Grantee Research Project Results
1999 Progress Report: Screening Environmental Chemical Mixtures for Effects on Prostate Cancer Invasion Properties
EPA Grant Number: R827152Title: Screening Environmental Chemical Mixtures for Effects on Prostate Cancer Invasion Properties
Investigators: Lindholm, Paul F. , Kajdacsy-Balla, Andre
Institution: Medical College of Wisconsin
EPA Project Officer: Hahn, Intaek
Project Period: November 15, 1998 through November 14, 2001
Project Period Covered by this Report: November 15, 1998 through November 14, 1999
Project Amount: $555,000
RFA: Chemical Mixtures in Environmental Health (1998) RFA Text | Recipients Lists
Research Category: Hazardous Waste/Remediation , Human Health , Safer Chemicals , Land and Waste Management
Objective:
The prevalence of prostate cancer is similar in American and Japanese populations while the mortality from prostate cancer is much higher in Americans and Japanese immigrants to America, suggesting that environmental factors may have a very important influence on the progression of prostate cancer. We hypothesize that environmental chemicals may activate latent, localized cancers to become invasive and metastatic. Cancer cell invasion and metastasis is a complex multistep process that requires complex changes in cellular phenotype and gene expression. This project is designed to test the hypothesis that complex environmental mixtures are capable of inducing invasive properties in already established prostate cancer cells. This hypothesis is being tested by measuring a panel of biomarkers of aggressive prostate cancer cells to design methods to screen chemical mixtures for their ability to induce metastatic markers in prostate cancer cells.Progress Summary:
The goals in this first year have been accomplished by testing several environmental chemical mixtures for induction of prostate cancer cell invasion biomarkers with the Transwell? invasion and motility assays, cellular adhesion to reconstituted basement membranes, the cDNA array, and the NF- B gel shift assay.The exposure of prostate cancer cells to small doses of cadmium chloride induced increased cancer cell invasiveness, adhesion to the basement membrane, and increased cell motility. Cadmium chloride also induced p38 MAPkinase, which was detected using cDNA array and confirmed by western blot. The induction of markers of cancer cell aggressiveness by cadmium was independent of increased cancer cell proliferation. Cigarette smoke concentrate (CSC), another environmental agent known to influence cancer cell progression, also was found to induce prostate cancer cell invasiveness. Additional studies are being performed to determine the mechanism by which CSC induces increased cancer cell invasiveness.
In contrast, pyrethroid insecticide mixtures had a profound effect on prostate cell proliferation. The effect of pyrethroids on cancer cell invasiveness was difficult to separate from the cell proliferative effect of the insecticide, but inhibitors of cell proliferation are being used to resolve this issue.
Our first year experience has shown that the proliferation and invasion assays were very sensitive and reproducible for determining the effects of some environmental agents on cancer cell invasion markers. We also have focused on testing several techniques for increased sensitivity and throughput. The NF- B electrophoretic mobility shift assay was not a sensitive indicator of the invasive phenotype because the effects of some environmental agents on NF- B DNA binding activity were not informative.
A byproduct of this project has been the identification of new metastasis-associated genes using subtractive hybridization and cDNA arrays. For example, we have submitted a paper showing the increased expression of the nuclear Ki antigen, a proteasome regulator, in the aggressive prostate cancer cells.
Future Activities:
As planned initially, the next step in this project will be to use additional chemical mixtures, including common pesticide mixtures, dioxin containing mixtures, and emission air pollution and rural air samples, to test their effect on prostate cancer cell aggressiveness. High throughput assays to determine the effects of complex chemical mixtures on cell invasiveness and signaling pathways will be further developed. The effect of chemical mixtures will be tested with additional prostate cancer cell lines to determine whether the effects of environmental chemical exposures have a similar effect on the invasive phenotype that was found using the PC-3 cell line.Journal Articles:
No journal articles submitted with this report: View all 7 publications for this projectSupplemental Keywords:
complex chemical mixtures, herbicides, tobacco, metastasis, screening methods., Health, RFA, Scientific Discipline, Air, PHYSICAL ASPECTS, Waste, ENVIRONMENTAL MANAGEMENT, Toxics, Health Risk Assessment, Physical Processes, pesticides, Risk Assessments, chemical mixtures, Environmental Chemistry, Epidemiology, Molecular Biology/Genetics, air toxics, cancer risk, Risk Assessment, carcinogens, cadmium, atrazine, carcinogenic, emission source pollution, human exposure, Endosulfan Sulfate, complex mixtures, epidemiological studies, effects assessment, prostate cancer, exposure, cancer risk assessment, cell biology, characterizing chemical mixtures, invasice properties, human health risk, tobacco smoke, exposure assessmentProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.