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Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy

TATURO UDAGAWA^*, ANTONIO FERNANDEZ^*,, EIKE-GERT ACHILLES^*,, JUDAH FOLKMAN^* and ROBERT J. D’AMATO^*,1

^* Department of Surgery, Division of Surgical Research, Children’s Hospital, and
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA;
Unidad de Investigacion, Hospital de Leon. Altos de Nava S/N. Leon Spain 24071; and
Department of Hepato-Biliary Surgery, University of Hamburg, University Hospital Hamburg, Germany

¹Correspondence: *Department of Surgery, Division of Surgical Research, Enders-1022, Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115, USA. E-mail: robert.damato{at}tch.harvard.edu

Some human tumor lines do not form visible tumors when inoculated into immunosuppressed mice. The fate of these human tumor lines was followed by transfecting them with green fluorescence protein before inoculating them into mice. Although the tumor lines failed to grow progressively, they formed small dormant microscopic foci maintained at constant mass by balanced proliferation and apoptosis. Transfecting the cells with either VEGF₁₆₅ or activated c-Ha-ras induced loss of dormancy, which correlated with a shift in the angiogenic balance toward increased vascularity with reduced tumor cell apoptosis. These results support a model in which loss of dormancy is controlled in part by a switch to an angiogenic phenotype. These tumor lines may serve as models for investigating the cellular mechanisms controlling dormancy and identifying those factors that promote the loss of balanced proliferation and apoptosis. Finally, these models may prove useful in the design and testing of therapies directed toward eradicating dormant tumors and preventing tumor recurrence.—Udagawa, T., Fernandez, A., Achilles, E.-G., Folkman, J., D’Amato, R. J. Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy.

Key Words: angiogenesis • dormant tumors • occult cancers

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