Dr. Harold Kim:
The Role of Prox-1 in Lymphangiogenesis and Cancer Metastasis
In 2006, approximately 22,000 new cases of breast cancer will be diagnosed in Canada; of those 5,300 will succumb to this disease. While many surgical and adjuvant treatments have been developed that have increased patient survival and decreased morbidity, this disease is still the second leading cause of death in women in North America. The mechanism of metastasis is believed to occur via two vascular systems that feed tumor growth, the well-characterized blood vasculature, and the ill characterized lymphatic vasculature. With the breadth of knowledge in angiogenesis, many chemotherapeutic agents have been developed that molecularly target this process. In contrast, the lymphatic system has not been scrutinized as a direct target for chemotherapeutic intervention due to the gap of knowledge in its molecular function. In spite of this, clinical oncologists rely heavily on the evaluation of the lymphatic system in order to assess patient prognosis and plan disease management.
A number of genes have been found to play key roles in its development and function, for example the vascular endothelial growth factor receptor-3 (VEGFR-3), the ligand Angiopoietin-2 and the nuclear protein Prox-1. This latter gene has been dubbed a ‘master regulatory’ switch as suggested by mouse studies that ablate this genes function; Prox-1 knockout mice lack functional lymphatics early in development resulting in lethality. Given the importance of Prox-1 in regulating lymphatic development as well as the clear role of lymphatics in metastasis, our hypothesis reasons that if Prox-1 is indeed a switch in lymphatic development, one could molecularly control lymphangiogenesis in an inducible fashion and potentially control breast cancer metastasis.
To this end, our specific aims revolves around two key goals; 1) to generate a novel inducible mouse model based on the gene Prox-1 to manipulate lymphangiogenesis at any time in development and; 2) test the ability to control breast cancer metastasis by regulating lymphangiogenesis via Prox-1. The general methodology for the first aim entails turning on or off Prox-1 expression i.e. regulating lymphatic growth and observing, a) gross changes in physiology; b) general vascular changes and, c) changes in molecular markers associated with either blood or lymphatic vasculature. In our second aim we will transplant tumor cells derived from the c-ErbB2 and the polyomavirus middle-T breast cancer models into the mammary gland of inducible Prox-1 mice in addition to interbreeding c-ErbB2 transgenic mice with Prox-1 mice. Prox-1 expression will be induced or silenced and tumor-bearing mice will be assessed for perivascular micrometastasis and dissemination rates into sentinel lymph nodes and distant organ sites.
The potential in lymphangiogenic research in breast cancer is clear; one can control lymphangiogenesis and address issues such as lymphedema and metastasis. From these studies, breast cancer management can see a new partner with antiangiogenic therapies, one that exploits the molecular mechanisms that govern lymphangiogenesis thereby attacking another conduit for metatastic spread related to breast cancer.
