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Metastatic Potential of Four Human Melanoma Xenografts in Young Athymic Mice following Tail Vein Inoculation

Charles River Biotechnical Services, Wilmington, Massachusetts 01887 [R. J. Z., E. T. G.], and V. T. Lombardi Cancer Research Center, Georgetown University, Washington, DC 20007 [A. G.]

We have investigated the lung colonizing ability of four newly established human metastatic melanoma xenografts, designated CRML1, CRML2, CRML3, and CRML4 following i.v. tail vein inoculation into 3- to 4-week-old gnotobiotic CD-1 athymic mice. The experimental metastatic potential of the tumors was assessed from the primary tumor samples through eight progressively growing s.c. passages. CRML1 and 2 were investigated in detail; five sublines (two from CRML1 and three from CRML2) were established from these tumors with various growth rates and lung colonizing abilities. The histopathologies of the patients' biopsies and the s.c. passaged parental lines were compared with these i.v.-derived sublines as one measure of tumor heterogeneity, in conjunction with the kinetics of lung tumor formation. The frequency and distribution of extrapulmonary tumor growth was also investigated after i.v. inoculation. In general, it reflected the clinical distribution of metastases, although their frequency of appearance was reduced. While CRML3 was the most aggressive disease clinically, it did not demonstrate the reproducible experimental metastasis of the other lines. CRML4 produced lung colonies routinely, but with latency periods of 20 weeks or more. On the other hand, the most rapidly growing sublines of CRML1 and CRML2 essentially replaced the normal lung tissue within 4 to 6 weeks following inoculation of 10⁵ cells.

The two sublines of CRML1 with higher effective metastatic potential were maximally able to colonize the lungs within only two i.v. cycles in one case, while the other line required six i.v. to i.v. passages to reach its maximum ability. In CRML2, two sublines were identified that rapidly increased in their lung colonizing ability, while another line remained effectively equal to the parental s.c. line over four cycles of reinoculation i.v. These results demonstrated that the athymic mouse can serve as a model for experimental metastasis of human tumors, and that aspects of the metastatic heterogeneity of these tumors can be investigated by using this system.

¹ Present address: Cetus Corporation, 1400 Fifty-third St., Emeryville, CA 94608. To whom requests for reprints should be addressed.

Received 9/18/86. Revised 1/ 6/87. Accepted 2/ 9/87.