For patients with Barrett's esophagus, expression of the enzyme cyclooxygenase (COX)-2 contributes to the rapid growth of abnormal cells in the lining of the esophagus, and inhibition of COX-2 may prevent the disease from progressing, a new study suggests.
Barrett's esophagus is a complication of chronic gastroesophageal reflux disease. Patients with Barrett's esophagus are at high risk of developing esophageal adenocarcinoma, but little is known about the processes involved in the progression to cancer.
COX-2 is an enzyme that is expressed in response to injury in the cells, and some studies have shown that inhibiting COX-2 has antineoplastic effects. In the March 20 issue of the Journal of the National Cancer Institute, Navtej S. Buttar, M.D., and Kenneth K. Wang, M.D., of the Mayo Graduate School of Medicine, Rochester, Minn., report that the selective COX-2 inhibitor NS-398 inhibited the proliferation of Barrett’s esophageal epithelial cells by 55% and decreased COX-2 activity.
Based on this finding and their additional experiments, they conclude that COX-2 activity "has a functional relevance in the proliferation of Barrett's esophageal epithelial cells and may have relevance to neoplastic progression in Barrett's epithelium. The inhibition of COX-2 activity may, therefore, have chemopreventive potential."
Contact: Kenneth K. Wang, M.D., wang.kenneth@mayo.edu
Mutations in Tumor Suppressor Region Interfere with Cell Senescence
Mutations in the locus that encodes two tumor suppressor proteins, p16 and Arf, may interfere with melanocyte senescence, and these mutations may favor melanocyte tumorigenesis by impairing senescence, cell differentiation, and cell death, a new study in mice has found.
The genes p16 and ARF are located at the INK4A-ARF locus, and mutations in this region, especially in p16, are associated with familial melanoma. In fibroblast cells, both p16 and ARF are involved in cellular senescence—the inability of normal cells to divide after a finite number of cell divisions. Elena V. Sviderskaya, Ph.D., Dorothy C. Bennett, Ph.D., and colleagues at the St. George's Hospital Medical School, London, assessed whether p16 and Arf had a similar effect in melanocytes, which are cells that produce the pigment melanin.
The researchers cultured melanocytes isolated from mice with one or both copies of Ink4a-Arf deleted. These melanocytes did not senesce and contained less melanin pigment than normal melanocytes. Restoring the expression of p16 stopped the growth of the melanocytes, which became highly melanized and expressed a marker of senescence. Restoring Arf expression did not affect senescence, but it increased cell death.
The authors conclude that mouse melanocyte senescence requires both copies of Ink4a-Arf and depends more on p16 than on Arf function. Furthermore, mutations in the INK4A-ARF locus may favor melanocyte tumorigenesis by impairing cell senescence and differentiation. They report their results in the March 20 issue of the Journal of the National Cancer Institute.
Contact: Dorothy C. Bennett, Ph.D., dbennett@sghms.ac.uk
Common Polymorphism May Be Associated with Decreased Risk of Colorectal Cancer
A common T-to-A polymorphism in a growth hormone gene (GH1) may be associated with a decreased risk of colorectal cancer, a new study has found.
GH1 may be associated with colorectal cancer directly or indirectly by increasing the plasma level of insulin-like growth factor-I (IGF-I). Plasma levels of IGF-I have been associated with the risk for colorectal, breast, and prostate cancers. A common T-to-A polymorphism in the GH gene is putatively associated with lower levels of GH and IGF-I, so Loïc Le Marchand, M.D., Ph.D., and colleagues at the Cancer Research Center of Hawaii investigated the relationship of this polymorphism to the risk of colorectal neoplasia in two case-control studies.
They found that a lower risk of cancer was consistently associated with the A allele rather than the T allele. The ratio of plasma IFG-I to IFG-I binding protein-3 reflects the amount of available IGF-I, and a lower ratio was found to be associated with the A allele rather than with the T allele. They concluded that the T-to-A polymorphism appears to be associated with a decreased risk of colorectal cancer. They report their results in the March 20 issue of the Journal of the National Cancer Institute.
Contact: Loïc Le Marchand, M.D., Ph.D., loic@crch.hawaii.edu
Lymphatic System Explored as Possible Route of Metastasis
Metastasis is the major cause of mortality from malignant tumors. Cancer cells can metastasize via the vascular system and/or the lymphatic system. In the March 20 issue of the Journal of the National Cancer Institute, Rakesh K. Jain, Ph.D., and Brenda T. Fenton, of the Department of Radiation Oncology at Massachusetts General Hospital and Harvard Medical School, provide a commentary regarding the current understanding of the lymphatic system as it relates to cancer biology.
The authors provide a detailed assessment of the association between clinicopathologic endpoints and the expression of several lymphangiogenic markers and describe how the identification of these molecules is changing the design and focus of lymphatic and vascular biology studies in cancer.
Contact: Rakesh K. Jain, Ph.D., jain@steele.mgh.harvard.edu
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Journal
JNCI Journal of the National Cancer Institute