Molecular Mechanisms of Gastric Carcinogenesis
Recently, we have also turned our attention to trying to understand the changes involved in the dysregulated expression of some genes found to be altered in gastric cancer. Worldwide, gastric cancer is second only to lung cancer as a cause of cancer death. In the United States, there are 22,000 new cases annually, resulting in 14,000 deaths in 1996. Early detection is not common, and the 5-year survival of less than 20% has remained unchanged over several decades. Clearly, new approaches are needed for treatment of this disease. The molecular mechanisms responsible for the development of gastric adenocarcinoma are unknown.
One characteristic common to many gastric cancers is that the expression of a key enzyme required for the synthesis of prostaglandins, cyclooxygenase-2 (cox-2), is upregulated relative to normal tissues. Although the overexpression of cox-2 is not likely to be the causative event for the development of gastric cancer, several studies have suggested that it may play an important role as a progression factor in the disease. Furthermore, since cox-2 expression is generally believed to be induced upon stimulation of cells by growth factors or inflammatory mediators, the constitutive overexpression of cox-2 in gastric cancer may be a reflection of a dysregulated cytoplasmic signal transduction pathway. In contrast to many colon carcinomas, mutated ras genes have not been detected in gastric cancersthus, it is likely that alterations in other, possibly parallel, signaling pathways have occurred which are responsible for the transformed phenotype.
The gene for c-met, the cell surface receptor for hepatocyte growth factor (HGF), is amplified and/or overexpressed in many cancers, including gastric, colon, and prostate. Signaling through c-met results in the development of an invasive growth phenotype. Hallmarks of this phenotype are cell proliferation, motility, extracellular matrix invasion, and protection from apoptosis. These same characteristics are also found in cells overexpressing the cox-2 gene.One of the goals of this project is to address the molecular biology, biochemistry, and cellular biology of the interplay between c-met, HGF and cox-2 in the progression of gastric cancer, and perhaps other cancers in general. The hypothesis to be tested is that overexpression of c-met (or HGF itself), enhances the motility, growth, and invasiveness of gastric cancer cells in part through the induction of cox-2 gene expression and the enhancement of prostaglandin synthesis. These studies will seek to determine the role that c-met/HGF plays in the regulation of cox-2 gene expression and identify the signal transduction mechanisms through which c-met acts to induce cox-2 gene expression. In addition, we will characterize the potential role of cox-2, and its products, in mediating some of the biological effects of HGF including invasiveness, proliferation, and protection from apoptosis. Results from these studies will thus help to delineate some of the mechanisms involved in the interactions between stromal cells and neoplastic epithelial cells.
DARPP-32 is recognized as a neuronal protein that, dependent upon which threonine residue is phosphorylated, acts as a protein phosphatase-1 inhibitor (PP1) or a protein kinase-A (PKA) inhibitor and is essential for dopamine signaling and slow synaptic transmission. We have recently demonstrated that DARPP-32, and a novel truncated isoform, are consistently overexpressed in gastric cancers. Current studies in collaboration with Wa’el El-Rifai and Steve Powell (UVA, Division of Gastroenterology) are exploring the role of the unique signal transduction intermediary in the regulation of carcinogenesis and normal gastric epithelial biology.
El-Rifai, W., M. F. Smith Jr., G. Li, A. Beckler, V. S. Carl, E. Montgomery, S. Knuutila , C. A. Moskaluk, H.F. Frierson Jr, and S.M. Powell 2002. Gastric Cancers Overexpress Neuronal DARPP-32 and a Novel Isoform (t-DARPP). Cancer Res. 62:4061-4064
Additional Gastric-cancer related studies:
Deng, D., G. Deng, M.F. Smith, Jr., J. Zhou, H. Xin, S.M. Powell, and Y. Lu. 2002. Simultaneous detection of CpG methylation and single nucleotide polymorphism by denaturing high performance liquid chromatography. Nucl. Acids Res. 30(3):E13.
D. Deng, W. El-Rifai, J. Ji, B. Zhu, P. Trampont, J. Li, M.F. Smith, and S. M. Powell 2003. Hypermethylation of Metallothionein-3 CpG Island in Gastric Carcinoma. Carcinogenesis. 24:25-29
Berr SS, Roche JK, El-Rifai W, Smith MF, Powell SM. 2003 Magnetic Resonance Imaging of Gastric Cancer in TFF-1 Knockout Mice. Magn. Reson. Med. In press