© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 8, 589,
April 19, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
Prostate cancer tends to be a slowly progressing disease of older men. As a result, a substantial proportion of men diagnosed with prostate cancer die of other causes. As these men age, the proportion increases. The presence of comorbid conditions may make accurate attribution of cause of death difficult. Newschaffer et al. (p. 613) compared the spectrum of underlying causes of death as specified in death certificates between two cohorts; the first consisted of men diagnosed with prostate cancer and the second of similar men without prostate cancer. The distributions of nonprostate cancer causes of death were largely similar between the two cohorts. However, the researchers found that, among men with underlying causes of death other than prostate cancer, those whose prostate cancer was aggressively treated were 51% more likely to have another cancer as the reported cause of death than those without prostate cancer. The authors conclude that the initial treatment may influence subsequent cause-of-death reporting.
In an accompanying editorial, Albertsen (p. 590) underscores the importance of accurate attribution of cause of death. He notes that reporting bias could seriously affect the ability to validate or refute the hypothesis that early detection and treatment lead to decreased prostate cancer mortality.
"This study . . . points out the possibility of an important limitation in vital statistics data, i.e., nondifferential misclassification of cause of death according to initial treatment status."
—Newschaffer et al.
Heregulin-
and Paget’s Disease of the Breast
In Paget’s disease of the breast (which occurs in about 1% of all patients with breast cancer), the epidermis of the nipple is infiltrated by large breast cancer cells of glandular origin. Breast cancer cells are attracted to the nipple by a motility factor that appears to act through the HER2/NEU receptor on the cancer cells. Schelfhout et al. (p. 622) isolated this motility factor from the culture medium of normal keratinocytes, sequenced peptides derived from the purified factor, and used these sequences to identify the motility factor as heregulin-. They then showed that heregulin- acted as a chemotactic factor for breast cancer cells and that the heregulin- receptors HER3, HER4, or both, as well as their coreceptor HER2/NEU, were expressed on breast cancer cells. They conclude that heregulin-, secreted by cells in the nipple, plays a key role in the pathogenesis of Paget’s disease.
Cell Migration in Follicular Center Lymphoma
Follicular center lymphoma is a common type of non-Hodgkin’s lymphoma that typically involves the lymph nodes at the time of diagnosis. Little is known about the mechanisms that control migration of the cancer cells. Corcione et al. (p. 628) investigated the role of stromal derived factor-1 (SDF-1), which is known to affect movement of a variety of human cells, in controlling migration of neoplastic B cells in vitro. They found that SDF-1 enhances the migration of follicular lymphoma B cells but not their normal counterparts, germinal center B cells. The authors conclude that SDF-1 may play a role in the local dissemination of lymphoma cells.
"Limited information is available with regard to the signals that drive the locomotion of malignant B lymphocytes."
—Corcione et al.
p14 Gene Transfer and Human Mesothelioma Cells
Mesothelioma is an asbestos-related malignancy characterized by rapidly progressive and diffusely local growth, late metastases, and poor prognosis. More than 70% of mesotheliomas have deletions at the p14ARF locus. (The p14ARF protein prevents the inhibition of the p53 protein by promoting the degradation of the MDM2 protein.) To evaluate its possible biologic and therapeutic uses, Yang et al. (p. 636) inserted p14ARF genes into mesothelioma cells that lack this gene by using an adenoviral vector containing the p14ARF gene. They showed that, in p14ARF-transfected cells, overexpression of p14ARF protein leads to increased amounts of p53 and p21WAF proteins, dephosphorylation of the retinoblastoma protein, cell cycle arrest in the G1 phase, and apoptotic cell death. The authors suggest that p14ARF gene therapy may be of use in the treatment of mesothelioma.
"The results presented herein suggest that Adp14ARF [the adenovirus carrying the p14ARF gene] may be useful for gene therapy for cancers that contain wild-type p53."
—Yang et al.
Circumventing Cisplatin Resistance
Although cisplatin is often effective in treating ovarian cancer, one of the most fatal tumors in women, development of resistance to cisplatin is a major obstacle to treatment. The mechanisms of cisplatin resistance are not well understood, but they appear to include overexpression of a metal-binding protein called metallothionein. Vandier et al. (p. 642) describe a model system in which the promoter of the metallothionein gene was linked to a "suicide" gene called thymidine kinase and was transfected into ovarian cancer cells that were either sensitive or resistant to cisplatin. Transfection of the cisplatin-resistant cells resulted in marked sensitization to the chemotherapeutic drug ganciclovir. The authors conclude that such a gene therapy strategy may eventually provide an alternative for treating cisplatin-resistant ovarian cancers.
"Although these experiments need to be validated in vivo, they offer a promising approach for the specific killing of cisplatin-resistant tumor cells."
—Vandier et al.
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