Emergence of higher levels of invasive and metastatic properties in the drug resistant cancer cell lines after the repeated administration of cisplatin in tumor-bearing mice.

To establish a more suitable model for reflecting biological aggressiveness in clinically recurrent cancers after chemotherapy, we made the in-vitro-established cisplatin-resistant cell lines, by exposing the parental tumor cell lines to cisplatin in a culture system, and also the in-vivo-established cisplatin-resistant cell lines by repeated cisplatin administration to parental tumor-bearing mice. Although both cell lines similarly demonstrated a clinically relevant low level of drug resistance (from 1.5 to 2.9 times more resistance to cisplatin than their parental cell lines), only the in-vivo-established cisplatin-resistant cell lines showed significantly enhanced metastatic properties with a 2.1- to 3.4-fold increase in the number of lung metastatic nodules. These enhanced metastatic properties were caused by tumor invasiveness in combination with various levels of enhancement of cell attachment, proteolytic enzyme activity and cell motility. We concluded that anticancer drugs such as cisplatin could promote tumor progression only in the drug-resistant cell lines established in vivo. As a result, these cell lines are considered to be a more faithful and useful model for expressing biological aggressiveness in clinically recurrent cancers after chemotherapy than the conventional drug-resistant cell lines established in vitro.