Telomerase is a specialized type of reverse transcriptase which catalyzes the synthesis and extension of telomeric DNA (for review, see ref.1). This enzyme is highly active in most cancer cells, but is inactive in most somatic cells. This striking observation led to the suggestion that telomerase might be important for the continued growth or progression of cancer cells. However, little is known about the molecular mechanism of telomerase activation in cancer cells. Human telomerase reverse transcriptase (hTRT) has recently been identified as a putative human telomerase catalytic subunit. We transfected the gene encoding hTRT into telomerase-negative human normal fibroblast cells and demonstrated that expression of wild-type hTRT induces telomerase activity, whereas hTRT mutants containing mutations in regions conserved among other reverse transcriptases did not. Hepatocellular carcinoma (20 samples) and non-cancerous liver tissues (19 samples) were examined for telomerase activity and expression of hTRT, the human telomerase RNA component (hTR; encoded by TERC) and the human telomerase-associated protein (hTLP1; encoded by TEP1). A significant correlation between hTRT expression and telomerase activity was observed. These results indicate that the hTRT protein is the catalytic subunit of human telomerase, and that it plays a key role in the activation of telomerase in cancer cells.

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Gene changes in multiple oncogenes, multiple growth factors and multiple tumor-suppressor genes are observed in stomach cancer. Among them, those most commonly implicated in both well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma are inactivation (mutations and allele loss) of the p53 gene, and activation (abnormal expression and amplification) of the c-met gene. Moreover, they occur at an early stage of stomach carcinogenesis. In addition, loss of heterozygosity (LOH) on chromosome 5q (APC locus) is frequently associated with well-differentiated adenocarcinoma. LOH on chromosome 18q (DCC locus) and LOH of the bcl-2 gene also are common events of well-differentiated adenocarcinoma. LOH on chromosomes 1q and 7q may be involved in the progression of well-differentiated adenocarcinoma. Conversely, the development of poorly differentiated adenocarcinoma, in addition to changes in p53 and c-met genes, requires reduction or dysfunction of cadherin. Overexpression of bcl-2 protein is observed in poorly differentiated adenocarcinoma or signet-ring cell carcinoma. Moreover, the K-sam gene is amplified preferentially in poorly differentiated adenocarcinoma of scirrhous carcinoma. K-sam amplification in scirrhous carcinoma often occurs independently of c-met gene amplification. LOH on chromosome 1p also is relatively common in poorly differentiated adenocarcinoma. Exceptionally, signet-ring cell carcinoma shares APC mutations. There are some differences in expression of the growth-factor/receptor system between well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma. Moreover, interaction between cell-adhesion molecules in tumor cells expressing c-met and hepatocyte growth factor (HGF) from stromal cells is linked with morphogenesis of two histological types of stomach cancer. Intestinal metaplasia and adenoma of the stomach also contain p53 mutations and K-ras mutations or tpr-met rearrangement. Taken together, different genetic pathways of stomach carcinogenesis may exist for poorly differentiated and well-differentiated stomach cancers. Some of the latter may develop by a cumulative series of gene alterations similar to those of colorectal cancer.

The expressions of epidermal growth factor (EGF) and its receptor were studied immunohistochemically in a total of 156 gastric carcinomas; 26 early and 130 advanced. No EGF immunoreactivity was found in early carcinomas, while EGF-positive tumor cells were detected in 38 (29.2%) of the 130 advanced carcinomas. EGF receptor immunoreactivity was detected in one (3.8%) of the 26 early carcinomas and in 44 (33.8%) of the 130 advanced carcinomas, the incidence being significantly different (p less than 0.01). Out of the 130 advanced carcinomas, 17 (13.1%) had synchronous expression of EGF and its receptor and most of the tumors with strong expression of EGF were positive to EGF receptor. A significant correlation was observed between the depth of tumor invasion and EGF or its receptor immunoreactivity in tumor cells (p less than 0.05). Furthermore, a good correlation was demonstrated between the synchronous expression of EGF and its receptor and the depth of tumor invasion or the tumor staging. The incidence of cases with EGF in metastatic tumors was significantly higher than that in primary tumors (p less than 0.05). Patients with synchronous expression of EGF and its receptor had a far poorer prognosis than those without EGF and receptor.

Gastric cancer remains a global killer with a shifting burden from the developed to the developing world. The cancer develops along a multistage process that is defined by distinct histological and pathophysiological phases. Several genetic and epigenetic alterations mediate the transition from one stage to another and these include mutations in oncogenes, tumour suppressor genes and cell cycle and mismatch repair genes. The most significant advance in the fight against gastric cancer came with the recognition of the role of Helicobacter pylori (H pylori) as the most important acquired aetiological agent for this cancer. Recent work has focussed on elucidating the complex host/microbial interactions that underlie the neoplastic process. There is now considerable insight into the pathogenesis of this cancer and the prospect of preventing and eradicating the disease has become a reality. Perhaps more importantly, the study of H pylori-induced gastric carcinogenesis offers a paradigm for understanding more complex human cancers. In this review, we examine the molecular and cellular events that underlie H pylori-induced gastric cancer.