1. Department of Surgery, Children's Hospital, and the ^* Department of Pathology, the Brigham and Women's Hospital, and The Departments of Surgery, Anatomy and Cellular Biology, and Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
2. ^† Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA and
3. ^‡ Department of Biochemistry and Biophysics, Hormone Research Institute, University of California, San Francisco, California 94143, USA

Abstract

IT is now well established that unrestricted growth of tumours is dependent upon angiogenesis^1,2. Previous studies on tumour growth, however, have not revealed when or how the transition to an angiogenic state occurs during early tumour development. The advent of transgenic mice carrying oncogenes that reproducibly elicit tumours of specific cell types^3–6 is providing a new format for studying multi-step tumorigenesis^7,8. In one of these models, transgenic mice expressing an oncogene in the -cells of the pancreatic islets heritably recapitulate a progression from normality to hyperplasia to neoplasia⁶. We report here that angiogenic activity first appears in a subset of hyperplastic islets before the onset of tumour formation. A novel in vitro assay confirms that hyperplasia per sedoes not obligate angiogenesis. Rather, a few hyperplastic islets become angiogenic in vitro at a time when such islets are neovascularized in vivo and at a frequency that correlates closely with subsequent tumour incidence. These findings suggest that induction of angiogenesis is an important step in carcinogenesis.