Stomach cancer pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]
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Overview
The pathophysiology of stomach cancer depends on histologic subtypes.
Pathophysiology
Molecular effect of H.pylori:
- There is a strong correlation between H. pylori seropositivity and gastric cancer incidence. [34,35].
- Regression of premalignant lesions has been demonstrated with eradication of H. pylori.[38,39],
- This is related to nitric oxides accumulation produced by inflammatory cells responding to H. pylori infection. [41]
- Nitric oxides may induce abnormalities in the DNA of epithelial cells.[43]
The exact pathway for oncogenesis is not known but many trials supported the adenoma-carcinoma sequence
Oncogenes
●Early involvement of K-ras mutations is suggested by their being found in invasive cancers, dysplasia, and intestinal metaplasia [51].
●Involvement of the c-met oncogene, encoding the hepatocyte growth factor receptor, is supported by the finding that gene expression is amplified in 19 percent of intestinal-type (and 39 percent of diffuse-type) gastric cancers.
Expression of the 6.0 kb c-met transcript in particular correlates well with more advanced disease stage at presentation [52].
In vitro, highly virulent strains of H. pylori that make the effector protein CagA appear to modulate c-met receptor signal transduction pathways, and this might influence cancer initiation and/or tumor progression [53].
Tumor suppressor genes
Approximately 50 percent of intestinal-type gastric cancers have alterations in genes that are thought to function as tumor suppressor genes, including TP53, TP73, APC (adenomatous polyposis coli), TFF (trefoil factor family), DCC (deleted in colon cancer), and FHIT (fragile histidine triad) [50,54-67].
Loss of TP53 expression by LOH or mutational inactivation is the most frequent genetic alteration in gastric cancer, occurring in over 60 percent of invasive tumors [50,62].
Abnormalities are also found in H. pylori-associated chronic gastritis, intestinal metaplasia and dysplasia [54,55,59,60,68].
p53 appears to be a key regulatory molecule in the response to microenvironmental chronic inflammatory stress [69].
inactivation of p53 in gastric epithelial cells may reduce their ability to undergo apoptosis in response to injury caused by H. pylori [61].
LOH, a transcription factor related to TP53 that also functions as a tumor suppressor gene, can be detected in gastric carcinomas [56],
and loss of expression has also been reported via epigenetic mechanisms (promoter methylation) in EBV-associated gastric cancers [58].
Mutations in the APC (adenomatous polyposis coli) gene are identified in significantly more intestinal-type than diffuse-type gastric cancers (33 versus 13 percent) [70]. These mutations are also found in H. pylori-associated dysplasia and intestinal metaplasia [71]. APC mutations modulate the Wnt/cateninsignaling pathway, as discussed below.
The trefoil factor family (TFF) of proteins comprises a group of gastrointestinal peptides that are involved in the protection of the mucous epithelium. TFF1 is normally expressed in the gastroduodenal mucosa, and TFF1 knockout mice develop multiple gastric adenomas and carcinomas [72]. Loss of TFF1 expression has been observed in intestinal metaplasia of the incomplete type [73] and in gastric carcinomas [74].
Cell cycle regulatory molecules
Cyclin E and Cyclin dependent kinase inhibitor 1B (CDKN1B,p27) are two important cell-cycle regulators that take part in the G1/S transition.
Cyclin E overexpression is a frequent event in gastric carcinomas [75,76], and it might be an indicator for malignant transformation of dysplasia [77], and/or tumor aggressiveness once an invasive cancer develops [76,78].
Decreased expression of cyclin dependent kinase inhibitor 1B also correlates with an adverse prognosis in invasive gastric cancer [78,79]. Furthermore, loss of CDKN1B expression increases susceptibility to gastric carcinogenesis in H. pylori-infected CDKN1B-knockout mice [80].
Epigenetic events
DNA methylation of gene promoters can silence the expression of certain genes, including CDH1 (the E-cadherin gene) in intestinal-type cancers [50,62,81,82].
promoter methylation may be closely associated with H. pylori infection [83-86]
Hypermethylation of the Reprimo gene has been found not only in the gastric tumors but also in the plasma of patients with gastric cancer, raising the possibility of blood-derived biomarkers in the detection of “early” gastric cancer [89].
Beta-catenin/Wnt signaling
Once established, the invading cells then redifferentiate from mesenchymal to epithelial phenotypes. This dynamic process of dedifferentiation, invasion, and redifferentiation cannot be explained solely by the accumulation of stable, irreversible genetic alterations, leading some to suggest that it is regulated by the tumor microenvironment [92].
The molecular abnormalities found in cells from the "advancing" edge of carcinomas differ from those of the cells showing tubulo-glandular formation.
A major difference is the pattern of expression of beta-catenin (picture 6 and picture 7) [93,94].
Beta-catenin is a critical component of the Wnt signaling pathway which, during embryonic development, regulates morphogenesis.
Tissue morphogenesis is a process that demands temporal and spatial coordination of individual events such as intercellular adhesion junctions, migration, proliferation, and differentiation.
Beta catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer [95].
In normal mucosa and well-differentiated tumor cells, beta-catenin is normally bound to protein complexes in the cell membrane that are involved in normal intercellular adhesions (picture 6). These complexes (picture 8) maintain cell-to-cell adhesions and the cellular polarity that is required for tubulo-glandular formation.
As long as Wnt signaling is inactive, cytoplasmic beta-catenin is either bound to an APC/axin/conductin complex or degraded.
Within the cytoplasm, the protein product of the wild-type APC gene prevents the accumulation of beta-catenin by mediating its phosphorylation and resultant degradation within proteosomes.
When activating mutations are present in a component of the Wnt pathway (such as in sporadic CRCs which have APC mutations or mutations in beta-catenin itself, (figure 4)) this leads to loss of regulation of beta-catenin.
The end result is cytoplasmic accumulation of beta-catenin, nuclear translocation, and constitutive activation of transcription by a beta-cetenin/T-cell factor (Tcf) complex. Among the target genes whose transcription is turned on by the beta-catenin/TCF complex include those that stimulate proliferation, angiogenesis, tumor invasion, and metastasis [94,96].
Thus, it has been proposed that gastric carcinogenesis involves an initial stage of dedifferentiation (gastric atrophy), followed by abnormal redifferentiation (intestinal metaplasia) and that this process is mediated by the effect of H. pylori infection (particularly CagA-containing strains) on beta-catenin [92,97].
The following observations provide support for this model of gastric carcinogenesis:
There are major differences in gastric cancer risk among different strains of H. pylori. Strains carrying virulence factors such as CagA and vacA s1 and m1 are more frequently associated with severe gastritis, precancerous lesions, and gastric cancer [98-100]. In vitro, CagA expression alone is sufficient to disrupt apical junctions and perturb the mechanisms that maintain normal epithelial differentiation, including cell adhesion, cell polarity, and the inhibition of migration [101].
Others have shown that CagA can induce proteolytic cleavage of E-cadherin, disrupting E-cadherin-dependent cell to cell contact [102], and that it impairs the complex formation between E-cadherin and beta-catenin, causing cytoplasmic and nuclear accumulation of beta-catenin and constitutive transcription of markers of intestinal differentiation [94,103,104].
In an animal model in which gerbils were infected with a rodent-adapted strain of oncogenic CagA-producing human H. pylori, gastric dysplasia developed by four weeks in 88 percent, and gastric adenocarcinoma was present in 75 percent of the animals by eight weeks [103]. Nuclear localization of beta-catenin was observed in a human gastric cell line after infection with this same H. pylori strain, but not with the original non-carcinogenic clinical isolate (B128).
Gross pathology
| Type | Description |
|---|---|
| Type 0 | (superficial) Typical of T1 tumors. |
| Type 1 | (mass) Polypoid tumors sharply demarcated from the
surrounding mucosa. |
| Type 2 | (ulcerative) Ulcerated tumors with raised margins
surrounded by a thickened gastric wall with clear margins. |
| Type 3 | (infiltrative ulcerative)
Ulcerated tumors with raised margins, surrounded by a thickened gastric wall without clear margins |
| Type 4 | (diffuse infiltrative)
Tumors without marked ulceration or raised margins, the gastric wall is thickened and indurated and the margin is unclear. |
| Type 5 | (unclassifiable)
Tumors that cannot be classified into any of the above types. |
Histopathology
- 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 ("back to back" aspect). Often, it associates 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 (mucinous, colloid): tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid (optically "empty" spaces). It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell".
World Health Organization histological classification of gastric tumors:
| Types | Histological features |
|---|---|
| Epithelial tumors |
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| Non-epithelial tumors | Leiomyoma
Schwannoma Granular cell tumour Glomus tumour Leiomyosarcoma GI stromal tumour Benign Uncertain malignant potential Malignant Kaposi sarcoma |
| Malignant lymphomas | Marginal zone B-cell lymphoma of MALT-type
Mantle cell lymphoma Diffuse large B-cell lymphoma |
Japanese histological classification of gastric tumors:
| Types | Histological features |
|---|---|
| Epithelial tumors |
Benign epithelial tumorAdenoma Malignant epithelial tumorCommon type Papillary adenocarcinoma Tubular adenocarcinoma Well-differentiated Moderately differentiated Poorly differentiated adenocarcinoma Solid type Non-solid type Signet-ring cell carcinoma Mucinous adenocarcinoma |
| Special types | Carcinoid tumor
Endocrine carcinoma Carcinoma with lymphoid stroma Hepatoid adenocarcinoma Adenosquamous carcinoma Squamous cell carcinoma Undifferentiated carcinoma |
| Miscellaneous carcinoma | Non-epithelial tumor
Gastrointestinal stromal tumor (GIST) Smooth muscle tumor Neurogenic tumor Miscellaneous non-epithelial tumors Lymphoma B-cell lymphoma MALT (mucosa-associated lymphoid tissue) lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Other B-cell lymphomas T-cell lymphoma Other lymphomas Metastatic tumor Tumor-like lesion Hyperplastic polyp Fundic gland polyp Heterotopic submucosal gland Heterotopic pancreas Inflammatory fibroid polyp Gastrointestinal polyposis Familial polyposis coli, Peutz–Jeghers syndrome |