receptor (CAR) T cells can effectively mediate remission of late-stage patient-derived PAC xenograft tumors[13].

This review will provide a concise and up to date overview of the impact of commensal gut microbiota in the development and management of PAC. Furthermore, we will focus on the pathophysiology and pathogenesis by which the gut flora can gain oncogenetic attributes and to what extent their alteration can affect the treatment and outcome of PAC.

DIAGNOSIS OF PC

Recent advances in imaging techniques have elevated the diagnostic acumen for PC. Abdominal ultrasound (US) is a non-invasive approach, which can detect pancreatic masses with an accuracy of 50%-70%[14]. Although there are no tell-tale characteristic signs of different pancreatic masses, a hypoechoic mass, pancreatic and/or biliary duct dilation could point towards an ominous pathology[14,15]. If a contrast enhanced US is available, the diagnostic accuracy could be significantly enhanced as hypovascularity of a mass point towards PAC whereas endocrine cell tumor is hyper vascularized and any pancreatitis associated mass is usually iso-vascularized[14,16].

CT with contrast is perhaps the most widely used-in detection and staging of PC. Hypovascularity, increased fibrous stroma, and decreased enhancement compared to surrounding tissue points towards PAC[17]. In hypoattenuating lesions and in instances where CT is equivocal, multi-detector row CT can be helpful as it provides three dimensional images and various phases of contrast enhancement-parenchymal, portal venous, and arterial-leading to earlier detection and accurate staging of the cancer[18-20]. Enhanced magnetic resonance imaging (MRI), due to better soft tissue visualization, has been shown to be equal or superior to CT imaging for blood vessel invasion and local extent, however, it is poor in detecting the involvement of portal venous system or duodenum[21-23]. The most accurate and sensitive method for detection of even the smallest tumors with or without vascular invasion is EUS-superior to MRI, CT, or US. It is also an excellent modality for diagnosis when combined with biopsy and has incredibly high sensitivity to detect metastasis to the lymph nodes as well as vascular invasion[24-27]. The biggest challenge in diagnosis is differentiating between chronic pancreatitis and PAC, this is when EUS with biopsy comes in handy.

STAGING OF PC

The staging of PC at the time of diagnosis is pivotal for prognosis and treatment planning as the aggressive or palliative care approach could be applied based on the stage. The role of CT imaging with contrast is pivotal in determining the stage, however, sometimes, sophisticated modalities such as enhanced MRI, EUS, or fluorodeoxyglucose-positron emission tomography could be needed. The tumor size, location in the pancreas, surrounding structures involvement-with or without vascular involvement, and spread to surrounding lymph nodes or metastasis are the components involved in staging for PC.

The T (tumor), N (Node), and M (Metastasis) is the widely accepted staging systems for PC as per The American Joint Committee for Cancer[28]. The T stage is classified based on the tumor size within the pancreas and/or involvement of vascular structures. The N and M stage is classified based on the involvement of regional lymph nodes and sites of metastasis, if any. Subsequently, based on the imaging, cancer is characterized as resectable, borderline resectable, locally advanced, or metastatic disease. Stages I and II do not involve any major blood vessels, stage III is a localized tumor but with involvement of a major blood vessel, whereas Stage IV is metastatic disease[28].

The National Comprehensive Cancer Network stages PC primarily based on tumor extent. This is primarily in the absence of metastatic disease and resection options are localized advanced/unresectable, borderline resectable, and resectable disease. Locally advanced/unresectable disease is predominantly when the tumor involves major vascular structures such as aorta, superior mesenteric or portal vein (unreconstructable), or > 180 degrees of tumor contact with the Superior mesenteric artery or celiac artery. Resectable disease or borderline resectable is defined as no involvement of any vascular structures mentioned above or ≤ 180 degrees of involvement[29].

PC-MODALITIES OF TREATMENT

Depending on the staging of PC, there are various modalities which are employed for the treatment. Surgical resection is always desirable, however, due to the relatively silent clinical course of PC, only 1/5th of patients have resectable tumors at the time of diagnosis[30,31]. The most utilized surgical procedures are total pancreatectomy, distal pancreatectomy, and Whipple’s procedure depending on the staging of the cancer[32]. Previously, in patients presenting with jaundice, preoperative biliary stenting was considered if there was a tumor on the head of the pancreas causing biliary obstruction, however, recent studies have shown that this modality is associated with increased time to surgery, increased rates of infection, and complications; preoperative biliary stenting is as a result, no longer recommended for head of the pancreas tumors which have not metastasized and can be easily resected[33,34]. However, preoperative stenting can be considered in patients who are undergoing neoadjuvant chemotherapy, if surgery is postponed by logistical constraints, or have severe jaundice[33,34].

In patients who present with PC s of ‘borderline resectability’, neoadjuvant therapy prior to surgical resection is a consideration. However, data is conflicting. While there is some evidence on increased survival amongst borderline resectable tumors with neoadjuvant gemcitabine-based chemotherapy, there are also studies which suggest an increased postoperative stay and increased surgical challenges in locally resectable tumor patients who received neoadjuvant chemotherapy[35-37]. Also, it is important to note that histological diagnosis is mandatory prior to starting the chemotherapy, which may further delay the time to surgery.

The overall prognosis of PC is abysmal, even post complete surgical resection. As a result, 5-Fluorouracil (with Leucovorin) or Gemcitabine adjuvant chemotherapy is frequently employed post-surgical resection. Which agent is better though, does remain a topic of discussion. Studies are equivocal with some showing no difference between the two whereas others favor gemcitabine[38]. In patients with metastatic disease, the armamentarium consists of psychosocial support, chemotherapy, treating a variety of other comorbid conditions, and targeted therapy. As far as chemotherapy is concerned in such a setting, Gemcitabine has been shown to be superior, by far and remains the first line standard of care[39]. Arguably, Conroy et al[40] have proven that FOLFIRINOX can super side Gemcitabine, as patients on FOLFIRINOX demonstrated not only a better response rate, but also improved one year, progression free, and overall survival[40]. In patients who are non-tolerant to first line gemcitabine, second line treatment consisting of oxaliplatin with fluoropyrimidines have demonstrated some clinical benefit[41,42]. Furthermore, if FOLFIRINOX was used as the first line, gemcitabine-based therapy should be tried as second line and has some clinical evidence of being beneficial[40].

Newer modalities of treatment include but are not limited to the use of epidermal growth factor receptor (EGFR) inhibitors. Medications like Cetuximab and Erlotinib which target the EGFR have been developed recently for targeted therapy and have been shown to be effective in many clinical trials. A combination of gemcitabine with Erlotinib is shown to increase overall survival rates and decrease the progression of PC[43]. PC cells are notorious to adapt in order to decrease the drug delivery to them by production of desmoplastic stroma and lead to resistance to chemotherapeutic agents[44]. Several therapies have recently been developed to decrease this stromal tissue and improve drug penetration despite the desmoplastic stroma, including nab-paclitaxel[45].

Radiation therapy has a somewhat beneficial role alongside surgery and chemotherapy. Neoadjuvant radiation therapy for PC has been described in prior literature. Pisters et al[46] demonstrated that minimal toxicity and a very small recurrence rate can be obtained with preoperative fractionation chemoradiation based on 5-Fluorouracil, Whipple’s procedure, and intraoperative radiation[46]. In another study, utilizing a similar strategy for treatment but replacing 5-Fluorouracil with paclitaxel-based chemotherapy, the results were similar, however, the toxicity levels were higher[47].

To improve the patient’s overall prognosis, radiation therapy is frequently being utilized for management of PC alongside chemotherapy. In the United States, adjuvant radiation therapy is a common norm after the Gastrointestinal Tumor Study Group’s prospective study in 1985. Patients with resectable PC were enrolled in this trial and were found to have a significantly longer and medial survival rate when treated with adjuvant chemoradiation[48]. Owing to this trial, adjuvant chemoradiation, the most commonly used adjuvant treatment for patients with resectable PC, is being practiced to date in the United States.

Novel techniques like stereotactic body radiotherapy have also been developed in recent years for targeted delivery of radiation. However, it has only been shown to slow local progression of the disease but has no effect on overall survival rates as the majority of mortality in PC patients is secondary to systemic and distant metastasis[49-51]. As PC is genetically a heterogeneous malignancy, there have also been baby steps in personalized chemotherapeutic regimen based on the patient’s genome to significantly increase the rates of chemotherapeutic efficacy by decreasing the resistance and making the response to chemotherapy consistent across all individuals. However, further research is needed on this novel therapeutic approach.

GUT MICROBIOTA AND PC
Mechanisms via which microbes regulate pancreatic oncogenesis

The gut microbiome, which refers to microbes naturally present in the human mucosal surfaces, has shown, when altered, to lead to oncogenesis and to some extent affect the response to therapy of several cancers, among which PAC[52]. The exact mechanisms by which oral and intestinal microbiota reach the pancreas remains unknown, but the proposed mechanisms involve the translocation via biliary/pancreatic ducts or through the blood circulation[52]. A summary can be found in Table 1.

Table 1 Gut microbiota associated with Pancreatic oncogenesis.
Bacteria
Primary site
Potential mechanism
Subsequent effect
Ref.
Porphyromonas gingivalisMouth TLR signaling disruption; Nitrosamines production; PPAD productionLoss of protective immunity; DNA adducts formation; P53 overactivity (loss of apoptosis); KRAS mutation (cellular overproliferation)[52-55]
Aggregatibacter actinomycetemcomitansMouth Nitrosamine production; DNA double-strand breaks; CagE productionDNA adducts formation; genome instabilities; dysregulation of DNA methylation expression[52,58,59]
Fusobacterium nucleatumMouth FadA production; Fap2 productionactivation of the Wnt/β-catenin pathway; suppression of the cytotoxic effects of NK cells and lymphocytes[59,61-63]
Helicobacter PyloriStomachcagA, cag PAI and vacA production Disruption of host intracellular signaling pathways[64]
Bacteroides fragilis, Bacteroides vulgatus, Listeria monocytogenes, Clostridium, Lactobacillus, BifidobacteriumLarge bowel Transformation of primary bile acids to secondary bile acidsReduction of susceptibility to apoptosis, induction of inflammatory mediators, and perturbation of membranes and cellular movement[76]
Escherichia coliLarge bowel Polyamines production Polyamines upregulation[81-83]

P. gingivalis, which is a bacterium mainly found in the mouth and associated with periodontal diseases, has shown the ability to disseminate and affect immune response. P. gingivalis infection has shown an involvement of toll-like receptors (TLRs) including TLR4, involved in protective immunity. TLR signaling, especially TLR4, has been shown to play an important role in human pancreatic tumors[53]. Furthermore, periodontal diseases, such as the ones caused by P. gingivalis can lead to an increased production of nitrosamines[54]. Nitrosamines can be metabolized by Cytochrome P450 and produce electrophiles that can effectively interact with the DNA and lead to the formation of DNA adducts that have a carcinogenic potential if not repaired[55]. Porphyromonas Peptidyl Arginine Deaminase (PPAD) is a protein produced by P. gingivalis that has been associated with cancer development by the way of P53 activity and KRAS (Kirsten-ras) mutation[52]. P53, which is a tumor suppressor gene, if mutated can lead impairment of cell cycle arrest and decrease of apoptosis increasing the risk of malignancy. KRAS, which is an oncogene with hydrolyzing effect on guanosine triphosphate, can lead uncontrolled and inappropriate cell proliferation, thus increasing the risk of malignancy[52]. P53 is a transcription factor that can activate the transcription of numerous genes, including the Cyclin-dependent kinase (CDK) inhibitor p21.

P53 is rapidly degraded and therefore not detectable within the cell. Mutation of the P53 gene results in a protein that fails to bind DNA effectively. Therefore, expression of the CDK inhibitor P21 gene is decreased, and P21 protein production is decreased. P21 protein is not available to stop the entry of the cell into S phase, again resulting in unregulated cell cycle progression, potentially leading to carcinogenesis[56]. The KRAS gene, an oncogene, is one of the most frequently mutated genes in PC. This gene is the human homolog of a transforming gene isolated from the Kirsten rat sarcoma virus, hence the name KRAS. Mutations in this gene, the vast majority of which are at codon 12, are activating, leading to abnormal activation of the protein product of the gene[57].

A. actinomycetemcomitans is also an oral microbiome that has been incriminated in PAC[52]. Similar to P. gingivalis, it can lead to periodontal infections and lead to increased nitrosamine production[54]. A. actinomycetemcomitan can also induce DNA double-strand breaks in host cells, independently of apoptosis, and cause the risk of genome instabilities and subsequently increase the risk of carcinogenesis[58]. Furthermore, the bacteria can produce the cytotoxin-associated gene E (CagE). CagE may have helicase activity, and its role in regulating DNA methylation expression is considered as possible mechanisms of tumorigenesis. CagE gene has been widely expressed in various cancer cell lines and cancer tissues including PC[59]. Fusobacterium nucleatum (F. nucleatum), which is another oral microbiome produces Fusobacterium adhesin A (FadA), that showed capacity of binding to host cells and is also the most characteristic virulence factor of F. nucleatum[59]. The host receptors for FadA are members of the cadherin family, mainly E-cadherin and vascular endothelial (VE) cadherin (CDH5)[60]. FadA binds to E-cadherin of epithelial cells, leading to phosphorylation and internalization of E-cadherin on the membrane; afterwards, canonical Wnt pathway is activated, accompanied by decreased phosphorylation of β-catenin, which accumulates in the cytoplasm and translocate to the nucleus[59]. Increase in Wnt signaling activity and subsequent activation of the Wnt/β-catenin pathway, has shown to be essential in the initiation of PC[61,62]. Furthermore, FadA binds VE-cadherin on VE cells, increasing endothelial penetrability[59]. Therefore, FadA not only directly invades host cells but also allows dissemination of itself and other bacteria into blood by increasing endothelial permeability[59]. F. nucleatum can produce a protein called familial adenomatous polyposis 2, which binds and interacts to human inhibitory receptor T cell immunoreceptor on natural killer (NK) cells and lymphocytes. Thus, suppressing the cytotoxic effects of NK cells and lymphocytes, leading to protection of tumors from the immune system and fostering a flourishing inflammatory context[63]. By a mechanism similar to P. gingivalis, F. nucleatum can be involved with the TLRs and lead to carcinogenesis as discussed previously[53].

H. Pylori is notorious for its association with gastric cancer and yields various virulence factors that may disrupt host intracellular signaling pathways and lower the threshold for neoplastic transformation. Of all virulence factors, cytotoxin-associated gene A and its pathogenicity island (cag PAI) and vacuolating cytotoxin A are the major pathogenic factors[64]. Whether H. Pylori infection is associated with PAC remains controversial with conflicting data in the literature. A study by Kumar et al[65] showed a very low incidence of H. Pylori among patients with PAC, whereas studies by Hirabayashi et al[66], and Nilsson et al[67] found an association.

Several members of the gut microbial community (especially of the large bowel), including Bacteroides fragilis, Bacteroides vulgatus, Listeria monocytogenes, Clostridium, Lactobacillus, Bifidobacterium, and Escherichia, are involved in the transformation of primary bile acids to secondary bile acids, either by deconjugation, oxidation, dehydroxylation, or epimerization[68-70]. Bile acids have multiple nuclear receptors, including farnesoid-X-receptor (FXR), liver-X receptor, CAR, vitamin D receptor (VDR), pregnane X receptor (PXR), and a non-nuclear receptor Takeda G Protein-Coupled Receptor 5/G-protein-coupled bile acid receptor (TGR5), that may impact carcinogenesis[71,72]. Secondary bile acids can behave as both pro- and anti-carcinogens, depending on the cancer concerned and the concentration of the bile acid present[71-73]. Furthermore, bile acids can modulate the composition of the microbiome and facilitate bacterial translocation into tissues, which is a key step in the carcinogenesis of PAC[74]. Bile acid levels have been shown to be elevated in PAC[75]. Bile acids can also affect risk factors for PAC such as pancreatitis and bile acid efflux disorders, type II diabetes, obesity, and hyperlipidemia; and they can reduce susceptibility to apoptosis, induce inflammatory mediators, and may perturb membranes and cellular movement[76]. A secondary bile acid, deoxycholic acid can bind to TGR5 and activate EGFR, mitogen-activated protein kinase, and signal transducer and activator of transcription 3 signaling in PAC cells, inducing cell cycle progression[77]. Other bile acid receptors such as VDR, FXR and PXR are also found to be highly expressed in PAC tissues compared to normal tissues[78-80].

Polyamines can be produced, accumulated, or used by the following gut bacteria Escherichia coli (E. coli), Enterococcus faecalis (E. faecalis), Staphylococcus aureus, Haemophilus influenzae, Neisseria flava, Pseudomonas aeruginosa, Campylobacter jejuni, Yersinia pestis, Vibrio cholerae, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides fragilis, Bacillus subtilis, and Proteus mirabilis[81,82]. A mouse study revealed that bacterial polyamine biosynthetic capacity was upregulated and aggravated by tumor progression in PAC and there was a correlated elevated serum level of polyamines[83].

As evidence by the work of Riquelme et al[84], Fecal Microbiotal Transplant from human subjects to mice, yielded from PC long term murine survivors, showed a significant reduction in tumor growth, however, that effect was lost with the use of antibiotics altering the fecal microbiota[84,85]. Furthermore, it was found that long term survivor mice that did not receive antibiotics were rich in CD8+ T-cell, enhancing the tumor immune cell infiltration. On the other hand, mice that were treated with antibiotics, thus altering the fecal microbiota, showed an increased number of CD4+FOXP3+ T-regs and myeloid derived suppressor cells which are well known to lower the immune system, thus promoting tumor growth[84,85].

NK cells are a group of cells that play an important role by mediating tumor initiation and progression. NK cells are often found in the circulation, preventing tumor cells from metastasizing[86,87]. When a patient is NK cells depleted, tumor escape and growth may ensue[86]. NK cells having the ability to inhibit CD8+ T cell responses during chronic infections, it has been hypothesized that NK cells can facilitate solid tumors infiltration, among which PC[86].

Hepatotropic viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) have been incriminated in pancreatic oncogenesis. HBV and HCV have the ability to delay host immune system clearance of the virus by integrating the DNA, modifying tissue viscoelasticity, and modulating the PI3K/AKT signaling pathway, which promotes metabolism, proliferation, cell survival, growth and angiogenesis in response to extracellular signals, via the HBV X protein, thus leading to oncogenesis[87].

It has been shown that fungal microbiota including Candida, Saccharomyces, Aspergillus or Malassezia spp. are involved in pancreatic oncogenesis. One proposed mechanism is that ligation of mannose-binding lectin, which binds to glycans of the fungal wall may lead to activation of the complement cascade and oncogenic progression[88].

Short-chain fatty acids (SCFA) which are metabolites from the gut microbiota and cathelicidin-related antimicrobial peptides secreted by normal pancreatic β-cells protect against tissue inflammation and control pancreatic bacterial overgrowth[89,90]. It has been shown that patients with PC have an abundance of a higher abundance of lipopolysaccharide-producing bacteria, and a reduction in beneficial microbes, such as butyrate-producing bacteria[91]. 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].

IMPACT OF GUT MICROBIOME ALTERATION ON THE TREATMENT OF PC

PAC is only resectable in approximately 15% to 20% of cases at the time of diagnosis, however, surgical resection offers the only chance of cure. PAC carries a dismal prognosis even after surgical resection with negative margins given its high rate of recurrence. Therefore, systemic chemotherapy, radiation therapy, and combined approaches (chemoradiotherapy) have been used both prior to and following surgical resection in an effort to improve cure rates[97]. More recently, immunotherapy and CAR T-cell therapy have gained favor for use in the treatment of PAC[13]. The gut microbiome has been shown to interact with those treatment modalities and affect their efficacy[13,42]. Furthermore, the gut microbiome has also shown some cytotoxic effect in PAC[42].

E. coli and Staphylococcus aureus strains have the potential to produce Cytolysin A (ClyA), which is a pore-forming cytotoxin that possesses anticancer properties[98]. ClyA exerts its cytotoxicity, by creating multimeric pores and imposing cell death in the eukaryotic membrane by the caspase-dependent pathway[99]. E. coli, A. actinomycetemcomitans, Campylobacter and Helicobacter are known to produce Cytolethal distending toxin (CDT)[100]. CDT is known to have genotoxic attributes by DNase activity which creates DNA double stranded breaks, leading to cell cycle arrest and cytotoxicity[49]. Streptococcus pyogenes secretes streptolysin O which is implicated in cytolysis and apoptosis[101].

Prebiotics are defined as nutrients that are degraded by gut microbiota and may affect not only the intestinal microenvironment but also distant organs. In a mice study by Trivieri et al[102] using xenograft mice model confronted with PC gene expression dataset (GSE16515) and investigating the impact of high levels of prebiotic resistant starch diet (RSD) on miRNA expression profiles in tumor tissues, RSD was associated with dysregulation of 19 miRNAs genes expression in comparison to control. subsequent analysis revealed that part of genes participating in the regulation of processes such as the development of carcinoma, inflammatory response, abdominal cancer, metabolic disease, growth, invasion, and metastasis were downregulated in a group of mice fed with RSD in comparison to control. Furthermore, genes participating in the synthesis of carbohydrates, glucose metabolism disorder, and cell death of cancer cell lines were significantly upregulated in mice fed with RSD. Thus, the authors concluded that there is prolonged overall survival and beneficial value of RSD in PAC[103].

Lactobacillus casei is a probiotic that can produce Ferrichrome, which has the potential to suppress the growth of refractory PC cells by inhibiting cancer cells progression and dysregulating cell cycle by activating P53[102,103]. Next-generation probiotics such as Akkermansia muciniphila (A. muciniphila), are identified using next-generation sequencing and bioinformatics tools. A. muciniphila has been shown to inhibit the proliferative activity of INS-1 (rat pancreatic islet cell tumor cells) in a mouse model[104].

FOLFIRINOX, which is a commonly used regimen in PAC is composed of leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin. Oxaliplatin has an immunomodulatory effect as well, potentiating tumoricidal T-cell immunity. In a mice model, a group with a defective TLR signaling pathway, demonstrated no response to oxaliplatin treatment[105]. Agonistic TLR molecules from microbial membranes were reported to help stimulate the immune system and increase reactive oxygen species production, thus enhancing the tumoricidal activity of oxaliplatin[105]. Irinotecan is characterized by common GI side effects limiting the dose and effectiveness of treatment. Those side effects can be modulated by enzymatic activity of the gut microbiome, with some bacteria improving the side effects profile, while others may worsen the side effects. The β-glucuronidase enzyme produced by intestinal bacteria cleaves the active irinotecan metabolite SN-38G into a toxic form that damages the colonic mucosa and causes GI side effects. The literature revealed that antibiotics or modification of gut microbiomes significantly alleviated the GI toxicity in cancer patients[106]. Furthermore, reduced risk of developing irinotecan toxicity has been shown with the use of indigestible fibers, using appropriate probiotics and adequate butyrate intake[107].

Several animal studies showed that mice housed in germ-free conditions and animals treated with broad-spectrum antibiotics showed reduced effects of immunotherapy by a combination of TLR-9 antagonist and anti-interleukin-10 antibody. Furthermore, the ineffectiveness of cancer immunotherapy directed against the major negative regulator of T cell activation cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) was observed when applied to antibiotic-treated animals or germ-free mice[108]. Monoclonal antibodies that neutralize CTLA-4 have been shown to rely on the intestinal microbiota, in particular, Bacteroidales and Burkholderiales[108]. A recent study used a gut microbe-derived metabolite trimethylamine N-oxide (TMAO) that showed enhanced anti-tumor immunity to PAC. TMAO was delivered either intraperitoneally or via a dietary choline supplement to orthotopic PAC bearing mice, and lead to reduced tumor growth and associated with an immunostimulatory tumor-associated macrophage phenotype and activated effector T cell response in the tumor microenvironment. The combination of TMAO and immune checkpoint inhibitors (ICI) such as programmed cell death 1, in a mouse model of PAC, proved to be superior in reducing tumor burden and improving survival compared to either therapy alone[109].

CAR T-cell therapy has shown tremendous results in hematologic malignancies. Only recently, it was tried on non-hematologic malignancies with promising preliminary data. CAR T-cell therapy of solid tumors faces a major issue in that commonly targeted tumor antigens are expressed at low levels in normal tissues, leading to on-target off-tumor toxicity. CEACAM7, which has low to undetectable expression in all normal tissues and with strong surface expression on a subset of primary human PAC tumors was identified as a potential target antigen for CAR T-cell therapy of PAC. CAR T-cells targeting CEACAM7 were generated in a study by Raj et al[13] and showed significant antitumor activity against patient-derived PAC tumor cultures both in vitro and in vivo[13]. A brief summary can be found in Table 2.

Table 2 Impact of gut microbiota in the treatment of Pancreatic cancer.
Bacteria
Primary site
Potential mechanism
Subsequent effect
Ref.
Escherichia coliLarge bowel Cytolysin A production; Cytolethal distending toxin production Imposing cell death in the eukaryotic membrane by the caspase-dependent pathway; DNA double stranded breaks, leading to cell cycle arrest and cytotoxicity[49,86,87]
Staphylococcus aureusVariableCytolysin A production Imposing cell death in the eukaryotic membrane by the caspase-dependent pathway[86]
Streptococcus pyogenesVariable Streptolysin O production Increase in apoptosis and cytolysis [88]
Aggregatibacter actinomycetemcomitans, Campylobacter and HelicobacterMouth, stomach, large bowel Cytolethal distending toxin production DNA double stranded breaks, leading to cell cycle arrest and cytotoxicity[87]
Lactobacillus caseiMouth and small intestine P53 activation Upregulation of apoptosis [90]
Bacteroidales, BurkholderialesLarge bowel CTLA-4 upregulationEnhancing activity of monoclonal antibody against CTLA-4[95]

Oncolytic adenoviruses have been engineered to replicate in cancer cells and controlling tumor progression. Oncolytic adenovirus AdNuPARmE1A with miR-222 binding sites, are made to withdraw the miRNA from the cellular environment. AdNuPAR-E-miR222-S mediated-decrease of miR-222 expression in pancreatic cancer cells was shown to strongly improve the viral yield and enhance the adenoviral cytotoxic effects[110].

INTRATUMORAL MICROBIOME IN PANCREATIC CA

Intratumoral microbiome is derived from 3 basic mechanisms; (1) Sloughing of the mucosal barrier; (2) Adjacent normal tissues; and (3) Hematogenous spread[111]. Interestingly, Nejman et al[112] demonstrated that amongst the tumors that they studied, every tumor was associated with a completely different microbiome composition[112]. The pancreas is traditionally thought to be a ‘bacteria-free’ organ. However, bacterial DNA belonging to the Proteobacteria phylum was very abundantly found in pancreatic cancer[112]. Another study which confirmed increased amounts of bacterial DNA in pancreatic cancer vs normal pancreatic tissue was the study by Geller et al[113]. Bacterial ribosomal DNA was detected via FISH technique in 76% of patients with PAC vs 15% of patients with normal pancreatic tissue[88]. Similarly, by using the FISH technique, Aykut et al[88] demonstrated that Pseudomonadota, Bacillota, and Bacteroides were the most abundant bacteria found intratumorally in pancreatic cancer patients[88]. Interestingly, the fungal mycobiome in pancreatic tissue samples obtained from patients with PAC was also found to be very distinct from healthy individuals with a high prevalence of Malassezia[88].

MICROBIOME IMBALANCE AND PANCREATIC CA

Dysbiosis or imbalance in the microbiome has been shown to impact the inflammatory cascade in a non-physiological way and in turn, contribute to the development of cancer[114]. The known risk factors for pancreatic carcinoma are smoking, advancing age, type 2 diabetes mellitus, chronic pancreatitis, and obesity. Interestingly, many of these risk factors have been recently found to be associated with an imbalance in the microbiome, which may increase the risk of PAC[115-118]. A meta-analysis by Maisonnuevve demonstrated a positive correlation between periodontal disease and PAC[119]. This may be related to an imbalance in the oral microbiome. Oral microbiomes have been shown to be associated with carcinogenesis via inducing systemic inflammation, and the most important being Porphyromonas Gingivalis[120-122]. A case control study demonstrated that the risk of PAC was 2-fold higher in patients with a higher level of antibodies against a specific strain of P. Gingivalis, whereas higher levels of antibodies against commensal oral microbiome were actually protective against PAC, with an almost 50% lower risk of the cancer in patients who had these antibodies[123]. In-vivo studies have shown that P. gingivalis enhances the proliferation of pancreatic tumor cells, regardless of the concentration of TLR-4. Furthermore, the concentration and proliferation of P. gingivalis is greatly increased in PAC tissue secondary to hypoxia, which is very prevalent in the cancer microenvironment[124]. Furthermore, bacteria that cause periodontitis are also found to cause K-ras and p53 mutations, and those have in turn been associated with poor prognosis in patients with pancreatic cancer[125]. They also demonstrated that the number of cases of pancreatic cancer were higher in patients who had GI infections from H. Pylori, Enterobacter, and Enterococcus species[125].

This prior literature leads us into sensibly concluding that possibly, an imbalance in the oral microbiome is associated with an increased risk of PAC, however, reverse causation is an important factor that needs to be excluded before exploring this aspect further. One study evaluated this and found that 2 oral bacteria-P. gingivalis and Aggregatibacter actinomycetemcomitans are associated with an increased risk whereas Leptotrichia genus of Fusobacterium species was associated with a reduced risk of PAC. Interestingly, even after excluding patients who developed the cancer within 2 years from the date of sample collection, the risks remained elevated[10]. This significantly reduces the likelihood of reverse causation. Another significant study going in favor of a causality between E. faecalis, and pancreatic cancer is the one by Maekawa et al[126], wherein the level of antibodies against E. faecalis capsular polysaccharide were found to be increased in the serum of pancreatic cancer patients[126]. However, larger cohort studies are needed on the subject to conclusively establish causation.

CONCLUSION

Despite advances in medicine and the discovery of newer anticancer therapies, the prognosis of pancreatic cancer remains dismal. By the way of this review, we found that a prebiotic resistant starch diet has been associated with better overall survival in PAC. We also found that periodontal diseases increase the risk of developing PAC. This is especially important as periodontal diseases should be avoided and promptly treated in patients with a family history of PAC, other risk factors for PAC, and those with known/suspected genetic mutations susceptible for the development of PAC. Furthermore, we found that the use of concomitant antibiotics can positively or negatively affect treatment of PAC. Some gut microbiomes can enhance the effect of therapy and improve tolerance to therapy as well. Thus, neutropenic diet can be avoided in select patients meeting the requirements. Newer therapeutics such as ICI and CAR T-cell therapies can play a major role in the outcome of PAC, however, most promising studies are done in animal models. We hope that in the near future, there will be more clinical trials in human subjects replicating the promising results from animal studies which will possibly offer newer ways to handle this very deadly malignancy.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: United States

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Gazouli M, Greece; Imai Y, Japan, Sitkin S, Russia S-Editor: Fan JR L-Editor: A P-Editor: Fan JR

References
1.  Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7-33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4235]  [Cited by in F6Publishing: 8401]  [Article Influence: 4200.5]  [Reference Citation Analysis (2)]
2.  Klimstra DS. Nonductal neoplasms of the pancreas. Mod Pathol. 2007;20 Suppl 1:S94-112.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 124]  [Cited by in F6Publishing: 112]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
3.  Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog. 2012;51:14-24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 165]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
4.  Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Griffin C, Cameron JL, Yeo CJ, Kern S, Hruban RH. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 2004;64:2634-2638.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 449]  [Cited by in F6Publishing: 436]  [Article Influence: 21.8]  [Reference Citation Analysis (0)]
5.  Gardiner A, Kidd J, Elias MC, Young K, Mabey B, Taherian N, Cummings S, Malafa M, Rosenthal E, Permuth JB. Pancreatic Ductal Carcinoma Risk Associated With Hereditary Cancer-Risk Genes. J Natl Cancer Inst. 2022;114:996-1002.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 1]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
6.  Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, Gerdes B, Kress R, Ziegler A, Raeburn JA, Campra D, Grützmann R, Rehder H, Rothmund M, Schmiegel W, Neoptolemos JP, Bartsch DK. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003;95:214-221.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 359]  [Cited by in F6Publishing: 325]  [Article Influence: 15.5]  [Reference Citation Analysis (0)]
7.  Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, Lin JC, Palmisano E, Brune K, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Parmigiani G, Kern SE, Velculescu VE, Kinzler KW, Vogelstein B, Eshleman JR, Goggins M, Klein AP. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 628]  [Cited by in F6Publishing: 569]  [Article Influence: 37.9]  [Reference Citation Analysis (0)]
8.  Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, Gallinger S, Schwartz AG, Syngal S, Cote ML, Axilbund J, Schulick R, Ali SZ, Eshleman JR, Velculescu VE, Goggins M, Vogelstein B, Papadopoulos N, Hruban RH, Kinzler KW, Klein AP. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41-46.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 354]  [Cited by in F6Publishing: 357]  [Article Influence: 27.5]  [Reference Citation Analysis (0)]
9.  Yeo TP, Hruban RH, Brody J, Brune K, Fitzgerald S, Yeo CJ. Assessment of "gene-environment" interaction in cases of familial and sporadic pancreatic cancer. J Gastrointest Surg. 2009;13:1487-1494.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 34]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
10.  Fan X, Alekseyenko AV, Wu J, Peters BA, Jacobs EJ, Gapstur SM, Purdue MP, Abnet CC, Stolzenberg-Solomon R, Miller G, Ravel J, Hayes RB, Ahn J. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut. 2018;67:120-127.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 386]  [Cited by in F6Publishing: 459]  [Article Influence: 76.5]  [Reference Citation Analysis (0)]
11.  Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, Perez-Perez G, Taylor PR, Virtamo J, Albanes D; ATBC Study. Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. J Natl Cancer Inst. 2001;93:937-941.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 125]  [Cited by in F6Publishing: 132]  [Article Influence: 5.7]  [Reference Citation Analysis (1)]
12.  Sobocki BK, Kaźmierczak-Siedlecka K, Folwarski M, Hawryłkowicz V, Makarewicz W, Stachowska E. Pancreatic Cancer and Gut Microbiome-Related Aspects: A Comprehensive Review and Dietary Recommendations. Nutrients. 2021;13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 11]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
13.  Raj D, Nikolaidi M, Garces I, Lorizio D, Castro NM, Caiafa SG, Moore K, Brown NF, Kocher HM, Duan X, Nelson BH, Lemoine NR, Marshall JF. CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2021;27:1538-1552.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 31]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
14.  Rickes S, Unkrodt K, Neye H, Ocran KW, Wermke W. Differentiation of pancreatic tumours by conventional ultrasound, unenhanced and echo-enhanced power Doppler sonography. Scand J Gastroenterol. 2002;37:1313-1320.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 77]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
15.  Karlson BM, Ekbom A, Lindgren PG, Källskog V, Rastad J. Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis. Radiology. 1999;213:107-111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 75]  [Cited by in F6Publishing: 78]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
16.  Kitano M, Kudo M, Maekawa K, Suetomi Y, Sakamoto H, Fukuta N, Nakaoka R, Kawasaki T. Dynamic imaging of pancreatic diseases by contrast enhanced coded phase inversion harmonic ultrasonography. Gut. 2004;53:854-859.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 175]  [Cited by in F6Publishing: 191]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
17.  Miura F, Takada T, Amano H, Yoshida M, Furui S, Takeshita K. Diagnosis of pancreatic cancer. HPB (Oxford). 2006;8:337-342.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 88]  [Cited by in F6Publishing: 83]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
18.  Catalano C, Laghi A, Fraioli F, Pediconi F, Napoli A, Danti M, Reitano I, Passariello R. Pancreatic carcinoma: the role of high-resolution multislice spiral CT in the diagnosis and assessment of resectability. Eur Radiol. 2003;13:149-156.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 52]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
19.  Prokesch RW, Chow LC, Beaulieu CF, Nino-Murcia M, Mindelzun RE, Bammer R, Huang J, Jeffrey RB Jr. Local staging of pancreatic carcinoma with multi-detector row CT: use of curved planar reformations initial experience. Radiology. 2002;225:759-765.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 110]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
20.  Vargas R, Nino-Murcia M, Trueblood W, Jeffrey RB Jr. MDCT in Pancreatic adenocarcinoma: prediction of vascular invasion and resectability using a multiphasic technique with curved planar reformations. AJR Am J Roentgenol. 2004;182:419-425.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 191]  [Cited by in F6Publishing: 151]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
21.  Ichikawa T, Sou H, Araki T, Arbab AS, Yoshikawa T, Ishigame K, Haradome H, Hachiya J. Duct-penetrating sign at MRCP: usefulness for differentiating inflammatory pancreatic mass from pancreatic carcinomas. Radiology. 2001;221:107-116.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 194]  [Cited by in F6Publishing: 201]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
22.  Schima W, Függer R, Schober E, Oettl C, Wamser P, Grabenwöger F, Ryan JM, Novacek G. Diagnosis and staging of pancreatic cancer: comparison of mangafodipir trisodium-enhanced MR imaging and contrast-enhanced helical hydro-CT. AJR Am J Roentgenol. 2002;179:717-724.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 111]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
23.  Romijn MG, Stoker J, van Eijck CH, van Muiswinkel JM, Torres CG, Laméris JS. MRI with mangafodipir trisodium in the detection and staging of pancreatic cancer. J Magn Reson Imaging. 2000;12:261-268.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Müller MF, Meyenberger C, Bertschinger P, Schaer R, Marincek B. Pancreatic tumors: evaluation with endoscopic US, CT, and MR imaging. Radiology. 1994;190:745-751.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 357]  [Cited by in F6Publishing: 293]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
25.  Legmann P, Vignaux O, Dousset B, Baraza AJ, Palazzo L, Dumontier I, Coste J, Louvel A, Roseau G, Couturier D, Bonnin A. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. AJR Am J Roentgenol. 1998;170:1315-1322.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 300]  [Cited by in F6Publishing: 315]  [Article Influence: 12.1]  [Reference Citation Analysis (0)]
26.  Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet. 1997;349:485-489.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 206]  [Cited by in F6Publishing: 219]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
27.  Chang KJ, Nguyen P, Erickson RA, Durbin TE, Katz KD. The clinical utility of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of pancreatic carcinoma. Gastrointest Endosc. 1997;45:387-393.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 437]  [Cited by in F6Publishing: 452]  [Article Influence: 16.7]  [Reference Citation Analysis (0)]
28.  Byrd DR, Carducci MA, Compton CC, Fritz A, Greene F.   AJCC cancer staging manual. Edge SB, editor. New York: Springer; 2010.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Pancreatic Adenocarcinoma  National Comprehensive Cancer Network, 2017. [cited 22 June 2017]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363:1049-1057.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1481]  [Cited by in F6Publishing: 1516]  [Article Influence: 75.8]  [Reference Citation Analysis (0)]
31.  Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Büchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004;91:586-594.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 618]  [Cited by in F6Publishing: 702]  [Article Influence: 35.1]  [Reference Citation Analysis (0)]
32.  Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605-1617.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2078]  [Cited by in F6Publishing: 2117]  [Article Influence: 151.2]  [Reference Citation Analysis (2)]
33.  van der Gaag NA, Rauws EA, van Eijck CH, Bruno MJ, van der Harst E, Kubben FJ, Gerritsen JJ, Greve JW, Gerhards MF, de Hingh IH, Klinkenbijl JH, Nio CY, de Castro SM, Busch OR, van Gulik TM, Bossuyt PM, Gouma DJ. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med. 2010;362:129-137.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 717]  [Cited by in F6Publishing: 638]  [Article Influence: 45.6]  [Reference Citation Analysis (0)]
34.  Jinkins LJ, Parmar AD, Han Y, Duncan CB, Sheffield KM, Brown KM, Riall TS. Current trends in preoperative biliary stenting in patients with pancreatic cancer. Surgery. 2013;154:179-189.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 59]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
35.  Lemmens VE, Bosscha K, van der Schelling G, Brenninkmeijer S, Coebergh JW, de Hingh IH. Improving outcome for patients with pancreatic cancer through centralization. Br J Surg. 2011;98:1455-1462.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 115]  [Cited by in F6Publishing: 123]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
36.  Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7:e1000267.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1085]  [Cited by in F6Publishing: 1096]  [Article Influence: 78.3]  [Reference Citation Analysis (0)]
37.  Kim HJ, Czischke K, Brennan MF, Conlon KC. Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? J Gastrointest Surg. 2002;6:763-769.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 96]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
38.  Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, Padbury R, Moore MJ, Gallinger S, Mariette C, Wente MN, Izbicki JR, Friess H, Lerch MM, Dervenis C, Oláh A, Butturini G, Doi R, Lind PA, Smith D, Valle JW, Palmer DH, Buckels JA, Thompson J, McKay CJ, Rawcliffe CL, Büchler MW; European Study Group for Pancreatic Cancer. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304:1073-1081.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1008]  [Cited by in F6Publishing: 936]  [Article Influence: 66.9]  [Reference Citation Analysis (0)]
39.  Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403-2413.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4270]  [Cited by in F6Publishing: 4052]  [Article Influence: 150.1]  [Reference Citation Analysis (0)]
40.  Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M; Groupe Tumeurs Digestives of Unicancer;  PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4838]  [Cited by in F6Publishing: 5136]  [Article Influence: 395.1]  [Reference Citation Analysis (1)]
41.  Custodio A, Puente J, Sastre J, Díaz-Rubio E. Second-line therapy for advanced pancreatic cancer: a review of the literature and future directions. Cancer Treat Rev. 2009;35:676-684.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 24]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
42.  Boeck S, Ankerst DP, Heinemann V. The role of adjuvant chemotherapy for patients with resected pancreatic cancer: systematic review of randomized controlled trials and meta-analysis. Oncology. 2007;72:314-321.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 68]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
43.  Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W; National Cancer Institute of Canada Clinical Trials Group. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960-1966.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2755]  [Cited by in F6Publishing: 2667]  [Article Influence: 156.9]  [Reference Citation Analysis (0)]
44.  Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, Tuveson DA. Stromal biology and therapy in pancreatic cancer. Gut. 2011;60:861-868.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 541]  [Cited by in F6Publishing: 596]  [Article Influence: 45.8]  [Reference Citation Analysis (0)]
45.  Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548-4554.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 755]  [Cited by in F6Publishing: 839]  [Article Influence: 64.5]  [Reference Citation Analysis (2)]
46.  Pisters PW, Abbruzzese JL, Janjan NA, Cleary KR, Charnsangavej C, Goswitz MS, Rich TA, Raijman I, Wolff RA, Lenzi R, Lee JE, Evans DB. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol. 1998;16:3843-3850.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 187]  [Cited by in F6Publishing: 187]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
47.  Krishnan S, Rana V, Evans DB, Varadhachary G, Das P, Bhatia S, Delclos ME, Janjan NA, Wolff RA, Crane CH, Pisters PW. Role of adjuvant chemoradiation therapy in adenocarcinomas of the ampulla of vater. Int J Radiat Oncol Biol Phys. 2008;70:735-743.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 54]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
48.  Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120:899-903.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1024]  [Cited by in F6Publishing: 928]  [Article Influence: 23.8]  [Reference Citation Analysis (0)]
49.  Schellenberg D, Kim J, Christman-Skieller C, Chun CL, Columbo LA, Ford JM, Fisher GA, Kunz PL, Van Dam J, Quon A, Desser TS, Norton J, Hsu A, Maxim PG, Xing L, Goodman KA, Chang DT, Koong AC. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2011;81:181-188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 172]  [Cited by in F6Publishing: 194]  [Article Influence: 14.9]  [Reference Citation Analysis (0)]
50.  Didolkar MS, Coleman CW, Brenner MJ, Chu KU, Olexa N, Stanwyck E, Yu A, Neerchal N, Rabinowitz S. Image-guided stereotactic radiosurgery for locally advanced pancreatic adenocarcinoma results of first 85 patients. J Gastrointest Surg. 2010;14:1547-1559.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 89]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
51.  Rwigema JC, Heron DE, Parikh SD, Zeh HJ 3rd, Moser JA, Bahary N, Ashby K, Burton SA. Adjuvant stereotactic body radiotherapy for resected pancreatic adenocarcinoma with close or positive margins. J Gastrointest Cancer. 2012;43:70-76.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 36]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
52.  Doocey CM, Finn K, Murphy C, Guinane CM. The impact of the human microbiome in tumorigenesis, cancer progression, and biotherapeutic development. BMC Microbiol. 2022;22:53.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 18]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
53.  Michaud DS, Izard J. Microbiota, oral microbiome, and pancreatic cancer. Cancer J. 2014;20:203-206.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 84]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
54.  Shapiro KB, Hotchkiss JH, Roe DA. Quantitative relationship between oral nitrate-reducing activity and the endogenous formation of N-nitrosoamino acids in humans. Food Chem Toxicol. 1991;29:751-755.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 59]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
55.  Li Y, Hecht SS. Metabolic Activation and DNA Interactions of Carcinogenic N-Nitrosamines to Which Humans Are Commonly Exposed. Int J Mol Sci. 2022;23.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 41]  [Article Influence: 20.5]  [Reference Citation Analysis (0)]
56.  Li H, Kern JA.   Genetic and Molecular Changes in Lung Cancer: Prospects for a Personalized Pharmacological Approach to Treatment. In: Grippi MA, Elias JA, Fishman JA, Kotloff RM, Pack AI, Senior RM, et al, editors. Fishman's Pulmonary Diseases and Disorders, 5e. New York, NY: McGraw-Hill Education, 2015.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143:545-554.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Teshima R, Hanada K, Akada J, Kawano K, Yamaoka Y. Aggregatibacter actinomycetemcomitans infection causes DNA double-strand breaks in host cells. Genes Cells. 2018;23:264-273.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
59.  Sun Z, Xiong C, Teh SW, Lim JCW, Kumar S, Thilakavathy K. Mechanisms of Oral Bacterial Virulence Factors in Pancreatic Cancer. Front Cell Infect Microbiol. 2019;9:412.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 7]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
60.  Fardini Y, Wang X, Témoin S, Nithianantham S, Lee D, Shoham M, Han YW. Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity. Mol Microbiol. 2011;82:1468-1480.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 153]  [Cited by in F6Publishing: 173]  [Article Influence: 13.3]  [Reference Citation Analysis (0)]
61.  Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013;14:195-206.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1511]  [Cited by in F6Publishing: 1367]  [Article Influence: 124.3]  [Reference Citation Analysis (0)]
62.  Zhang Y, Morris JP 4th, Yan W, Schofield HK, Gurney A, Simeone DM, Millar SE, Hoey T, Hebrok M, Pasca di Magliano M. Canonical wnt signaling is required for pancreatic carcinogenesis. Cancer Res. 2013;73:4909-4922.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 130]  [Cited by in F6Publishing: 138]  [Article Influence: 12.5]  [Reference Citation Analysis (0)]
63.  Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, Enk J, Bar-On Y, Stanietsky-Kaynan N, Coppenhagen-Glazer S, Shussman N, Almogy G, Cuapio A, Hofer E, Mevorach D, Tabib A, Ortenberg R, Markel G, Miklić K, Jonjic S, Brennan CA, Garrett WS, Bachrach G, Mandelboim O. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015;42:344-355.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 580]  [Cited by in F6Publishing: 781]  [Article Influence: 86.8]  [Reference Citation Analysis (0)]
64.  Ahn HJ, Lee DS. Helicobacter pylori in gastric carcinogenesis. World J Gastrointest Oncol. 2015;7:455-465.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 64]  [Cited by in F6Publishing: 65]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
65.  Kumar S, Metz DC, Kaplan DE, Goldberg DS. The association of Helicobacter pylori with pancreatic cancer. GastroHep. 2020;2:157-164.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
66.  Hirabayashi M, Inoue M, Sawada N, Saito E, Abe SK, Hidaka A, Iwasaki M, Yamaji T, Shimazu T, Tsugane S. Helicobacter pylori infection, atrophic gastritis, and risk of pancreatic cancer: A population-based cohort study in a large Japanese population: the JPHC Study. Sci Rep. 2019;9:6099.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 13]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
67.  Nilsson HO, Stenram U, Ihse I, Wadstrom T. Helicobacter species ribosomal DNA in the pancreas, stomach and duodenum of pancreatic cancer patients. World J Gastroenterol. 2006;12:3038-3043.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 61]  [Cited by in F6Publishing: 69]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
68.  Gérard P. Metabolism of cholesterol and bile acids by the gut microbiota. Pathogens. 2013;3:14-24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 331]  [Cited by in F6Publishing: 356]  [Article Influence: 32.4]  [Reference Citation Analysis (0)]
69.  Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes. 2016;7:22-39.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 532]  [Cited by in F6Publishing: 600]  [Article Influence: 75.0]  [Reference Citation Analysis (0)]
70.  Hirano S, Masuda N, Mukai H, Hirakawa K, Imamura T. [Transformation of bile acids by Bacteroides fragilis strains isolated from the human intestine (author's transl)]. Nihon Saikingaku Zasshi. 1979;34:403-411.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Mikó E, Vida A, Kovács T, Ujlaki G, Trencsényi G, Márton J, Sári Z, Kovács P, Boratkó A, Hujber Z, Csonka T, Antal-Szalmás P, Watanabe M, Gombos I, Csoka B, Kiss B, Vígh L, Szabó J, Méhes G, Sebestyén A, Goedert JJ, Bai P. Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness. Biochim Biophys Acta Bioenerg. 2018;1859:958-974.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 103]  [Article Influence: 17.2]  [Reference Citation Analysis (0)]
72.  Kovács P, Csonka T, Kovács T, Sári Z, Ujlaki G, Sipos A, Karányi Z, Szeőcs D, Hegedűs C, Uray K, Jankó L, Kiss M, Kiss B, Laoui D, Virág L, Méhes G, Bai P, Mikó E. Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer. Cancers (Basel). 2019;11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 63]  [Article Influence: 12.6]  [Reference Citation Analysis (0)]
73.  Luu TH, Bard JM, Carbonnelle D, Chaillou C, Huvelin JM, Bobin-Dubigeon C, Nazih H. Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells. Cell Oncol (Dordr). 2018;41:13-24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 66]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
74.  Slocum MM, Sittig KM, Specian RD, Deitch EA. Absence of intestinal bile promotes bacterial translocation. Am Surg. 1992;58:305-310.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Rees DO, Crick PJ, Jenkins GJ, Wang Y, Griffiths WJ, Brown TH, Al-Sarireh B. Comparison of the composition of bile acids in bile of patients with adenocarcinoma of the pancreas and benign disease. J Steroid Biochem Mol Biol. 2017;174:290-295.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 29]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
76.  Feng HY, Chen YC. Role of bile acids in carcinogenesis of pancreatic cancer: An old topic with new perspective. World J Gastroenterol. 2016;22:7463-7477.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 61]  [Cited by in F6Publishing: 60]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
77.  Nagathihalli NS, Beesetty Y, Lee W, Washington MK, Chen X, Lockhart AC, Merchant NB. Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids. Cancer Res. 2014;74:2062-2072.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 61]  [Cited by in F6Publishing: 78]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
78.  Hummel D, Aggarwal A, Borka K, Bajna E, Kállay E, Horváth HC. The vitamin D system is deregulated in pancreatic diseases. J Steroid Biochem Mol Biol. 2014;144 Pt B:402-409.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 24]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
79.  Chen XL, Xie KX, Yang ZL, Yuan LW. Expression of FXR and HRG and their clinicopathological significance in benign and malignant pancreatic lesions. Int J Clin Exp Pathol. 2019;12:2111-2120.  [PubMed]  [DOI]  [Cited in This Article: ]
80.  Koutsounas I, Giaginis C, Alexandrou P, Zizi-Serbetzoglou A, Patsouris E, Kouraklis G, Theocharis S. Pregnane X Receptor Expression in Human Pancreatic Adenocarcinoma: Associations With Clinicopathologic Parameters, Tumor Proliferative Capacity, Patients' Survival, and Retinoid X Receptor Expression. Pancreas. 2015;44:1134-1140.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 7]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
81.  Sittipo P, Shim JW, Lee YK. Microbial Metabolites Determine Host Health and the Status of Some Diseases. Int J Mol Sci. 2019;20.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 71]  [Article Influence: 14.2]  [Reference Citation Analysis (0)]
82.  Goodwin AC, Destefano Shields CE, Wu S, Huso DL, Wu X, Murray-Stewart TR, Hacker-Prietz A, Rabizadeh S, Woster PM, Sears CL, Casero RA Jr. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc Natl Acad Sci U S A. 2011;108:15354-15359.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 399]  [Cited by in F6Publishing: 374]  [Article Influence: 28.8]  [Reference Citation Analysis (0)]
83.  Mendez R, Kesh K, Arora N, Di Martino L, McAllister F, Merchant N, Banerjee S. Microbial dysbiosis and polyamine metabolism as predictive markers for early detection of pancreatic cancer. Carcinogenesis. 2020;41:561-570.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 59]  [Article Influence: 14.8]  [Reference Citation Analysis (0)]
84.  Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, Quesada P, Sahin I, Chandra V, San Lucas A, Scheet P, Xu H, Hanash SM, Feng L, Burks JK, Do KA, Peterson CB, Nejman D, Tzeng CD, Kim MP, Sears CL, Ajami N, Petrosino J, Wood LD, Maitra A, Straussman R, Katz M, White JR, Jenq R, Wargo J, McAllister F. Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell. 2019;178:795-806.e12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 469]  [Cited by in F6Publishing: 758]  [Article Influence: 189.5]  [Reference Citation Analysis (0)]
85.  Merali N, Chouari T, Kayani K, Rayner CJ, Jiménez JI, Krell J, Giovannetti E, Bagwan I, Relph K, Rockall TA, Dhillon T, Pandha H, Annels NE, Frampton AE. A Comprehensive Review of the Current and Future Role of the Microbiome in Pancreatic Ductal Adenocarcinoma. Cancers (Basel). 2022;14.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 8]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
86.  Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, Elford AR, Dhanji S, Shaabani N, Tran CW, Dissanayake D, Rahbar R, Ghazarian M, Brüstle A, Fine J, Chen P, Weaver CT, Klose C, Diefenbach A, Häussinger D, Carlyle JR, Kaech SM, Mak TW, Ohashi PS. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci U S A. 2012;109:1210-1215.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 236]  [Cited by in F6Publishing: 248]  [Article Influence: 19.1]  [Reference Citation Analysis (0)]
87.  Yu Q, Xiu Z, Jian Y, Zhou J, Chen X, Chen C, Chen H, Yang S, Yin L, Zeng W. microRNA-497 prevents pancreatic cancer stem cell gemcitabine resistance, migration, and invasion by directly targeting nuclear factor kappa B 1. Aging (Albany NY). 2022;14:5908-5924.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
88.  Aykut B, Pushalkar S, Chen R, Li Q, Abengozar R, Kim JI, Shadaloey SA, Wu D, Preiss P, Verma N, Guo Y, Saxena A, Vardhan M, Diskin B, Wang W, Leinwand J, Kurz E, Kochen Rossi JA, Hundeyin M, Zambrinis C, Li X, Saxena D, Miller G. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature. 2019;574:264-267.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 265]  [Cited by in F6Publishing: 418]  [Article Influence: 83.6]  [Reference Citation Analysis (0)]
89.  Chen Y, Bai X, Zhang Q, Wen L, Su W, Fu Q, Sun X, Lou Y, Yang J, Zhang J, Chen Q, Wang J, Liang T. The hepatitis B virus X protein promotes pancreatic cancer through modulation of the PI3K/AKT signaling pathway. Cancer Lett. 2016;380:98-105.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 26]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
90.  Nista EC, Del Gaudio A, Del Vecchio LE, Mezza T, Pignataro G, Piccioni A, Gasbarrini A, Franceschi F, Candelli M. Pancreatic Cancer Resistance to Treatment: The Role of Microbiota. Biomedicines. 2023;11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 5]  [Reference Citation Analysis (0)]
91.  Attebury H, Daley D. The Gut Microbiome and Pancreatic Cancer Development and Treatment. Cancer J. 2023;29:49-56.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Reference Citation Analysis (0)]
92.  Bastos AR, Pereira-Marques J, Ferreira RM, Figueiredo C. Harnessing the Microbiome to Reduce Pancreatic Cancer Burden. Cancers (Basel). 2023;15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
93.  Chai Y, Huang Z, Shen X, Lin T, Zhang Y, Feng X. Microbiota Regulates Pancreatic Cancer Carcinogenesis through Altered Immune Response. Microorganisms. 2023;11:1240.  [PubMed]  [DOI]  [Cited in This Article: ]
94.  Binda C, Gibiino G, Sbrancia M, Coluccio C, Cazzato M, Carloni L, Cucchetti A, Ercolani G, Sambri V, Fabbri C. Microbiota in the Natural History of Pancreatic Cancer: From Predisposition to Therapy. Cancers (Basel). 2022;15.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
95.  Yang T, Li QQ, Liu YM, Yang B. T cells in pancreatic cancer stroma: Tryptophan metabolism plays an important role in immunoregulation. World J Gastroenterol. 2023;29:2701-2703.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
96.  Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD, Pelczar P, Kylies D, Puelles VG, Bielecka AA, Peschka M, Cortesi F, Riecken K, Jung M, Amend L, Bröring TS, Trajkovic-Arsic M, Siveke JT, Renné T, Zhang D, Boeck S, Strowig T, Uzunoglu FG, Güngör C, Stein A, Izbicki JR, Bokemeyer C, Sinn M, Kimmelman AC, Huber S, Gagliani N. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature. 2023;615:168-174.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 74]  [Article Influence: 74.0]  [Reference Citation Analysis (0)]
97.  Sohal DP, Mangu PB, Khorana AA, Shah MA, Philip PA, O'Reilly EM, Uronis HE, Ramanathan RK, Crane CH, Engebretson A, Ruggiero JT, Copur MS, Lau M, Urba S, Laheru D. Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34:2784-2796.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 193]  [Cited by in F6Publishing: 215]  [Article Influence: 26.9]  [Reference Citation Analysis (0)]
98.  Wai SN, Lindmark B, Söderblom T, Takade A, Westermark M, Oscarsson J, Jass J, Richter-Dahlfors A, Mizunoe Y, Uhlin BE. Vesicle-mediated export and assembly of pore-forming oligomers of the enterobacterial ClyA cytotoxin. Cell. 2003;115:25-35.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 349]  [Cited by in F6Publishing: 368]  [Article Influence: 17.5]  [Reference Citation Analysis (0)]
99.  Sawant SS, Patil SM, Gupta V, Kunda NK. Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment. Int J Mol Sci. 2020;21.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 33]  [Article Influence: 8.3]  [Reference Citation Analysis (0)]
100.  Bezine E, Vignard J, Mirey G. The cytolethal distending toxin effects on Mammalian cells: a DNA damage perspective. Cells. 2014;3:592-615.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 52]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
101.  Yang WS, Park SO, Yoon AR, Yoo JY, Kim MK, Yun CO, Kim CW. Suicide cancer gene therapy using pore-forming toxin, streptolysin O. Mol Cancer Ther. 2006;5:1610-1619.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 46]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
102.  Trivieri N, Panebianco C, Villani A, Pracella R, Latiano TP, Perri F, Binda E, Pazienza V. High Levels of Prebiotic Resistant Starch in Diet Modulate a Specific Pattern of miRNAs Expression Profile Associated to a Better Overall Survival in Pancreatic Cancer. Biomolecules. 2020;11.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 9]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
103.  Kita A, Fujiya M, Konishi H, Tanaka H, Kashima S, Iwama T, Ijiri M, Murakami Y, Takauji S, Goto T, Sakatani A, Ando K, Ueno N, Ogawa N, Okumura T. Probioticderived ferrichrome inhibits the growth of refractory pancreatic cancer cells. Int J Oncol. 2020;57:721-732.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 29]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
104.  Liu MN, Zhang L, Dong XY, Liu M, Cheng G, Zhang XL, He F, Wang GQ. [Effects of Akkermansia muciniphila on the Proliferation, Apoptosis and Insulin Secretion of Rat Islet Cell Tumor Cells]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2020;51:13-17.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
105.  Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S, Dai RM, Kiu H, Cardone M, Naik S, Patri AK, Wang E, Marincola FM, Frank KM, Belkaid Y, Trinchieri G, Goldszmid RS. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342:967-970.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1253]  [Cited by in F6Publishing: 1455]  [Article Influence: 132.3]  [Reference Citation Analysis (0)]
106.  Wallace BD, Wang H, Lane KT, Scott JE, Orans J, Koo JS, Venkatesh M, Jobin C, Yeh LA, Mani S, Redinbo MR. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science. 2010;330:831-835.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 620]  [Cited by in F6Publishing: 685]  [Article Influence: 48.9]  [Reference Citation Analysis (0)]
107.  Lin XB, Farhangfar A, Valcheva R, Sawyer MB, Dieleman L, Schieber A, Gänzle MG, Baracos V. The role of intestinal microbiota in development of irinotecan toxicity and in toxicity reduction through dietary fibres in rats. PLoS One. 2014;9:e83644.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 50]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
108.  Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Bérard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079-1084.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1834]  [Cited by in F6Publishing: 2179]  [Article Influence: 242.1]  [Reference Citation Analysis (0)]
109.  Mirji G, Worth A, Bhat SA, El Sayed M, Kannan T, Goldman AR, Tang HY, Liu Q, Auslander N, Dang CV, Abdel-Mohsen M, Kossenkov A, Stanger BZ, Shinde RS. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer. Sci Immunol. 2022;7:eabn0704.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 74]  [Article Influence: 37.0]  [Reference Citation Analysis (0)]
110.  Raimondi G, Gea-Sorlí S, Otero-Mateo M, Fillat C. Inhibition of miR-222 by Oncolytic Adenovirus-Encoded miRNA Sponges Promotes Viral Oncolysis and Elicits Antitumor Effects in Pancreatic Cancer Models. Cancers (Basel). 2021;13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 3]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
111.  Xie Y, Xie F, Zhou X, Zhang L, Yang B, Huang J, Wang F, Yan H, Zeng L, Zhou F. Microbiota in Tumors: From Understanding to Application. Adv Sci (Weinh). 2022;9:e2200470.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 23]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
112.  Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, Rotter-Maskowitz A, Weiser R, Mallel G, Gigi E, Meltser A, Douglas GM, Kamer I, Gopalakrishnan V, Dadosh T, Levin-Zaidman S, Avnet S, Atlan T, Cooper ZA, Arora R, Cogdill AP, Khan MAW, Ologun G, Bussi Y, Weinberger A, Lotan-Pompan M, Golani O, Perry G, Rokah M, Bahar-Shany K, Rozeman EA, Blank CU, Ronai A, Shaoul R, Amit A, Dorfman T, Kremer R, Cohen ZR, Harnof S, Siegal T, Yehuda-Shnaidman E, Gal-Yam EN, Shapira H, Baldini N, Langille MGI, Ben-Nun A, Kaufman B, Nissan A, Golan T, Dadiani M, Levanon K, Bar J, Yust-Katz S, Barshack I, Peeper DS, Raz DJ, Segal E, Wargo JA, Sandbank J, Shental N, Straussman R. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020;368:973-980.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 490]  [Cited by in F6Publishing: 957]  [Article Influence: 239.3]  [Reference Citation Analysis (0)]
113.  Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D, Gavert N, Zwang Y, Cooper ZA, Shee K, Thaiss CA, Reuben A, Livny J, Avraham R, Frederick DT, Ligorio M, Chatman K, Johnston SE, Mosher CM, Brandis A, Fuks G, Gurbatri C, Gopalakrishnan V, Kim M, Hurd MW, Katz M, Fleming J, Maitra A, Smith DA, Skalak M, Bu J, Michaud M, Trauger SA, Barshack I, Golan T, Sandbank J, Flaherty KT, Mandinova A, Garrett WS, Thayer SP, Ferrone CR, Huttenhower C, Bhatia SN, Gevers D, Wargo JA, Golub TR, Straussman R. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357:1156-1160.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 944]  [Cited by in F6Publishing: 912]  [Article Influence: 130.3]  [Reference Citation Analysis (0)]
114.  Helmink BA, Khan MAW, Hermann A, Gopalakrishnan V, Wargo JA. The microbiome, cancer, and cancer therapy. Nat Med. 2019;25:377-388.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 444]  [Cited by in F6Publishing: 459]  [Article Influence: 91.8]  [Reference Citation Analysis (0)]
115.  Rogers CJ, Prabhu KS, Vijay-Kumar M. The microbiome and obesity-an established risk for certain types of cancer. Cancer J. 2014;20:176-180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 45]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
116.  Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490:55-60.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3971]  [Cited by in F6Publishing: 4333]  [Article Influence: 361.1]  [Reference Citation Analysis (0)]
117.  Brubaker L, Luu S, Hoffman K, Wood A, Navarro Cagigas M, Yao Q, Petrosino J, Fisher W, Van Buren G. Microbiome changes associated with acute and chronic pancreatitis: A systematic review. Pancreatology. 2021;21:1-14.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 6]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
118.  Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, Al-Soud WA, Sørensen SJ, Hansen LH, Jakobsen M. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One. 2010;5:e9085.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1783]  [Cited by in F6Publishing: 1897]  [Article Influence: 135.5]  [Reference Citation Analysis (0)]
119.  Maisonneuve P, Amar S, Lowenfels AB. Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis. Ann Oncol. 2017;28:985-995.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 91]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
120.  Hayashi C, Gudino CV, Gibson FC 3rd, Genco CA. Review: Pathogen-induced inflammation at sites distant from oral infection: bacterial persistence and induction of cell-specific innate immune inflammatory pathways. Mol Oral Microbiol. 2010;25:305-316.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 166]  [Cited by in F6Publishing: 177]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
121.  Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860-867.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10123]  [Cited by in F6Publishing: 10622]  [Article Influence: 482.8]  [Reference Citation Analysis (0)]
122.  Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436-444.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6912]  [Cited by in F6Publishing: 7761]  [Article Influence: 485.1]  [Reference Citation Analysis (0)]
123.  Michaud DS, Izard J, Wilhelm-Benartzi CS, You DH, Grote VA, Tjønneland A, Dahm CC, Overvad K, Jenab M, Fedirko V, Boutron-Ruault MC, Clavel-Chapelon F, Racine A, Kaaks R, Boeing H, Foerster J, Trichopoulou A, Lagiou P, Trichopoulos D, Sacerdote C, Sieri S, Palli D, Tumino R, Panico S, Siersema PD, Peeters PH, Lund E, Barricarte A, Huerta JM, Molina-Montes E, Dorronsoro M, Quirós JR, Duell EJ, Ye W, Sund M, Lindkvist B, Johansen D, Khaw KT, Wareham N, Travis RC, Vineis P, Bueno-de-Mesquita HB, Riboli E. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut. 2013;62:1764-1770.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 283]  [Cited by in F6Publishing: 274]  [Article Influence: 24.9]  [Reference Citation Analysis (0)]
124.  Gnanasekaran J, Binder Gallimidi A, Saba E, Pandi K, Eli Berchoer L, Hermano E, Angabo S, Makkawi HA, Khashan A, Daoud A, Elkin M, Nussbaum G. Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells. Cancers (Basel). 2020;12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 57]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
125.  Wei MY, Shi S, Liang C, Meng QC, Hua J, Zhang YY, Liu J, Zhang B, Xu J, Yu XJ. The microbiota and microbiome in pancreatic cancer: more influential than expected. Mol Cancer. 2019;18:97.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 154]  [Article Influence: 30.8]  [Reference Citation Analysis (0)]
126.  Maekawa T, Fukaya R, Takamatsu S, Itoyama S, Fukuoka T, Yamada M, Hata T, Nagaoka S, Kawamoto K, Eguchi H, Murata K, Kumada T, Ito T, Tanemura M, Fujimoto K, Tomita Y, Tobe T, Kamada Y, Miyoshi E. Possible involvement of Enterococcus infection in the pathogenesis of chronic pancreatitis and cancer. Biochem Biophys Res Commun. 2018;506:962-969.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 59]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]