[Alteration of metastatic potential of ovarian cancer in clinical course].

Abstract

Ovarian cancer is one of the significant and deadly disease. Since 1980 when cisplatin was introduced in the chemotherapy, about 30% of the patients with advanced disease have achieved 5-year survival. However, remaining patients have had progressive disease or recurrence after achieving NED. Forty-seven% of recurrent disease was discovered as distant metastasis, while at initial therapy. In the recurrent disease, distantly metastatic lesions were encountered more frequently than those in primary disease. In the recurrent tumor, expression of immunohistochemical markers of malignancy, such as p53 protein and CD44v6 antigen were increased. These clinical data suggest that recurrent ovarian cancer which are exposed to anticancer agents attain increased metastatic potential. In order to assure that anticancer agent contribute to this increment, an experimental system using two human ovarian cancer cell lines (HRA, KF) and nude mice in which cancer cells were exposed to cisplatin in vivo was introduced. Cancer cells exposed to cisplatin in vivo (treated cells) made spontaneously more metastatic nodules in the mouse lung than those exposed to PBS (untreated cells). This result suggest that cisplatin induce the increase of metastatic potential of cancer cells in vivo. Treated cells showed higher invasiveness compared with untreated cells when inoculated in the footpad. Three major factors which were generally proposed to be necessary for cancer cell to give rise to invasion, such as attachment to extracellular matrix, production of proteolytic enzyme, and cellular mobility. For all of these factors, treated cells were superior to untreated cells. These results obtained suggests that cisplatin could increase the metastatic potential of cancer by enhancing potential of invasion. To investigate the mechanism of this phenomenon from the standpoint of genetic mutation, clonal analysis of experimental cancer in vivo was performed using southern blot method. Cancer cells before inoculation to the mice consisted of multiple clones. In 5 week after inoculation, tumor was wholely occupied by only one clone which showed one band on the lane. At this point cisplatin were administered. In 6 week, new single clone appeared with different band pattern from that of the clone at the administration of cisplatin. Furthermore, the cisplatin-induced new clone metastasized to the lung, while no metastasis was observed in the mouse with PBS-treated tumor during the same period. These data suggest that increased metastatic potential after cisplatin treatment is due not to selection but to creation of highly metastatic clone caused by potential of genetic mutation of cisplatin. In conclusion, chemotherapeutic agent has a potential to create highly malignant cancer cells as well as a potential to kill cancer cells.