EWOC-4 conference abstract

Breast cancer angiogenesis: Therapy target and prognostic factor

It has been well established that the vascularization of solid tumors is a prerequisite if a clinically relevant size is to be reached. For progressive tumor growth, the vessel network must continuously expand to satisfy the neoplastic cells' nutritional needs and waste product removal requirements. This utter reliance of the tumor on its vasculature provides a logical target for new approaches to cancer therapy. Indeed, there currently exists a great deal of enthusiasm for the development of interventions that compromise the growth and/or function of the tumor neovasculature. Two primary directions are being pursued. Inhibitors of angiogenesis seek to interrupt the angiogenic process to prevent new vessel formation. Antivascular approaches aim to cause direct damage to the tumor endothelium and thus lead to extensive secondary neoplastic cell death. The application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies. Copyright 2003, Elsevier Science (USA). All rights reserved.

Background and purpose: The neovascularization of tumor cells is a prerequisite if a clinically relevant tumor size is to be reached. A continuously expanding vessel network supplying nutritional requirements and removing waste products is essential for continued tumor development, growth and survival.

Results: In many tumors, the growing endothelium is unable to fully support the demands of the neoplastic cell population. As a consequence of the inadequacies of the resulting aberrant vasculature, microenvironmental conditions develop in tumors which are not only detrimental to the response of tumors to conventional anticancer treatments, but may lead to or predispose cells to genetic modifications resulting in more aggressive phenotypes and higher metastatic potential. Yet the utter dependence of the tumor on its induced vessel formation for growth, survival and spread has also created a great deal of enthusiasm for developing therapeutic approaches to specifically targeting the tumor microcirculation.

Conclusions: The application of such strategies as adjuvants to conventional radiation treatments offers unique opportunities to develop more effective cancer therapies.

Angiostatin is an inhibitor of tumor angiogenesis that induces regression of experimental tumors and enhances the antitumor effects of radiation therapy. We report that the cytotoxic effects of angiostatin are restricted to the proliferating endothelial cell population. In addition, angiostatin and ionizing radiation (IR) interact by inducing death of dividing endothelial cells. We also show that angiostatin and IR interact to inhibit endothelial cell migration. These findings demonstrate that angiostatin targets the proliferating tumor vasculature and provide a mechanistic basis for the cytotoxic interaction of angiostatin and IR.

We studied tumour specimens from 106 patients with primary breast tumours seen at the University Hospital of Patras, Greece, with a follow-up period of 3–10 years, focusing on the role of breast cancer angiogenesis as a prognostic factor. Angiogenesis was assessed in the primary tumour using an immunohistochemical stain for the CD31 antigen assay for quantitation of microvessel counts. Multiple regression analysis using microvessel count and other clinical-histological findings (age, tumour size, grade and lymphnode metastases) showed that only microvessel counts were significantly predictive of haematogenous metastases to lung, bones, liver and brain (χ² test, P = 0.022). This study shows that angiogenesis is significantly predictive of haematogenous metastases.