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Inhibition of Breast Cancer Tumor Progression by Class-3 Semaphorins
Tumor Cell Biology I
i n breast cancer, poor prognosis is linked to the initiation of tumor angiogenesis. Members of the class-3 semaphorin subfamily have recently been characterized as regulators of developmental angiogenesis. Semaphorin-3F (s3f) was characterized as an inhibitor of tumor angiogenesis while other semaphorins such as semaphorin-3A (s3a) and semaphorin-3E (s3e) repel endothelial cells and may also inhibit tumor angiogenesis. Furthermore, s3f and semaphorin-3B (s3b) were characterized as tumor suppressors that are inactivated in small cell lung cancer. Therefore, semaphorins may perhaps be used as anti-angiogenic and anti-tumorigenic drugs. Most class-3 semaphorins bind to receptors of the neuropilin gene family which in turn form complexes with receptors of the plexin family, to generate functional semaphorin holo-receptors. Class-3 semaphorins may also activate plexins directly, as recently shown for s3e. There are nine different human plexins and two neuropilins, indicating that responses to semaphorins may vary depending on available plexin/neuropilin combinations. The neuropilins also function as VEGF receptors and modulate the activity of VEGF tyrosine kinase receptors. It is therefore not surprising that some semaphorins inhibit VEGF activity by inhibiting VEGF binding to neuropilins. Because semaphorins repel endothelial cells they may also be able to enhance the effects of anti-angiogenic agents that employ different anti-angiogenic mechanisms. The complexity of semaphorin signaling indicates that different tumors may respond to different semaphorins in unique ways and that a better understanding of the biology is required. We propose to characterize the expression of semaphorin receptors in human breast cancer tumors and in their associated blood vessels and also in tumors that develop following implantation of breast cancer cells in mice. We will then establish cell lines derived from endothelial cells expressing the combinations of neuropilins and plexins found in breast cancer tumors. These cell lines will be used to determine which semaphorins inhibit the proliferation and migration of the cells. We will then determine the effects of active semaphorins and of semaphorin combinations on the development and progression of tumors derived from breast cancer cells implanted in mammary fat pads of mice. The proposed studies should identify class-3 semaphorins that may be considered for use as potential anti-tumorigenic agents in breast cancer.
Tumor angiogenesis is the process by which new blood vessels grow out of the surrounding vasculature to feed the growing tumor. Angiogenesis is usually tightly regulated by complex pro and anti-angiogenic cues. Many studies indicate that poor prognosis in breast cancer is associated with the induction of angiogenesis. The main protein that induces angiogenesis in many types of tumors is vascular endothelial growth factor (VEGF). Several years ago a new species of VEGF receptors has been identified. These receptors do not transduce angiogenic signals of VEGF on their own but rather enhance the activity of other known VEGF receptors. These receptors are encoded by the two neuropilin genes. However, the neuropilins were originally identified as receptors for semaphorins , proteins that participate in the guidance of nerves to their correct targets during embryonic development. The identification of neuropilins and of their associated plexin receptors as receptors residing not only in nerve cells but also in cells that make up blood vessels indicates that semaphorins may also function as regulators of angiogenesis. Indeed, several recent studies indicate that semaphorins may be able to inhibit tumor development by repelling newly formed blood vessels. Furthermore, semaphorin receptors have been found on several types of cancer cells and there is evidence that semaphorins may also be able to affect directly the behavior of tumor cells. All the above does not mean that we can start to use semaphorins as anti-cancer drugs. To function as semaphorin receptors, neuropilins associate with several types of additional receptors, and the properties of most of the semaphorins have not been studied in detail. We propose to carry out a study in which we will first determine which semaphorin receptors are expressed in various breast cancer tumors. Secondly, we propose to screen several different semaphorins for their effect on cells expressing the combinations of semaphorin receptors we will identify in the tumors. Lastly, we will test the effects of the active inhibitory semaphorins we will identify, and of combinations of these semaphorins, on the development of tumors derived from breast cancer cells in mouse models. We will determine the effect of the semaphorins on the malignancy of the resulting tumors and on tumor angiogenesis. The proposed studies should reveal if class-3 semaphorins may be considered for use as potential anti-tumorigenic agents in breast cancer .