From Journal of the National Cancer Institute
Other highlights in the Jan. 2 issue of JNCI Matrix Metalloproteinases May Play a Role in Spread of Prostate Cancer to the Bone; Genetic Marker May Be Useful In Predicting Survival of Patients with Diffuse Large B-Cell Lymphoma; Possible Mechanism Found for Relationship Between Oral Contraceptives and Risk of Ovarian Cancer; Loss of Heterozygosity An Effective Method for Predicting BRCA1 Mutations
Matrix Metalloproteinases May Play a Role in Spread of Prostate Cancer to the Bone
Prostate cancer that has spread to the bone is associated with pain, impaired mobility, pathologic fractures, spinal cord compression, and other problems. Enzymes called matrix metalloproteinases (MMPs) are involved in both the normal remodeling of bone and the metastasis of prostate cancer to the bone. These enzymes function by digesting tissue around cells.
In the Jan. 2 issue of the Journal, Jeffrey A. Nemeth, Ph.D., Michael L. Cher, M.D., and colleagues from Wayne State University School of Medicine, Detroit, Mich., investigate the role of MMPs in prostate cancer metastasis. They showed that MMPs are produced by prostate cancer cells residing in the bone as well as normal bone cells. The researchers used batimastat (an MMP inhibitor) to treat mice that had been implanted with human bone fragments and then injected with human prostate cancer cells into the bone fragments.
The batimastat treatment reduced the number of osteoclasts per millimeter of bone, prevented bone degradation, and reduced the number of proliferating cancer cells by about two-thirds. The researchers conclude that tumor growth and bone turnover are linked in a mutually supportive cycle that can be disrupted by inhibiting MMP activity.
Contact: Steve Townsend, Wayne State University School of Medicine, (313) 577-1429; fax: (313) 993-4333; email@example.com
Genetic Marker May Be Useful In Predicting Survival of Patients with Diffuse Large B-Cell Lymphoma
The natural history of diffuse large B-cell lymphoma can vary widely among patients with the disease. Advances in treatment and the identification of clinical symptoms have led to better prognosis, but the therapy fails in about half of patients and they die of their disease. Previous studies have suggested that a DNA repair enzyme called O6-methylguanine DNA methyltransferase (MGMT) is effectively silenced by promoter hypermethylation in several human cancers. This silencing has been associated with a favorable prognosis in patients with brain tumors treated with alkylating agents such as carmustine.
In the Jan. 2 issue of the Journal of the National Cancer Institute, Manel Esteller, M.D., James G. Herman, M.D., and colleagues at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins analyzed the MGMT promoter methylation status in tumor DNA of patients with diffuse large B-cell lymphoma who received the alkylating agent cyclophosphamide as part of a multidrug regimen. The presence of MGMT methylation was associated with a statistically significant increase in overall survival and progression-free survival, and the marker also appeared to be independent of and stronger than established prognostic factors such as age, disease stage, and performance status.
The researchers conclude that MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with diffuse large B-cell lymphoma who are treated with multidrug regimens that include cyclophosphamide.
Contact: Vanessa Wasta, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 410-955-1287; fax: 410-614-2611; firstname.lastname@example.org
Possible Mechanism Found for Relationship Between Oral Contraceptives and Risk of Ovarian Cancer
Oral contraceptive use is associated with a reduced risk of ovarian cancer, but the exact mechanism for the possible association is unknown. In primate studies, progestin, a component of some oral contraceptives, induces apoptotic cell death in the ovarian epithelium. Cell death may also be regulated by a specific growth factor called transforming growth factor-â (TGF-â).
Gustavo C. Rodriguez, M.D., of Evanston Northwestern Healthcare, and his colleagues sought to determine the association between progestin-induced apoptosis and the expression of TGF-â in the ovarian epithelium of female cynomolgus macaques. The monkeys were split into groups and were fed a diet containing no hormones, the oral contraceptive Triphasil, or each of its constituents, estrogen or progestin, alone. An analysis of the ovaries from all of the monkeys revealed that, compared with monkeys treated with estrogen alone or no hormones, animals treated with progestin had a marked decrease in the expression of TGF-â1 and an increase in the expression of the TGF-â2/3 isoforms.
These results suggest that, in the ovarian epithelium, progestin induces differential regulation of TGF-â, and a change in the expression of TGF-â is highly associated with apoptotic cell death. The researchers conclude that the data suggest a possible biologic mechanism for the protective association between oral contraceptive use and reduced ovarian cancer risk. In addition, these results, the authors say, may provide an effective strategy for ovarian cancer prevention. The results are reported in the Jan. 2 issue of the Journal of the National Cancer Institute.
Contact: Carin Ganz, Evanston Northwestern Healthcare, (847) 570-3141; fax: (847) 570-3290; email@example.com
Loss of Heterozygosity An Effective Method for Predicting BRCA1 Mutations
Mutations in the BRCA1 gene increase a woman's risk of ovarian cancer, one of the most common hereditary cancers in women. Because testing for BRCA1 gene mutations is cumbersome and impractical for large populations, John P. Geisler, M.D., Richard E. Buller, M.D., Ph.D., and colleagues at the University of Iowa Holden Comprehensive Cancer Center developed a strategy to detect various kinds of BRCA1 dysfunction that included both mutation and gene silencing. They present their study in the Jan. 2 issue of the Journal of the National Cancer Institute.
In this study of 221 epithelial ovarian cancer tumor samples, 51 (23.1%) of them had BRCA1 dysfunction. The investigators also tested all of the samples for loss of heterozygosity, meaning that one of the BRCA1 alleles was not expressed. Among the 121 tumor samples that exhibited LOH or had inconclusive results, 45 (37.2%) had BRCA1 dysfunction.
The authors conclude that using LOH of BRCA1 as the first step in a screening strategy of ovarian cancers appears to increase the chance of identifying tumors with BRCA1 dysfunction without having to screen entire populations of women.
Contact: Becky Soglin, University of Iowa Health Science Relations, (319) 335-6660; fax: (319) 384-4638; firstname.lastname@example.org