Stomach cancer pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Omer Kamal, M.D.[2], Parminder Dhingra, M.D. [3], Mohammed Abdelwahed M.D[4]

Overview[edit | edit source]

Gastric cancer may occur secondary to a variety of causes including H. pylori and gastric cancer have strong correlation. This is related to nitric oxide accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends upon the histologic subtype. K-ras mutations is found in invasive cancers and intestinal metaplasia. Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis. DNA methylation of gene promoters can silence the expression of CDH1. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. There are many diseases associated with gastric cancer such as, hereditary diffuse gastric cancer, gastric adenocarcinoma, proximal polyposis of the stomach, Lynch syndrome, familial adenomatous polyposis, Li-Fraumeni syndrome, Peutz Jeghers syndrome, juvenile polyposis, hereditary breast and ovarian cancer syndrome and Cowden's syndrome. There are five gross pathological types of gastric cancer; superficical, ulcerative, infiltrative ulcerative, diffuse infiltrative, and unclassified. There are two major histological classifications for gastric cancer including Japanese classification and WHO classification. The main two types are intestinal type adenocarcinoma and diffuse type adenocarcinoma.

Physiology of gastric acid secretion[edit | edit source]

• The stomach consists of two functional areas; oxyntic and pyloric glands. The oxyntic area contains parietal cells that produce gastric acid.
• Parietal cells are filled with secretory vesicles that coalesce with stimulation to form channels that drain to the apical lumen.^[1]
• The secretory membrane contains hydrogen-potassium-ATPase acid-secreting pump. While stimulated hydrogen-potassium exchange occur. The collected hydrogen unifies with chloride forming hydrochloric acid.^[2]
• The antrum contains pyloric glands that secrete gastrin and somatostatin.
• Gastrin enhances gastric acid secretions from parietal cells by increasing synthesis of histamine.^[3]
• Somatostatin: The secretion of somatostatin is increased by gastric acid and gastrin level.^[4]

Pathophysiology of gastric cancer[edit | edit source]

The pathophysiology of gastric cancer is based on various factors leading to decreased apoptosis, increased proliferation and abnormal differentiation of gastric epithelial cells. The following etiological factors contribute to the development of gastric cancer:^[5]

• Helicobacter pylori infection leading to activation and dysregulation of three signaling pathways, involving three major components:^[6]
  • Nuclear factor-κB
  • Wnt/β-catenin
  • Proliferation/stem cell
• Dietary habits involving high consumption of starch, decreased consumption of high quality protein, fresh fruits and vegetables. These diets favor acid-catalyzed nitrosation in the stomach and leads to mechanical damage to the gastric mucosa.
• Family history of hereditary conditions which may lead to an increased risk of gastric cancer for example, Li-Fraumeni syndrome and hereditary non-polyposis colon cancer.^[7]

Pathogenesis of intestinal type gastric cancer[edit | edit source]

Molecular effect of H.pylori:

• There is a strong correlation between Helicobacter pylori and gastric cancer incidence.^[8]
• The main cause of this correlation is related to nitric oxides accumulation produced by inflammatory cells responding to H. pylori infection.^[9]
• Nitric oxides may induce abnormalities in the DNA of epithelial cells.
• Incidences of gastric cancer has been known to decrease with eradication of H. pylori infection.^[10]
• The exact pathway for oncogenesis is not known but many trials support the adenoma-carcinoma sequence.
• The intestinal type of gastric adenocarcinoma is the most common type of gastric cancer. The development of intestinal type gastric carcinoma progresses from chronic superficial (non atrophic) gastritis, to chronic atrophic gastritis to intestinal metaplasia, followed by dysplasia and finally, gastric adenocarcinoma.^[11]
• H. pylori hosts a virulence factor called cytotoxin-associated gene A (cag A) which leads to induction of growth factor receptors, increased proliferation, inhibition of apoptosis, and promotion of invasion and angiogenesis.^[12]
• H. pylori also leads to production of reactive oxygen and nitrogen species and leads to suppression of the host antioxidant defense mechanisms, causing oxidative DNA damage.^[13]

Beta-catenin/Wnt signaling

• Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer.^[14]
• Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation.
• Beta-catenin is normally bound to protein complexes in the cell membrane that are involved in normal intercellular adhesions.
• APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells.^[15]

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Pathogenesis of diffuse-type gastric cancer[edit | edit source]

• Diffuse gastric carcinomas do not have a precancerous lesion.
• They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastic.^[16]
• Intracellular mucin pushes the nucleus giving the histological figure of signet ring carcinoma.
• The E-cadherin gene (CDH1) encodes a transmembrane cellular adhesion protein. Its cytoplasmic tail interacts with catenins making the adhesion.
• Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.^[17]
• Prostate stem cell antigen gene is also involved in regulating gastric epithelial cell proliferation.^[18]

Apoptosis pathway[edit | edit source]

Neutrophil activation [edit | edit source]

• H. pylori infection results in the migration of neutrophils to the site of infection and adhesion to the surface epithelium.
• The neutrophils produce nitric oxide synthase which damage DNA.
• CD11a/CD18- and CD11b/CD18-neutrophils interact with intercellular adhesion molecule-1 (ICAM-1).^[19]
• Epithelial cells respond by signaling pathways leading to apoptosis, proliferation, differentiation, and autophagy.

Apoptotic pathways[edit | edit source]

• Apoptosis occurs as a protective mechanism to prevent replication of mutated DNA which leads to atrophy of epithelium so called atrophic gastritis which returns to normal following eradication therapy.^[20]
• H. pylori enhances expression of the Fas receptor on gastric epithelial cells and may mediate apoptosis through signaling mechanisms related to the Fas death receptor.
• Another trial supported that the source of tumorigenesis is from bone marrow-derived cells that differentiate into gastric epithelial cells in the presence of H. pylori.^[21]

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Genetics[edit | edit source]

Mutations of the following genes may lead to the development of gastric cancer:

Oncogenes[edit | edit source]

• K-ras mutations are found in invasive cancers and intestinal metaplasia.^[22]
• C-met receptor has a high affinity for hepatocyte growth factor (HGF). Mutations leading to increased expression of c-met are known to be associated with some types of gastric cancer ( for example intestinal-type gastric cancer). Effector protein CagA made by H.pylori modulates c-met receptor signal transduction pathways.^[23][24]

Tumor suppressor genes[edit | edit source]

• Almost 50% of gastric cancers have alterations in genes TP53, TP73, APC, TFF, DCC, LOH, and FHIT.^[25]
• Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis.^[26]

• Abnormalities are found in intestinal-type, intestinal metaplasia and dysplasia, and H. pylori-associated chronic gastritis.^[27]
• Mutations in the APC gene are found in intestinal-type gastric cancers. APC mutations alternate the Wnt/catenin signaling pathway.^[28]
• The trefoil factor family (TFF) is normally expressed in the gastroduodenal mucosa. Loss of TFF1 expression has been observed in gastric carcinomas.^[29]

Cell cycle regulatory molecules[edit | edit source]

• Cyclin E overexpression is found in gastric carcinomas.^[30]
• Cyclin E and Cyclin-dependent kinase inhibitor 1-B are cell cycle regulators.^[31]

Epigenetic events[edit | edit source]

• DNA methylation of gene promoters can silence the expression of CDH1.^[32]
• Hypermethylation of the Reprimo gene has been found in the plasma of patients with gastric cancer.

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Associated Disorders[edit | edit source]

Familial predisposition[edit | edit source]

• Although most gastric cancers are sporadic, 10 percent of cases are familial.

Hereditary diffuse gastric cancer^[33][edit | edit source]

• CDH1 gene encodes the cell adhesion protein E-cadherin, mutations in this gene have been identified in hereditary diffuse gastric cancer.
• It is inherited as an autosomal dominant trait with high penetrance.^[34]
• Promoter hypermethylation, mutation, and loss of heterozygosity result is loss of expression of the cell adhesion molecule E-cadherin.
• The asymptomatic carriers of a pathogenic CDH1 gene mutation may require prophylactic gastrectomy.
• Risk for gastric cancer for CDH1 gene mutation carriers is 70 percent in men and 56 percent in women.^[35]
• Women in these affected families are also at high risk of developing breast cancer. The cumulative risk of breast cancer at 80 years of age for CDH1 mutation carriers is 42 percent.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)[edit | edit source]

• GAPPS is an autosomal dominant fundic gland polyposis that is restricted to the proximal stomach, with no evidence of duodenal or colorectal polyposis or other hereditary gastrointestinal cancer syndrome.^[36]

Familial intestinal gastric cancer (FIGC)[edit | edit source]

• FIGC should be considered a potential diagnosis when histopathological reports denote intestinal-type gastric cancers that segregate within families without gastric polyposis.^[37]

Other hereditary cancer syndromes:^[37][edit | edit source]

• Lynch syndrome (hereditary nonpolyposis colorectal cancer)
• Familial adenomatous polyposis (FAP)
• Li-Fraumeni syndrome
• Peutz Jeghers syndrome
• juvenile polyposis
• Hereditary breast and ovarian cancer syndrome
• Cowden's syndrome

Gross Pathology[edit | edit source]

The gross pathological findings in gastric cancer may be classified into the following types based on appearance of the tumor:

Video Showing Growth Pathology Of Gastric Cancer[edit | edit source]

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Histopathology[edit | edit source]

• Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. It invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and hence the muscularis propria. Histologically, there are two major types of gastric cancer (Lauren classification): intestinal type and diffuse type.
  • Intestinal type adenocarcinoma:
    • Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, and reduced stroma. It induces intestinal metaplasia in neighboring mucosa.
    • Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiated.
  • Diffuse type adenocarcinoma:
    • Tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid. It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery giving a signet ring cell appearance.

World Health Organization histological classification of gastric tumors:[edit | edit source]

Japanese histological classification of gastric tumors:[edit | edit source]

Video shows microscopic pathology of gastric cancer {{#ev:youtube|lRvq1fEW8sY}} {{#ev:youtube|lWeECaiEfSs}}

References[edit | edit source]

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