After analyzed 24 studies using a random effects model, including a total of 274, 0958 patients. This meta-analysis aimed to clarify that long-term use of PPI may increase the risk of hepato-biliary-pancreatic cancer.
Based on the results of our study, a normal dose of PPI is associated with an increased risk of developing hepato-biliary-pancreatic cancer. We found no correlation between higher dose of PPI use (cDDD > 2000/per patient) and the risks of hepato-biliary-pancreatic cancer.
Several mechanisms suggest a potential oncogenic effect of PPI in hepato-biliary-pancreatic cancer. These effects include an increase in levels of abnormal gastrointestinal hormones and intestinal microbiota, as well as the production of carcinogens.
4.1 Abnormal levels of gastrin and cholecystokinin
Prolonged use of PPI leads to a rise in gastric pH and an increase in gastrin production by G-cells with negative feedback. In addition to stimulating the secretion of digestive glands and accelerating nutrient absorption, gastrin seems to induce the development and growth of gastrointestinal cancers by binding to CCK-BR on the surface of the enterochromaffin-like cells (ECL) (30). In hepatocellular carcinoma, CCK-BR and a precursor form of gastrin are expressed in tumor cells (31), and this expression may be associated with apoptosis (32). Gastrin-releasing peptide promotes hepatocellular carcinoma cell growth not only by interacting with homologous receptors of gastrin-releasing peptide co-expressed in tumor cells but also by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) pathway through a non-dependent mechanism of the epidermal growth factor receptor (EGFR) (32), it can also inhibit the growth of normal liver cells by blocking the activation of ER (33). A DNA vaccine targeting gastrin-releasing peptide has been shown to inhibit the growth of blood vessels in liver tumors and to destroy tumor cells (34, 35). However, in cholangiocarcinoma, gastrin appears to have the opposite effect to that of hepatocellular carcinoma, inhibiting the proliferation of cholangiocarcinoma cells and inducing apoptosis via the Ca2 + dependent protein kinase C (PKC)-α pathway (36). However, when gastrin receptors are the target of pancreatic cancer treatment, specific antagonists can inhibit the growth of pancreatic cancer cells by blocking the cellular stimulatory effect of gastrin. Current clinical studies have demonstrated that these drugs have the potential to prolong survival and are no less effective than conventional treatments for pancreatic cancer (37), however, further research is needed on their safety and long-term efficacy (38).
A current study has proved long-term PPI use may pose a risk for gallbladder dysfunction and biliary complications (39), a retrospective analysis of stone recurrence in patients after endoscopic retrograde cholangiopancreatography (ERCP) found that PPI may pose a risk for recurrence of common bile duct stone (CBDS) in ERCP patients (40). long-term PPI use may be associated with the abnormal secretion of CCK, a gastrointestinal peptide released from the upper part of the small intestine, which has a similar peptide structure to gastrin. CCK has functions that include stimulation of intestinal motility, stimulation of pancreatic enzyme secretion, and stimulation of gastric acid secretion (41). Its primary function is to trigger gallbladder emptying by binding to the CCK A-type receptor (CCKAR) and mediating the activation of post-membrane signaling pathways in smooth muscle, defects in CCKAR are a key point of impairment of gallbladder motility, which in turn may form the background for GBC (42, 43), abnormal level of CCK results in reduced or delayed postprandial gallbladder contraction, leading to bile stagnation and creating an environment for cholesterol supersaturation and subsequent gallstone formation (41, 43–46). Both CCK and its receptor CCKAR are important in the pathogenesis of biliary tract tumors, CCK is currently thought to exhibit growth-stimulating effects on biliary tract-derived cancer cell line (44), an analysis of the biliary tract tumor in Shanghai, China, found that women with the CCKAR genotype were at increased risk of gallbladder cancer, and biliary tumorigenesis may be inhibited when CCKAR is in an antagonistic state (45). However, CCKAR receptors are more highly expressed in patients with cholelithiasis than in the normal population, while CCKAR expression is reduced in patients with GBC (46), it may be because CCK remains chronically high in CA patients, leading to a decrease in receptor number and activity responsiveness. However, Kazmi observed a significant increase in CCKAR mRNA and protein expression in GBC tissues (47). Furthermore, gastrin or CCK showed a definite growth stimulating effect on biliary tract-derived cancer cell lines, and CCKAR and CCK-BR mRNA were detected in all biliary and pancreatic cancer (48). CCK also has a pro-pancreatic function in the normal gastrointestinal environment, and high CCK levels have been found to stimulate abnormal pancreatic growth and promote early carcinogenesis and malignant tumor growth by binding to CCKAR, pro-carcinogenic effect of CCK can be inhibited by antagonizing CCKAR (49). Although CCKR expression has been widely reported in many tumors (31), relevant studies have shown that none of the cancer samples had statistically higher CCKR expression than all normal samples (50). Therefore, the association between CCK and Hepato-biliary-pancreatic cancer still needs to be further investigated (51).
4.2 Abnormal gut microbiota
The distribution of microorganisms in the gastrointestinal tract depends mainly on the pH gradient and the abundance of oxygen, and the changes in pH due to long-term PPI use are limited to the duodenum and proximal small intestine (52), this part of the gastrointestinal tract is more closely related to the hepatobiliary and pancreas, bacteria may enter the body circulation through portal vein transfer and activate pro-inflammatory pathways organs (53), which may induce solid tumor growth if these pathways are activated over time (54). When the inflammatory pathway is activated, it may lead to the abnormal metabolism of bile acids, thus inducing cholestatic liver cancer (55). Bacteria can disrupt the normal DNA repair by producing toxins and alter the bile acid metabolism process by enzymes on the surface of bacteria, thus leading to local inflammation and vascular proliferation in the tissues and increasing the possibility of biliary tract stone formation, which are potential biliary tumor carcinogenic mechanisms (56–58).
long-term PPI reduces gastrointestinal microbial diversity by blocking gastric acid secretion and affecting gut microbiota diversity (59, 60), it can increase the growth of potentially pathogenic bacteria such as Clostridium difficult, Enterococcus, Streptococcus, Staphylococcus, and E. coli (61, 62), as well as the disruption of the intestinal barrier and the alteration of intestinal permeability, these changes in the normal structure and microbiota can lead to excessive accumulation of lipopolysaccharides (LPS) and increased levels of deoxycholic acid in the tumor microenvironment, and hyper-deoxycholic acidemia can induce the development of HCC by damaging DNA (63), LPS promotes HCC pathogenesis and metastasis and affects prognosis by upregulating toll-like receptor (TLR4) expression, thereby increasing cell proliferation, inhibiting apoptosis and producing a specific systemic inflammatory response. Activation of TLR2 by lipid wall phosphate in bacteria and ursodeoxycholic acid leads to upregulation of the senescence-associated secretory phenotype (SASP) and cyclooxygenase 2 (COX-2), which mediates prostaglandin 2 inhibition of antitumor immunity via EP4 receptors, thereby inducing HCC progression (64).
As an important secretory organ of the body, the pancreas requires the assistance of intestinal microorganisms for the application of its digestive enzymes. The antimicrobial activity of pancreatic fluid protects the pancreas from retrograde infection and contributes to the diversity of the gut microbiota. However, intestinal microorganisms can reach the pancreas via the circulatory system or the biliary/pancreatic duct, especially in the case of abnormal gut microbiota (65). The current study suggests that the abnormal distribution of Enterococcus faecalis and Escherichia coli may be associated with the progression of pancreatic tumors associated with pancreatitis (66). Microorganisms promote tumor development, invasion and migration by activating the inflammatory response, increasing pro-inflammatory cell recruitment and cytokine secretion, increasing exposure to oxidative stress, altering energy dynamics, and damaging DNA, ultimately leading to molecular alterations and tumor transformation. In addition, chronic inflammation caused by non-pathogenic bacteria can induce the production of angiogenic factors, which increase the oxygen as well as nutrient supply to tumor and directly accelerate cancer cell growth. Alterations in several molecular mechanisms: oncogene mutations, oncogene inactivation, loss of heterozygosity, and chromosomal and microsatellite instability are also involved in inflammation-mediated oncogenesis. Cells within the microenvironment control tumor growth through the production of autocrine, paracrine, and endocrine mediators (67). It is believed that abnormal gut microbiota is an important cause of weight-related tumors, weight abnormalities aggravate the homogeneity of the gut microbiota by increasing deoxycholic acid production, which can lead to DNA damage, and activate the K-RAS pathway to induce pancreatic cancer (68). LPS on the cytosolic surface of bacteria are involved in the progression and invasion of pancreatic cancer through a cascade reaction generated by LPS-TLR, but no studies have shown this mechanism increases the risk of pancreatic cancer (69–71).
Bile acid concentrations in the digestive tract are significantly higher in GERD patients receiving long-term PPI therapy than in healthy individuals (72), Bile acids can directly disrupt the plasma membrane and cause activation of the PKC and p38 MAPK pathways, which result in a cascade reaction that activates the downstream IL-6 and Janus kinase (JAK) - signal transducer and activator of transcription 3 (STAT3) pathways, then leading to HCC (73), and persistently high bile acid levels can stimulate the development of HCC (74).
Insufficient gastric acid leads to microbiota translocation and overgrowth in the digestive tract leading to dysbiosis, and an increased pH leads to bacterially catalyzed N- nitrosamine leading to nitrosamine reduction and rapid nitrosamine production in the lumen. Faster nitrosation triggers the production of potentially carcinogenic N-nitrosamines in the digest tract (75). The association between nitrosamines and various types of cancer has been extensively studied (76). The association between nitrosamines and various types of cancer has been extensively studied (77), which can increase the risk of pancreatic cancer by affecting β2-AR signaling and upregulating HIF-1α expression (78), it also caused DNA damage and decreased repair capacity in the pancreatic duct epithelium in synergy with glucagon (79, 80), however, a meta-analysis of the association between nitrosamine exposure and pancreatic cancer development did not report a direct association (81, 82). In hepatocellular carcinoma, nitrosamine induces apoptosis in human normal liver cell lines through endogenous and exogenous pathways of caspases (83), nitrosamine has been shown to induce hepatocellular carcinoma in mouse models (84). Therefore, it is reasonable to assume that nitrites produced by gut microbiota disorders have varying degrees of induction in Hepato-biliary-pancreatic cancer.
Long-term abnormal hormonal stimulation, decreased diversity of gut microbiota, production of carcinogenic substances, chronic inflammation, and activation of tumor pathways may all be biologically linked to long-term PPI use, and therefore the amplification of these biological mechanisms and the synergy between them should be further investigated.
4.3 Significance of the study
Current guidelines for GERD, hemorrhagic ulcers and H. pylori infection use IPPs as the drug of choice, but PPI also have the potential to alter the structure of upper gastrointestinal pH, which has potential links to previous studies on the pathogenesis of hepato-biliary-pancreatic cancer, and our study supports the view that excessive use of PPI increases the risk of hepatobiliary-pancreatic cancer. This may lead clinicians to be more careful in choosing indications and to control the dose of the drug so that the disease population is treated properly without worrying about increased tumor risk.