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Interleukin-12 Inhibits Angiogenesis and Growth of Transplanted but not in Situ Mouse Mammary Tumor Virus-induced Mammary Carcinomas¹

Departments of Medicine [J. C. L., M. S. G., W. M. F. L.], Microbiology [D. C. K., S. R. R.], Radiology [C. M. S.], and Pathology and Laboratory Medicine [M. D. F.], School of Medicine; Biomedical Graduate Program [M. S. G.]; Cancer Center [S. R. R., W. M. F. L.]; and Section of Radiology, School of Veterinary Medicine [H. M. S.], University of Pennsylvania, Philadelphia, Pennsylvania 19104

We examined the ability of recombinant murine interleukin-12 (rmIL-12) to inhibit the vasculature and growth of mammary carcinomas arising in situ in mouse mammary tumor virus (MMTV)-infected female C3H/HeN mice. Although it is a potent antiangiogenic and antitumor agent in many transplanted murine tumor models, rmIL-12 failed to inhibit the vascularity, reduce the perfusion, or alter the growth of these autochthonous carcinomas. Factors intrinsic to these tumor cells were unlikely to be responsible for therapy failure. This is because primary cells derived from these carcinomas responded to IFN-, and rmIL-12 was effective against transplanted tumors arising from Mm5MT cells, a line established from a MMTV-induced mammary carcinoma in C3H mice. Factors intrinsic to the mice that host the autochthonous mammary carcinomas were also not responsible for failure, because they sponsored rmIL-12 antiangiogenic and antitumor effects against transplanted K1735 murine melanoma tumors. Instead, the autochthonous nature of the mammary carcinomas and their possession of a high percentage of mature, pericyte-covered vessels that are resistant to therapeutic regression may be responsible. This is supported by the observation that transplanted Mm5MT tumors had a lower proportion of pericyte-covered vessels and responded to rmIL-12 therapy. These results point to significant differences between the vasculature of transplanted and autochthonous murine tumors and indicate that their susceptibility to antivascular therapy may differ substantially.

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