Cancer has always been the focus of human attention around the world, and the incidence of cancer, such as breast, prostate and lung cancer, has increased rapidly in recent years. Gastrointestinal cancer leads the way in terms of morbidity and mortality and causes a significant socioeconomic burden.
Gastrointestinal cancers include stomach, liver, esophagus, pancreatic and colorectal cancers, accounting for more than a quarter of all cancers.
▷ Life behavior affects gastrointestinal cancer
Current evidence suggests that socio-economic development has led to some lifestyle changes. For example, smoking and alcohol consumption are the most common risk factors for cancer, and there is a growing consensus that dietary habits are listed as risk factors for gastrointestinal cancer. These behaviors are directly or indirectly associated with the emergence of various chronic noncommunicable diseases and gastrointestinal cancers.
▷ Gut microbes affect gastrointestinal cancer
The gut microbiota plays an important role in both human health and disease status. Numerous studies have demonstrated that the gut microbiota has an impact on gastrointestinal cancers, including esophageal, gastric, colorectal, liver, and pancreatic cancers.
In this article, some basic characteristics of gastrointestinal cancer are described, and the impact of unhealthy behaviors, diets, and changes in the gut microbiota affected by them in the context of social progress on gastrointestinal cancers is discussed. It is hoped that it will help in the prevention, diagnosis and treatment of gastrointestinal cancers in the future.
This article is mainly covered in three parts
Part 1: Some basic features of gastrointestinal cancer
Part 2: Effects of poor lifestyle on gastrointestinal cancer
Part3: The relationship between gut microbes and gastrointestinal cancer
Part 1
Gastrointestinal cancers
Gastrointestinal (GI) cancers, including stomach, liver, esophageal, pancreatic, and colorectal cancers, which are the most common cancers and one of the leading causes of death worldwide, are on the rise.
According to pre-pandemic statistics, in 2018, there were about 5 million new cases of gastrointestinal cancer and more than 3 million related deaths.
Gastrointestinal cancers are a serious hazard to people's health
DATA OBTAINED FROM THE GLOBOCAN DATABASE ESTIMATES THAT THERE WERE MORE THAN 600,000 NEW CASES OF ESOPHAGEAL CANCER AND MORE THAN 500,000 RELATED DEATHS IN 2020.
Using the same database, the analysis estimated that there were 1.1 million new cases of gastric cancer and more than 700,000 related deaths worldwide in 2020.
Similarly, the incidence of colorectal cancer has been rising at an alarming rate, with an estimated 1.9 million new cases and 900,000 related deaths globally in 2020.
Gastrointestinal cancer has become a health problem that cannot be ignored, let's take a look at these cancers:
Esophageal carcinoma
Esophageal cancer is the fourth most common cancer of the gastrointestinal tract.
Squamous cell carcinoma is the most common histological type of esophageal cancer
There are two main histological subtypes of esophageal cancer: adenocarcinoma and squamous cell carcinoma (SCC). Squamous cell carcinoma is the leading subtype worldwide.
More than 90% of esophageal cancers in mainland China are squamous cell carcinoma, and a few are adenocarcinoma. Most patients with esophageal cancer present with advanced disease; As a result, the average 5-year overall survival rate is only 18%.
Note: Adenocarcinoma ranks first in the United States and Northern Europe (about 60%).
✦Symptoms of esophageal cancer
There are no obvious symptoms in the early stages
Esophageal cancer is often asymptomatic in the early stages, and occasionally presents with retrosternal dull pain and discomfort. As the tumor enlarges, patients experience discomfort swallowing or a foreign body sensation when eating. It often presents with a slowing rate of eating and often requires soup to be delivered.
Exacerbation causes the tumor to enlarge and obstruct the esophagus
After a few months, because the tumor further enlarged and blocked the lumen of the esophagus, the patient could only eat liquids, and when the tumor completely blocked the lumen, the patient showed "dripping difficulty". It usually takes about a year from symptom onset to complete obstruction.
Therefore, if you have suspicious symptoms, you should go to the hospital as soon as possible for examination.
✦The incidence of esophageal cancer is higher in men than in women
There are large differences between men and women in esophageal cancer, and the proportion of esophageal cancer in men is significantly higher than that in women. Esophageal cancer occurs three times more often in men than in women.
The main risk factors for squamous cell carcinoma are alcohol consumption and smoking, while the main risk factors for adenocarcinoma are gastroesophageal reflux (especially erosive esophagitis and Barrett's esophagus), smoking, and obesity.
Clinical gastroesophageal reflux syndrome and damage to the esophageal mucosa caused by excessive contact (or exposure) of gastric juice in the gastroesophageal lumen is called gastroesophageal reflux.
gastric cancer
Stomach cancer is the fifth most common cancer worldwide and the third leading cause of cancer-related mortality.
✦Symptoms of stomach cancer
According to the depth of invasion of cancer tissue, it is divided into early gastric cancer and advanced gastric cancer (intermediate and advanced gastric cancer).
Gastric cancer is more difficult to diagnose in the early stages
Symptoms of gastric cancer and precancerous lesions are insidious and non-specific, so early gastric cancer is difficult to detect. In fact, only 5~10% of stomach cancer in China can be diagnosed early.
Such as unpredictable epigastric discomfort, dull pain, pantothenic acid, loss of appetite, mild anemia and other symptoms similar to gastroduodenal ulcer or chronic gastritis.
As the disease progresses, stomach symptoms gradually become obvious, including epigastric pain, loss of appetite, weight loss, weight loss and anemia. In the later stage, there are often cancer metastasis, abdominal mass, left supraclavian lymph node swelling, melena, ascites and severe malnutrition.
✦Stomach cancer varies greatly among different populations
Non-cardia gastric cancer (NCGC) accounts for nearly 75% of gastric cancer cases. Similar to other gastrointestinal cancers, the epidemiology of noncardia gastric cancer varies greatly among different populations.
Incidence of non-cardia gastric cancer in East Asia (34 per 100,000 in Korea; Japan has 28 per 100,000 people) significantly higher than Europe or the United States (6 per 100,000 people).
✦Risk factors affecting stomach cancer
In addition to Helicobacter pylori infection, other major risk factors for stomach cancer include increasing age, sex, ethnicity, type of dietary intake, socioeconomic status, genetics, and smoking.
Although the incidence of stomach cancer in the United States has declined over the past few decades, the incidence of non-cardia gastric cancer has increased in people 50 years of age or younger, and late diagnosis and poor prognosis are often present.
Colorectal cancer
Colorectal cancer is a common malignancy of the digestive tract and the second leading cause of cancer-related death, with approximately 1.8 million new cases worldwide each year.
The onset is mostly after the age of 40, and the common site is the rectum and the junction of the rectum and sigmoid colon, and the male to female ratio is about 2:1.
✦Symptoms of colorectal cancer
The clinical manifestations of colorectal cancer vary according to the size, location and pathological type of the lesion.
Early symptoms:
Abdominal discomfort: may be manifested as abdominal distention, abdominal dull pain and other uncomfortable symptoms, pain mostly appears in the middle and lower abdomen, gradually worsening;
Changes in bowel habits: frequent stools, diarrhea or constipation may occur, diarrhea and constipation may alternate, and there may be dull abdominal pain, distention, etc.
Mid-stage symptoms:
Abdominal mass: when the tumor grows to a certain size, it may palpate the mass in the abdomen, which can be pushed at the beginning, but it is not easy to push after invading the surrounding tissues;
Nausea and vomiting: when the tumor invades the stomach, patients may experience symptoms such as nausea and vomiting;
Late symptoms:
Intestinal obstruction: more common in the left colon, invades and infiltrates from the tumor to the periphery of the intestinal wall, resulting in intestinal obstruction caused by narrowing of the intestinal lumen, mostly chronic incomplete intestinal obstruction. Abdominal distension, abdominal pain, hyperactive bowel sounds, constipation, thinning of stool, etc. may occur first;
Symptoms of systemic poisoning: more common in the right colon, because the tumor consumes nutrients in the body, and causes chronic long-term bleeding, and can also be secondary infection, so anemia, weight loss, fever, weakness, edema and other systemic poisoning symptoms can occur;
Metastasis symptoms: multiple metastases can occur in the advanced stage of colon cancer, and liver metastasis can cause hepatic enlargement, jaundice, and ascites; Pulmonary metastases may present with symptoms such as cough, shortness of breath, bloody sputum, or dyspnea; Brain metastases may cause hemiplegia and coma; Bone metastases may include bone pain, claudication, etc. Eventually, cachexia manifestations may appear, causing systemic multi-organ failure.
✦Risk factors affecting colorectal cancer
More than 90% of colorectal cancer cases are episodic, highlighting the importance of environmental risk factors in addition to cancer-related genes. Examples include unhealthy eating patterns, being overweight, obesity, type 2 diabetes, being sedentary, smoking, and drinking alcohol.
As observed in other epidemiological studies of gastrointestinal cancers, colorectal cancer incidence varies widely between countries and geographic regions, with the highest incidence in Australia and New Zealand and the lowest incidence in Central and South Asia.
Industrialization has affected the incidence of colorectal cancer
Several studies support the relationship between high HDI and colorectal cancer morbidity and mortality; Developed countries typically report the highest incidence. Although economic development and consequent industrialization promise to improve access to healthcare, this has greatly influenced lifestyles and unhealthy habits.
Still, incidence is rising in many less developed countries, and large differences in colorectal cancer rates in countries such as Canada and Brazil may be related not only to health policies but also to regional poverty.
hepatocarcinoma
It is generally divided into hepatocellular carcinoma and intrahepatic cholangiocarcinoma
Primary liver cancer can generally be divided into hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which account for about 75-85% of liver cancer cases.
A poor prognosis is a hallmark of the disease; Therefore, the incidence and mortality of liver cancer are closely related. Liver cancer ranks third in the incidence and mortality rate of gastrointestinal cancers. In addition, liver cancer is the sixth to seventh most common cancer worldwide and the fourth leading cause of cancer-related death.
✦Symptoms of liver cancer
Early symptoms: liver cancer from the first cancer cell formation to the development of conscious symptoms, it takes about 2 years, during this period, patients may not have any symptoms or signs, a small number of patients will appear loss of appetite, upper abdominal distension, fatigue, etc., some patients may be mild hepatomegaly.
Intermediate and advanced symptoms: The typical symptoms and signs of liver cancer generally appear in the middle and late stages, mainly including liver pain, fatigue, weight loss, jaundice, ascites, etc.
Metastatic symptoms: If liver cancer metastasizes, corresponding symptoms may occur. Pulmonary metastases may present with symptoms such as cough and sputum, and bone metastases may present with painful symptoms.
✦Liver cancer varies greatly by region
The global distribution of liver cancer varies widely, with nearly 75% of cases occurring in Asia, with China accounting for more than 50% of cases and Mongolia having the highest incidence (93.7 per 100,000).
Over the past four decades, some countries, such as the United States, Canada, New Zealand and Australia, have seen an increase in liver cancer cases.
✦Risk factors affecting liver cancer
viral hepatitis
Hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as alcohol consumption, are considered the most important risk factors for hepatocellular carcinoma worldwide.
Nonalcoholic fatty liver disease
With the high prevalence of obesity, diabetes, and related metabolic syndromes, nonalcoholic fatty liver disease is considered one of the most common causes of chronic liver disease and associated causes of hepatocellular carcinoma.
The process of industrialization has affected the socio-economic environment, changes in people's lifestyles, favored a high-calorie Westernized diet, and increased the incidence of obesity and diabetes.
pancreatic cancer
Pancreatic cancer is the least common of the five major gastrointestinal cancers, with a cumulative 5-year survival rate of only 5–15%.
The incidence of pancreatic cancer has shown a rapid increase in recent years, and the mortality rate ranks first, so it is also known as the "king of cancer".
✦Symptoms of pancreatic cancer
Pancreatic cancer is one of the deadliest cancers, which is characterized by: difficult to detect (mostly advanced), short course of disease, rapid progression and deterioration, median survival of 3-6 months, the so-called "silent killer".
The early clinical manifestations of pancreatic cancer are often non-specific and similar to many other common diseases. The main symptoms in the middle and late stages are: unexplained anorexia, indigestion and weight loss; discomfort or pain in the abdomen; Jaundice.
✦Risk factors affecting pancreatic cancer
Pancreatic cancer incidence and mortality are 3-4 times higher in high HDI countries, with North America, Europe and Australia/New Zealand reporting the highest incidence, with slightly higher rates in men than in women.
High body mass index (BMI), type 2 diabetes, and alcohol and smoking are variable risk factors for pancreatic cancer. Regarding the risk of pancreatic cancer, the incidence ratio of smokers to non-smokers was found to be about 1.74. Heavy alcohol consumption appears to be associated with pancreatic cancer and is a related cause of pancreatitis, which is also an established risk factor for pancreatic cancer.
Note: Pancreatic cancer is usually highly aggressive and difficult to diagnose due to nonspecific clinical findings. In addition, the diagnostic accuracy varies greatly across countries and regions within the same country, mainly related to cities, metropolises, and highly developed centers.
Part 2
Affects the lifestyle behavior of gastrointestinal cancer
China has the largest number of new cases and deaths from liver, esophageal and gastric cancer in the world, with 1.21 million new confirmed cases in 2020. The incidence of colorectal cancer in China is also rising rapidly, accounting for more than 40% of the global incidence in 2020.
China has a heavy burden of gastrointestinal tumors, and the incidence is higher than the world average.
★ Cancers of the gastrointestinal tract are associated with lifestyle habits
China has experienced rapid changes in lifestyle such as diet and nutrition, physical activity and smoking in recent decades. There is substantial evidence to support the association of gastrointestinal cancers with diet and other lifestyle risk factors.
Measuring temporal trends in life factors such as diet associated with gastrointestinal cancer risk will help measure future trends in gastrointestinal cancer incidence caused by these factors, influence public health policies to prevent cancer, and optimize resource allocation for health promotion.
The research team described and predicted temporal trends in dietary and lifestyle factors and related gastrointestinal cancer burden in China based on data from the China Health and Nutrition Survey (CHNS) from 1991 to 2011.
Wu Y, et al. Gastroenterology.2021
Here's a look at the specific relationship between these lifestyles and gastrointestinal cancers:
Drinking
Alcohol consumption is a major risk factor for the global burden of disease, and drinking alcohol increases the risk of cancer. Since 1990, global per capita adult alcohol consumption has increased, with current drinking rates increasing from 45% to 47% and lifetime abstinence rates from 46% to 43%, both of which are expected to continue by 2030.
✦ Heavy drinking increases cancer risk
Alcoholic beverages cause nearly 4% of cancers, and the highest risk is associated with heavy alcohol consumption. Taking into account different drinking patterns, studies have shown different associations between cancer risk and frequency of alcohol consumption, the amount of alcohol typically consumed each day, and occasional heavy drinking, all of which are associated with increased risk.
Educational status, diet, smoking, personal preferences, and regional and religious habits are some of a variety of lifestyle factors associated with drinking or abstinence patterns that may confound the results of current studies.
Several gastrointestinal cancers have been linked to alcohol consumption:
Squamous cell esophageal cancer is associated with alcohol consumption but not esophageal adenocarcinoma.
Studies have shown mixed outcomes for colorectal and pancreatic cancer; The risk of pancreatic cancer appears to be associated with heavy alcohol consumption, while the risk of colorectal cancer is associated with moderate or heavy alcohol consumption.
Regarding stomach cancer, a 2018 World Cancer Research Fund/American Institute for Cancer Research report observed an increased risk of stomach cancer in people with an alcohol intake of >45 g/day.
Hepatocellular carcinoma is directly associated with alcohol consumption; This association is primarily driven by alcohol-related cirrhosis, alcohol consumption by people living with hepatitis B or C virus, and possibly heavy alcohol consumption.
✦Some ways alcohol causes cancer
Alcohol may promote carcinogenesis through a variety of pathways, including: ethanol and its metabolite acetaldehyde affect DNA methylation, leading to the expression of oncogenes; Acetaldehyde forms DNA adducts that impair DNA synthesis and repair and lead to mutations.
In addition to this, inflammation, induction of oxidative stress, disruption of folate absorption, decreased immune system function, dysbiota, cirrhosis, and changes in estrogen regulation may also play a role in cancer development.
smoking
Smoking is a major risk factor for a variety of diseases, including gastrointestinal cancers.
★ Tobacco is very harmful
Despite the decline in smoking rates in recent decades, smoking-related illness and death remains a serious concern and a global health problem.
The 2019 Global Burden of Disease, Injury and Risk Factors Study identified smoking as the dominant factor among 87 risk factors in terms of disability-adjusted life expectancy.
Tobacco smoke contains different chemical agents, including reactive oxygen species (ROS) and reactive nitrogen species (RNS). Oxidative damage leads to genetic and epigenetic alterations, gene dysregulation, disruption of regulatory elements, and activation of inflammatory response pathways, leading to further production of reactive oxygen species in a vicious cycle and possibly eventually the development and progression of cancer.
✦Smokers have a higher risk of gastrointestinal cancer
Increased risk of esophageal squamous cell carcinoma
Research over the past few decades supports the relationship between smoking and gastrointestinal cancer. Smoking is also associated with a 20-30% increased risk of esophageal squamous cell carcinoma, and it is important to note the synergistic effect of the combination of alcohol and tobacco.
People who smoke have a higher risk of stomach cancer
The data also suggest that smoking is a risk factor for cardia and non-cardia gastric cancer. For other gastrointestinal cancers, smokers with higher smoking rates have a higher risk of stomach cancer.
Meta-analyses also support the role of smoking in the development of colorectal cancer. Smoking is a recognized risk factor for liver and pancreatic cancer. A 2014 report by the U.S. Secretary of Health showed that current smokers have a 70 percent increased risk of liver cancer from smoking, and former smokers have increased their risk of liver cancer by 40 percent.
The risk of pancreatic cancer was highest among those who smoked the most daily times. Meta-analysis studies have found that the ratio of patients with pancreatic cancer is higher in current smokers compared to non-smokers, but higher in heavy smokers, which decreases proportionally with the number of years after quitting smoking.
The benefits of quitting smoking have been well documented. People who quit smoking have a reduced risk of death and cancer.
Smoking cessation and tobacco consumption control require strategic planning. Successful attempts to quit smoking are associated with socioeconomic status, education level, access to former tobacco advertising, anti-tobacco campaigns, and living with other smokers.
High-fat diet
High-fat diets can significantly promote the occurrence and progression of gastrointestinal tumors, mainly involving metabolic reprogramming and alteration of various carcinogenic molecules.
Association of high-fat diets with gastrointestinal cancers
Tong Y, et al. Theranostics.2021
✦The incidence of esophageal cancer is higher under a high-fat diet
As early as 1994, it was found that mice fed a high-fat diet had a higher incidence of esophageal cancer, suggesting an association between high-fat diet and esophageal cancer.
Changes in the bile acid composition
A high-fat diet can lead to changes in the bile acid composition of mice, especially taurocholic acid and taursodeoxycholic acid, leading to an increased incidence of esophageal and esophageal cancer in mouse Barrett.
Barrett's esophagus – The squamous epithelium in the lower esophagus is covered by a columnar epithelium, which may be associated with reflux esophagitis and may develop adenocarcinoma.
Increased pro-inflammatory and tumorigenic factors
Eesophageal adenocarcinoma in mice fed a high-fat diet had higher growth and metabolic activity, increased expression of pro-inflammatory and tumorigenic factors (e.g., leptin, IGFBP) in adipose tissue, and decreased anti-inflammatory and growth-inhibiting molecules.
In clinical epidemiological studies, "meat and fat" have been found to be strongly associated with esophageal adenocarcinoma and esophageal squamous cell carcinoma. At the same time, it was also found that a higher proportion of fat exacerbates the occurrence of esophageal cancer and esophageal gastric adenocarcinoma, while carbohydrates reduce the occurrence of esophageal adenocarcinoma.
✦Excessive dietary fat can easily lead to stomach cancer
Many epidemiological studies have reported that dietary fat may be a risk factor for stomach cancer.
Leptin plays an important role in stomach cancer
Leptin is thought to play an important role in obesity-related gastrointestinal malignancies because of its role in angiogenesis, apoptosis, cell proliferation, and cell migration.
Leptin is a hormone secreted by adipose tissue, and its amount in serum is proportional to the size of the animal's adipotic tissue. Leptin acts on receptors located in the central nervous system, thereby regulating the behavior of organisms as well as metabolism.
It has also been shown to promote mucin production and gastrointestinal tumorigenesis by regulating mTOR, STAT3 and ERK-dependent, PI3K-dependent, and MAPK-dependent pathways.
Mechanism of action
Excessive leptin and leptin signaling activation leads to gastric tumors by inhibiting inhibitors of cytokine signaling 3 in gastrointestinal epithelial cells and increasing the expression of ectopic molecules associated with the intestinal epithelium such as enteric mucin 2 and the Panez cell marker PLA2, as well as decreased expression of transcription factor SRY-box transcription factor 2 and H+/K+ATPase.
Precancerous lesions associated with high-fat diets are induced by lipotoxicity associated with a high-fat diet due to the disruption of gastric epithelial organelle homeostasis, tissue integrity, and stem gene expression mediated by leptin receptor (OBR) signaling.
In short, a high-fat diet promotes β-catenin and disrupts organelle homeostasis through upregulation of the PI3K-Akt pathway in epithelial cells, and can upregulate the properties of cancer stem cells.
One study found that mitochondrial damage to the cells of the parietal of the stomach developed during 8-20 weeks of feeding on a high-fat diet, accompanied by an increase in mucosal thickness. The addition of free fatty acids (FFAs) can replicate this expression and promote epigenetic changes, suggesting that lipid toxicity of free fatty acids induces parietal cell death and the occurrence of precancerous lesions.
It has also been found that a high-fat diet can provide sufficient energy for transfer and increase O-Glc-N-acylation levels, thereby promoting transcriptional activation of the fatty acid receptor CD36. The upregulation of CD36 leads to increased fat uptake by cancer cells, forming a vicious cycle that promotes cancer metastasis.
✦High-fat diet promotes liver cancer
Studies have confirmed that a high-fat diet leads to a significant increase in liver retention of hydrophobic bile acids, which is significantly associated with changes in the gut microbiome. At the same time, the synthesis and transport of bile acids in the liver are disordered, resulting in the release of a variety of inflammatory cytokines and severe deposition of bile acids, which promotes the occurrence of cancer.
In addition, various molecules that regulate metabolism have also changed. For example, diet-induced reductions in FGF21 and CPT2 in the livers of obese mice were enhanced, while FGF15, IRE1α, and leptin were upregulated, which were then linked to other pathological changes that promoted carcinogenesis.
Decreased FGF21 is strongly associated with excessive proliferation, TGF-β and Smad signaling, and abnormal expression of epithelial-mesenchymal transition and Wnt signaling pathway/β-catenin signaling in the liver.
The fatty acid oxidase CPT2 was significantly downregulated in high-fat fed mice, resulting in the accumulation of acylcarnitine in hepatocellular carcinoma tissues and serum, synergistically inhibiting fatty acid oxidation and activating STAT3, and jointly promoting the occurrence of liver cancer.
Metabolic changes produced by a high-fat diet lead to inflammation of the liver
Long-term high-fat diet reduces the expression of geraniyl geranilate bisphosphate synthase in mice. Hepatic geranil geranil bisphosphate synthase knockout enhances hepatic kinase B1 hyperfarnesylation, disrupts mitochondrial function and promotes glycolysis by regulating AMPK activity. These metabolic changes lead to liver inflammation, macrophage and pro-inflammatory cytokine infiltration, which in turn promotes the progression of liver pathology.
IRE1α is associated with cancer endoplasmic reticulum stress and drives pathogenesis. On the one hand, IRE1α promotes the activation of obesity-related inhibitors of the NFκB pathway, leading to the production of typical pro-inflammatory cytokines such as tumor necrosis factor and interleukin-6 in the liver.
On the other hand, it maintains the activation of STAT3, which promotes hepatocyte proliferation. The leptin signaling pathway can activate mTOR through downstream PI3K/Akt signaling, while mTOR indirectly activates eukaryotic initiation factor 4E, thereby stimulating the translation of mRNA encoding proliferation and anti-apoptotic factors.
At the same time, a high-fat diet significantly increases serum DPP4 levels, promotes the DPP4/CL2/angiogenesis cascade and DPP4-regulated macrophage infiltration-mediated inflammatory response, all of which play a key role in the progression of high-fat diet-associated hepatocellular carcinoma.
✦High-fat diet has an effect on pancreatic cancer
A high-fat diet reduces the epithelium's defense against cancer
A high-fat diet promotes cell proliferation and inhibits the clearance of abnormal cells. The Western diet induced excessive proliferation of pancreatic epithelial cells in mice and led to an increase in the frequency and likelihood of mutations. High-fat diet feeding significantly reduced the clearance capacity of RasV12-transforming cells, thereby impairing epithelial defense against cancer.
A high-fat diet can create an inflammatory and immunosuppressive tumor microenvironment. Pancreatic tissue from mice fed a high-fat diet was found to have higher KRAS activity, fibrotic matrix, shorter survival times, and a higher degree of pancreatic intraepithelial tumors and pancreatic ductal adenocarcinoma.
A high-fat diet leads to hyperinsulinemia
High-fat diets can also lead to hyperinsulinemia and accelerate formation and progression in mice with pancreatic intraepithelial tumors. At the same time, increased endogenous insulin was found to promote precancerous lesions induced by high-fat diets and pancreatic cancer, suggesting a possible oncogenic mechanism.
The mechanism of development of adenocarcinoma of the pancreatic ducts may be related to DNA damage. Mice fed a high-sugar, high-fat diet, and normal pancreatic cell lines treated with high sugar showed significant DNA damage and increased KRAS mutations in vitro, and they also found that KRAS mutant cells had a growth advantage under both normal and high-glucose conditions.
✦High-fat diet promotes the occurrence and metastasis of colorectal cancer
Epidemiological studies of colorectal cancer and high-fat diets confirm the link between them.
A high-fat diet promotes the occurrence and metastasis of colorectal cancer. Accompanied by heterozygous loss of APC genes and downregulation of ERK1/2, AKT, and mTOR signaling pathways.
Several pathways play a key role in promoting colorectal cancer with a high-fat diet:
The JNK pathway plays a vital role in obesity and insulin resistance and promotes carcinogenic transformation and cell proliferation.
The STRA6 pathway acts as a bridge between a high-fat diet and colorectal cancer, maintaining colorectal cancer stem cells. A high-fat diet promotes an increase in STRA6 in tumor tissue, while STRA6 activates the transduction of JAK2-STAT3 signaling cascade.
A high-fat diet can also activate the MAPK, ERK, and PI3K/Akt signaling pathways. In one study, obesity caused by a high-fat diet promoted the development of inflammation-associated colorectal cancer, driven by increases in the PI3K/Akt pathway and IL-12, MCP-1, IL-6, and TNF-α in the tumor microenvironment.
There have also been many studies on the effects of high-fat diets on cytokines or obesity factors. Elevated serum levels of insulin, leptin, TNF-α, IGF1, and proliferating nuclear antigen, COX-2, cyclin D1, β-catenin, and NFκB protein indicate that a high-fat diet promotes colon adenoma formation through inflammation and metabolic abnormalities and affects the cell cycle.
Chronic psychological stress
Chronic psychological stress is also considered a risk factor for the development of several diseases, including cancer.
Chronic stress stimulates the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, leading to the synthesis of stress-related mediators and activation of the renin-angiotensin system .
Excessive production of corticosteroids and catecholamines leads to pro-inflammatory cytokine production and metabolic changes, including increased insulin resistance and lipolysis to release free fatty acids.
✦Chronic psychological stress creates an inflammatory environment
Taken together, these alterations appear to create an inflammatory environment that exacerbates the pathogenesis of metabolic syndrome, diabetes and insulin resistance, and the development of other noncommunicable chronic and immune-mediated diseases, all of which may be mediated by chronic psychological stress.
In cancer, adrenergic receptors are overexpressed in tumor cells and the tumor microenvironment. Downstream activation of adrenergic receptors in turn inhibits apoptosis and DNA repair and has protocarcinogenic effects that enhance cell cycle progression.
Activation of adrenergic receptors induces the PI3K/AKT signaling pathway, which stimulates cell proliferation and angiogenesis. In addition, stress-mediated inflammatory responses and altered immune function may impair immune surveillance mechanisms and further promote carcinogenesis.
Viral infection
The development of malignant tumors is a multi-step process, and the virus has been identified as a tumor promoter. Tumor promoters stimulate signaling pathways and cell proliferation, ultimately leading to cancer.
✦Hepatitis B virus and hepatitis C virus infection can easily induce liver cancer
Hepatitis B virus and hepatitis C virus infection are currently the most important global risk factors for hepatocellular carcinoma, the main histological type of hepatocellular carcinoma.
Note: Patients from areas with a high prevalence of hepatocellular carcinoma tend to be younger at diagnosis than patients in areas with a prevalence.
Chronic necrotizing inflammatory disease caused by hepatitis B virus induces hepatocellular mutations, with an estimated risk of developing hepatocellular carcinoma of 10 to 25%, and depends on the presence of active hepatitis B virus infection or cirrhosis.
Hepatitis C virus is an RNA virus that does not integrate into the host genome. Tumorigenesis caused by hepatitis C virus can be the result of repeated injury, regeneration, and fibrosis, and nearly 90% of hepatitis C virus-associated hepatocellular carcinomas are preceded by cirrhosis.
Other factors that affect gastrointestinal cancer
The research team applied comparative risk assessment methods to estimate the population attribution score for gastrointestinal cancers attributed to each risk factor
Gastrointestinal cancer attribution scores for different lifestyle risk factors in China in 2011
Wu Y, et al. Gastroenterology.2021
•High red meat intake was associated with 51,405 colorectal cancer cases (PAF=19.0%)
•High body mass index (BMI) is estimated to be responsible for 55,244 new cases of liver cancer (PAF=16.6%)
•Smoking was the leading attributable risk factor for esophageal cancer, accounting for 48,364 cases (PAF=16.5%)
•High sodium intake was associated with the largest (68,858) cases of gastric cancer (PAF = 6.6%).
The research team also estimated temporal trends of lifestyle factors based on the 1991-2011 China Health and Nutrition Survey, while predicting the prevalence of lifestyle factors and the associated burden of gastrointestinal cancers from 2011 to 2031.
History and predicted trends in gastrointestinal cancer cases by lifestyle risk factors, 1991 to 2031
Wu Y, et al. Gastroenterology.2021
• Reduced sodium intake reduces stomach cancer
Sodium intake, low vegetable intake, low fruit intake, and smoking improved over time. The average sodium intake of the population has decreased from 7.5 g/day in 1997 to 5.6 g/day in 2011 and is expected to decrease further to 3.3 g/day by 2031.
The corresponding attributable gastric cancer cases are estimated at 138796, 68,858, and 35,484, with a decrease of about 50% every 20 years.
• Increased intake of vegetables and fruits can help reduce gastrointestinal cancers
As average vegetable intake increased from 252.6 g/day to 323.8 g/day, the number of cases associated with liver, esophageal and gastric cancer decreased from 52,774 in 1997 to 34,623 in 2011.
Fruit intake showed a similar trend, with overall fruit intake of 18.2 g/day in 1997 and 69.6 g/day in Chinese 2011, a decrease of 10,262 new cases compared to 1997; Annual incidence is expected to decline again by 2031 due to increased fruit intake.
Extended reading: Effects of common fruits on intestinal flora, intestinal motility and constipation
• Smoking reduces the incidence of gastrointestinal cancers and also decreases
Meanwhile, a reduction in smoking was associated with a 12,940 fewer gastrointestinal cancer events compared to 2011 and 1991, with a further reduction expected between 2011 and 2031.
•Alcohol consumption has led to an increase in cases of gastrointestinal cancer
From 1997 to 2011, alcohol-related cases of gastrointestinal cancer increased by 5,539, and the predicted trend since then has stabilized at about 84,000 cases per year.
• Exercise, dairy and dietary fiber intake affect colorectal cancer
Physical activity, dairy products, and dietary fiber intake were only associated with colorectal cancer. Insufficient physical activity was estimated to be associated with 45,531 colorectal cancer cases in 2011, with a further 7,248 expected by 2031.
The projected average dietary intake for dairy products in 1997, 2011 and 2031 was 5.8 g, 12.4 g and 17.6 g, and dietary fiber was 10.5 g, 10.8 g and 11.1 g, respectively. In 2011, inadequate intake resulted in 29,961 and 45,283 cases of colorectal cancer, respectively.
Part 3
Gut microbes and gastrointestinal cancers
The human gut microbiota plays an important role in both human health and disease states. Over the past decade, the interaction between microbes and tumors has attracted a lot of attention, with efforts to understand the various characteristics of complex microbial communities and the possible mechanisms by which the microbiota is involved in cancer prevention, carcinogenesis, and anti-cancer.
Numerous studies have shown that microbial dysregulation promotes cancer susceptibility through multiple pathways. Intestinal microbes contribute to the development of tumors of the digestive tract mainly through their bacteria or secreted metabolite components.
The microbiota and its associated metabolites are not only closely associated with carcinogenesis by inducing inflammation and immune dysregulation, but also interfere with the pharmacodynamics of anticancer drugs.
Association of gut microbiome with gastrointestinal cancers
Tong Y, et al. Theranostics.2021
Intestinal microbes and gastric cancer
√ Helicobacter pylori affects the prevalence of gastric cancer
Stomach cancer is considered a type of cancer associated with inflammation. H. pylori infection is known as a class I risk factor and stimulates immune response and inflammation, regulates many signaling pathways, and induces achlorhydria, epithelial atrophy, and dysplasia. Therefore, effective eradication of Helicobacter pylori can prevent gastric cancer.
Oncoprotein cytotoxin-associated genes A (CagA) and vacuolar toxin A (VacA) are key virulence factors for Helicobacter pylori. Helicobacter pylori infection significantly increases the risk of stomach cancer.
Vacuolar toxin A can inhibit GSK3 through the PI3K/Akt signaling pathway by directly acting on mitochondria, leading to cellular vacuolar formation, and inducing autophagy in human gastric epithelial cells, upregulating MAP kinase and ERK1/2 expression, activating vascular endothelial growth factor, upregulating the Wnt/β-catenin signaling pathway necessary for cell growth and differentiation.
Increased inflammatory cytokines in individuals infected with Helicobacter pylori
Increased accumulation of inflammatory cytokines, including interferon-γ, tumor necrosis factor, IL-1, IL1β, IL-6, IL-7, IL-8, IL-10, and IL-18, is found in the stomach of individuals infected with Helicobacter pylori.
As a result, many types of immune cells are stimulated, including lymphocytes, peripheral monocytes, eosinophils, macrophages, neutrophils, mast cells, and dendritic cells.
The activity of the carcinogenic pathways containing ERK/MAPK, PI3K/Akt, NF-κB, Wnt/β-catenin, and STAT3 is regulated with Helicobacter pylori infection. In contrast, the tumor suppressor pathway is inactivated by induced P53 mutations.
In addition, Helicobacter pylori infection can lead to CpG island methylation of E-cadherin and tumor suppressor genes, including genes encoding trilobite factor 2 (TFF2) and forkhead box transcription regulator (FOXD3), resulting in a significantly increased risk of gastric cancer.
Extended reading: Correct understanding of Helicobacter pylori
√ other microbiota
Current sequencing technology allows researchers to delve into the complexity of the gut microbiome.
The microflora of H. pylori positive individuals is characterized by an increase in the number of the following bacteria:
Proteobacteria ↑↑↑
Spirochaetes ↑↑↑
Phylum Acidobacteria ↑↑↑
And the number of the following flora decreases:
Actinobacteria ↓↓↓
Bacteroidetes ↓↓↓
Firmicutes ↓↓↓
In contrast, H. pylori negative individuals carry richer concentrations of Firmicutes, Bacteroides, and Actinomycetes.
√ intestinal microbial dysregulation increases the incidence of gastric cancer
Microbial dysregulation is also associated with the development of stomach cancer. Using quantitative PCR, it has been shown that the microbiota composition of gastric cancer patients is very diverse.
Examples include a decrease in porphyromonas, Neisseria, prevotella pallens, and Streptococcus sinensis, as well as a decrease in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and the family Trichocetidae Lachnospiraceae).
Pathogenic components derived from Helicobacter pylori, such as outer membrane protein phospholipase C-γ2, BAK protein and nickel-binding protein, help microorganisms colonize the gastric mucosal layer, which then exacerbates the course of gastritis, ultimately increasing the likelihood of tumorigenesis in the stomach.
Intestinal microbes and esophageal cancer
Esophageal cancer has been reported to be closely associated with common underlying risk factors, such as infection with human papillomavirus and Epstein-Barr virus, although the pathogenesis remains controversial. In addition to viruses, bacterial infections can also lead to the formation of malignant tumors of the esophagus.
Esophageal cancer √ population infected with Helicobacter pylori is declining
Over the last 20 years, the incidence of esophageal adenocarcinoma has been declining in the general population infected with Helicobacter pylori, especially in eastern populations. At the same time, the incidence of esophageal squamous cell carcinoma has also decreased.
Gastroesophageal reflux disease is the leading cause of Barrett's esophagus, a precancerous lesion of esophageal adenocarcinoma. By inhibiting parietal cell function or inducing the development of atrophic gastritis, chronic Helicobacter pylori infection can inhibit parietal cell secretion of hydrochloric acid, thereby increasing the pH of the gastrointestinal tract, ultimately leading to a decrease in esophageal adenocarcinoma.
Patients with √ esophagitis have a high abundance of Enterobacteria
Patients with esophagitis and Barrett's esophagus have a higher relative abundance of Enterobacter gastroenteridae compared with the normal population.
It has been suggested that antibiotics may alter the microbiome in the esophagus of patients with GERD. The gut microbiota colonized in the esophagus and stomach was significantly altered by treatment with proton pump inhibitors (PPIs). However, the jury is out on whether the changes induced by proton pump inhibitors are beneficial.
The latest systematic review and meta-analysis suggest that proton pump inhibitors do not reduce the development of dysplasia and Barrett's oesophageal-associated esophageal adenocarcinoma.
√ microorganisms in the esophagus are involved in the carcinogenic process
The esophagus has traditionally been considered a microbionic-free site, with only a limited number of microorganisms coming from swallowing and gastroesophageal reflux. Through the application of 16S rRNA sequencing technology, some specific microorganisms were found to inhabit the esophageal mucosa, including Firmicutes, Bacteroides, Proteobacteria, Actinomycetes, and Fusobacteria.
In addition, different microbial communities have been found in the esophagus of patients with esophageal squamous cell carcinoma (stage I-II) and esophageal squamous dysplasia (ESD) compared to normal esophagus.
Consistent with normal gastric mucosal microbiota, the most common phylums in samples from early esophageal squamous cell carcinoma and esophageal squamous dysplasia are Proteobacteria, Firmicutes, and Bacteroides. When the esophageal microbiota is dysbied, they are involved in the tumorigenic process of the esophagus.
The human distal esophagus has been found to have its own characteristic microbiota. Gram-positive bacteria, including Firmicutes and Streptococcus, predominate in the normal esophagus, while Gram-negative anaerobics/microaerobic bacteria, such as Bacteroides, Proteobacteria, Fusobacterium, and Spirochetes, are primarily associated with esophagitis and Barrett's esophagus.
Note: Lipopolysaccharides are an important part of the cell wall of gram-negative bacteria and are involved in the tumorigenesis process through multiple mechanisms. These include activation of innate immune responses leading to NF-κB activation, promoting the release of inflammation-related mediators including IL1β, IL6, IL8, and TNFα, and delaying gastric emptying.
Gut microbes and colorectal cancer
The gut microbiome in the colorectum is the most complex community in the human body. The bacterial population mainly includes the phylum Firmicutes and Bacteroides and Proteus.
√ diet, microbial metabolites affect colorectal cancer
Various factors can contribute to colorectal cancer, and diet is an important environmental factor associated with colorectal cancer. Many different gut microbiota metabolites have tumorigenic or anti-tumor properties.
Lipopolysaccharide receptors expressed on colon cells inhibit cell death, activate cellular immune responses through Toll-like receptor 2, and then stimulate downstream pro-inflammatory cytokine signaling, leading to tumorigenesis.
Lipoteichoic acid is an element derived from the cell wall of gram-positive bacteria and is considered a counterpart to lipopolysaccharides. A high-fat diet increases the relative abundance of sulfate-reducing bacteria, such as Vibrio desulfurizensis common, which converts primary bile acids into secondary bile acids such as lithocholic acid and deoxycholic acid, which are potentially tumorigenic.
Butyrate has an antitumor effect
Instead, butyric acid, an important short-chain fatty acid produced by colonic bacteria from fermentable fiber in the diet, has been shown to have antitumor effects.
The most important butyrate-producing microbiota involved in the fermentation process are Faecalibacterium prausnitzii and Eubacterium rectale.
Butyric acid is utilized by mitochondria in colon cells, which helps maintain a healthy energy balance and benefits colonic epithelial cell proliferation. GPR109a is a short-chain fatty acid receptor expressed on immune cells that primarily activates the ligand of butyric acid and then inhibits inflammatory cytokines, thereby inhibiting the inflammatory process. The host immune response is anti-cancer effects correspondingly by interferon γ against DNA methylation-mediated GPR109a silencing.
Butyric acid exerts various chemopreventive effects by inducing P21 gene expression, inhibiting the activating protein-1 (AP-1) signaling pathway, and increasing phosphorylation of c-Fos and ERK1/2. In addition, urolithias, such as urolithiin A, is a metabolite of the gut microbiota of fruits and nuts and contains large amounts of ellagic acid. They have been reported to inhibit Wnt signaling and have shown benefits for cancer.
√ long-term inflammation can easily lead to colorectal cancer
Pathways caused by gut microbiota
If H,et al. Semin Cancer Biol.2021
Chronic inflammation produces a large number of inflammatory mediators, such as tumor necrosis factor, interleukin 6, interleukin 1b, and other cytokines, which activate NF-κB, which leads to colon cancer.
Inflammatory bowel disease is associated with a higher risk of colorectal cancer. For example, people with pancolitis have a higher risk of cancer compared to people with localized colitis.
Patients with inflammatory bowel disease have a lower diversity and dysbiosis of gut microbiota compared to healthy subjects, characterized by lower abundance of the phylum Firmicutes and Bacteroides.
Bacteroides enterotoxigenis fragilis is significantly associated with the presence of inflammatory bowel disease. Both inflammatory bowel disease and colorectal cancer share a common process of elevated levels of transforming growth factor-β (TGF-β), TNFα, NF-κB, ROS, and other signaling molecules, leading to dysregulation of the gut microbiome.
It has been shown that colorectal cancer patients with inflammatory bowel disease have a worse prognosis than patients without inflammatory bowel disease.
√ dysbacteriosis of the gut leads to an increased risk of colorectal cancer
If the gut microbiota remains in a dysregulated state, the diversity and abundance of beneficial symbionts can be minimized. Once disturbed microorganisms overgrow, they produce accumulated exotoxins and endotoxins.
Such as the cell-lethal bulking toxin and colibactin of Escherichia coli, the cell-lethal bulking toxin of Shigella dysenteriae, the fragile bacillus toxin of Bacillus fragillus, extracellular superoxide and hydrogen peroxide of Enterococcus faecalis.
These bacterial toxins can directly or indirectly induce DNA damage, genomic instability, tumorigenesis, and adenocarcinoma.
In addition, dysbiosis leads to an increase in the exposure of colonic epithelial cells to carcinogens. The accumulation of unrepaired DNA and base excision repair (BER) intermediates leads to genomic instability and ultimately carcinogenesis.
Note: Microbial dysbiosis can dysplastic the immune response and increase inflammation, leading to mutations in the PIK3CA gene, which may accelerate the onset or growth of colorectal cancer.
Fusobacterium adhesin A can be used as a biomarker
Fusobacterium adhesin A (FadA) is a cell surface virulence factor expressed by Fusobacterium and is often detected in patients with adenomatous polyps or colorectal cancer.
FadA interacts with E-cadherin on the endothelium and regulates the E-cadherin/β-catenin pathway, resulting in increased expression of transcription factors, oncogenes, and inflammatory genes.
It also promotes Fusobacterium adhesion and invasion of E-cadherin-expressing cells, which directly affects the proliferation and growth of epithelial cells. A recent report suggests that the overall abundance of Fusobacterium in colorectal cancer tissue is more than 400 times higher than in adjacent normal tissue. Therefore, FadA may be a potential biomarker for colorectal cancer diagnosis and treatment.
Intestinal microbiota and liver cancer
While the liver is generally considered sterile, the liver environment is greatly influenced by pathogens or metabolites produced by the gastrointestinal microbiota through the hepatic portal venous system.
Hepatocellular carcinoma and cholangiocarcinoma are the most common histologic types of liver cancer. Alcoholic liver disease, nonalcoholic fatty liver disease, and foodborne pollutants aflatoxin B1, hepatitis B or C virus infection are considered major risk factors for hepatocellular carcinoma.
It is worth noting that dysbacteriosis of the gut is one of the main triggers of nonalcoholic fatty liver disease.
Disorders of the √ gut microbiota can lead to liver cancer
The liver has an important impact on the host microbial community by filtering the bloodstream and by metabolizing and neutralizing toxins produced by gut microbes. Intestinal microbial dysregulation can lead to liver cancer because the microbiota and microbial metabolites can be detected by the liver's resident immune cells and can alter liver metabolism.
E. coli in the feces of patients with hepatocellular carcinoma is much more abundant than E. coli in the feces of healthy controls, while Dietziaceae, Pseudomonas, and Oxalobacteraceae are more abundant in bile duct samples from cholangiocarcinoma patients than samples from non-cholangiocarcinoma individuals.
It has been hypothesized that the overgrowth of gut microbes may promote the development of liver cancer, which needs to be further explored.
√ Helicobacter pylori promotes the growth and migration of liver cancer
Helicobacter pylori usually inhabits the human stomach. However, Helicobacter pylori from the intestine can reach liver tissue through the bloodstream of the portal vein, survive phagocytosis elimination, or migrate backwards through the duodenum.
Metabolites produced by Helicobacter pylori have been found in the liver tissue of patients with hepatocellular carcinoma. It has been shown that lipopolysaccharides from Helicobacter pylori directly promote the growth and migration of liver cancer by increasing levels of interleukin 8 and transforming growth factor β1.
As a member of the Helicobacter family, Helicobacter pylori leads to the development of hepatocellular carcinoma by activating NF-κB and Wnt signaling pathways, hepatocyte turnover, and oxidative stress.
In addition, some Helicobacter species, such as H. bilis, H. ganmani, and H. hepaticus, are specifically associated with cholangiocarcinoma but not with non-tumor diseases in the bile ducts.
√ intestinal microbial metabolites affect liver cancer
Microbial metabolites disrupt metabolic pathways and immune responses in the liver.
Toll-like receptor 4 (TLR4) recognizes lipopolysaccharides (LPS) from bacteria and activates Kupffer cells via lipopolysaccharide-induced TNF-β and IL-6. It can also stimulate stellate cells through growth factors such as epithelial regulatory proteins and initiate various inflammatory and carcinogenic pathways. The LPS-TLR4 pathway promotes hepatocellular carcinoma, while removal of lipopolysaccharides or inactivation of the Toll-like receptor 4 gene reduces the development of hepatocellular carcinoma.
Kupfer cells – are specialized macrophages located in the liver and are part of the mononuclear phagic cell system.
Bile acid and chenodeoxycholic acid are the main primary bile acids produced by the liver. They induce the development of liver cancer by increasing the production of reactive oxygen species leading to DNA damage.
In addition, bile acids have also been shown to regulate the gut microbiota. A decrease in the number of bile acids can lead to an overgrowth of the intestinal flora and accelerate inflammation. The enterohepatic circulation of deoxycholic acid produced by Clostridium causes DNA damage and triggers an aging-related secretory phenotype in hepatic stellate cells.
This process involves many inflammatory cytokines and growth factors, leading to inflammation and obesity-associated hepatocellular carcinoma transitions. Deoxycholic acid and lithocholic acid have been shown to directly promote cancer through DNA damage.
Intestinal microbes and pancreatic cancer
The pancreas is an extragastric digestive organ. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide and is the most common type of pancreatic cancer. A growing body of research suggests that the gut microbiota may influence pancreatic cancer development by promoting inflammation, activating the immune response, and perpetuating cancer-associated inflammation.
√ Helicobacter pylori infection is a risk factor for pancreatic ductal carcinoma
A review of hundreds of meta-analyses of pancreatic cancer suggests that Helicobacter pylori infection is an important risk factor for pancreatic ductal adenocarcinoma. In addition to adenocarcinoma of the pancreatic ducts, Helicobacter pylori is involved in acute and chronic pancreatitis as well as autoimmune pancreatitis.
Many pathogenic components derived from Helicobacter pylori, including ammonia and lipopolysaccharides, and the resulting large amounts of inflammatory cytokines, can damage the pancreas.
Helicobacter pylori infection activates NF-κB and AP-1, leading to dysregulation of cellular processes. Elevated levels of interleukin 8 accelerate the inflammatory response, which ultimately leads to pancreatic cancer.
In addition, sustained activation of STAT3 by Helicobacter pylori infection can promote pancreatic cancer progression by upregulating the expression of anti-apoptotic and proproliferative proteins including Bcl-xL protein, MCL-1, survival hormone, c-myc, and cyclin D1.
√ inflammation and immune response and pancreatic cancer
Microorganisms cause mild and persistent immune and inflammatory reactions that can lead to the formation of pancreatic cancer.
Many studies have been conducted to explore possible mechanisms. Toll-like receptors expressed on various immune cells enable immune cells to recognize multiple microbial-associated molecular patterns (MAMPs) and noninfectious inflammatory injury-associated molecular patterns (DAMPs), and then activate NF-κB and MAPK signaling pathways. These processes trigger and perpetuate pancreatitis, ultimately contributing to the progression of pancreatic cancer.
NLRs are cytoplasmic pattern recognition receptors (PRRs) involved in the activation of NF-κB and the formation of inflammasomes. P38 mitogen-activated protein kinases (P38 MAPKs) respond to cytokines and are involved in cell differentiation, apoptosis, and autophagy, thereby accelerating the process of pancreatic ductal adenocarcinoma. Therefore, P38 inhibitors may be drugs to treat cancer.
Taste receptor type 2 member 38 (TAS2R38) is a bitter taste receptor. Interestingly, T2R38 is expressed not only in oral cells, but also in pancreatic cancer cells. Pseudomonas aeruginosa, a unique ligand for T2R38, is said to activate T2R38, induce multidrug resistance-associated protein 1 (ABCB1), and be involved in cancer invasion and metastasis.
In addition, Fusobacterium is present in 8.8% of pancreatic cancer tissue. Of note, the status of Fusobacterium is an independent negative prognostic biomarker for pancreatic cancer.
√ the role of other gut microbes on cancer
Tong Y, et al. Theranostics.2021
Conclusion
Studies have shown that lifestyle has an increasing influence on gastrointestinal cancer risk. Smoking, drinking, diet, obesity, etc. are all important factors affecting gastrointestinal cancer.
The gut microbiota is closely related to humans and also plays an important and unique role in human health and disease. The gut microbiota is also able to exert synergistic effects with chemotherapeutic agents and immunotherapeutic agents.
Based on the study of the gut microbiota, new therapeutic targets are also being explored, as well as the use of human gut microbiota to diagnose, predict and prognosis cancer biomarkers. Accelerating the translation of gut microbiome research in precision medicine.
The precise relationship between lifestyle behavior and gut microbiota and gastrointestinal cancers needs to be further explored and will have a significant impact on our daily lives and clinical treatment.
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