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Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis

Nava Almog^*, Vanessa Henke^*, Ludmila Flores, Lynn Hlatky, Andrew L. Kung, Renee D. Wright, Raanan Berger, Lloyd Hutchinson^*, George N. Naumov^*, Elise Bender^*, Lars A. Akslen^*, Eike-Gert Achilles^|| and Judah Folkman^*,1

^* Vascular Biology Program and Department of Surgery, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA;

Department of Radiation Oncology,

Department of Pediatric Oncology,

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA; and

^|| Clinic for Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Hamburg, Germany

¹Correspondence: Vascular Biology Program, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA. E-mail: judah.folkman{at}childrens.harvard.edu

ABSTRACT

The disease state of cancer appears late in tumor development. Before being diagnosed, a tumor can remain for prolonged periods of time in a dormant state. Dormant human cancer is commonly defined as a microscopic tumor that does not expand in size and remains asymptomatic. Dormant tumors represent an early stage in tumor development and may therefore be a potential target for nontoxic, antiangiogenic therapy that could prevent tumor recurrence. Here, we characterize an experimental model that recapitulates the clinical dormancy of human tumors in mice. We demonstrate that these microscopic dormant cancers switch to the angiogenic phenotype at a predictable time. We further show that while angiogenic liposarcomas expand rapidly after inoculation of tumor cells in mice, nonangiogenic dormant liposarcomas remain microscopic up to one-third of the normal severe combined immune deficiency (SCID) mouse life span, although they contain proliferating tumor cells. Nonangiogenic dormant tumors follow a similar growth pattern in subcutaneous (s.c.) and orthotopic environments. Throughout the dormancy period, development of intratumoral vessels is impaired. In nonangogenic dormant tumors, small clusters of endothelial cells without lumens are observed early after tumor cell inoculation, but the nonangiogenic tumor cannot sustain these vessels, and they disappear within weeks. There is a concomitant decrease in microvessel density, and the nonangiogenic dormant tumor remains harmless to the host. In contrast, microvessel density in tumors increases rapidly after the angiogenic switch and correlates with rapid expansion of tumor mass. Both tumor types cultured in vitro contain fully transformed cells, but only cells from the nonangiogenic human liposarcoma secrete relatively high levels of the angiogenesis inhibitors thrombospondin-1 and TIMP-1. This model suggests that as improved blood or urine molecular biomarkers are developed, the microscopic, nonangiogenic, dormant phase of human cancer may be vulnerable to antiangiogenic therapy years before symptoms, or before anatomical location of a tumor can be detected, by conventional methods.—Almog, N., Henke, V., Flores, L., Hlatky, L., Kung, A. L., Wright, R. D., Berger, R., Hutchinson, L., Naumov, G., Bender, E., Akslen, L., Achilles, E.-G., Folkman, J. Prolonged dormancy of human liposarcoma is associated with impaired tumor angiogenesis.

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