Dendritic cells (DC) are antigen-presenting cells. Human dendritic cells are broken into two groups or subpopulations known as DC1 and DC2. It is well known that the role of these dendritic cells is to direct or instruct the activity of immune cells. However, the role of these dendritic cells at tumor angiogenesis is unknown. We propose research to expand our knowledge and understanding of the function of dendritic cells in tumor angiogenesis.

Our current understanding of DC1 is that it may play a positive role in cancer immunity by activating potentially protective T-cell function. However, our understanding of DC2 cells is poor. It has been assumed that DC2 may function as DC1 to enhance tumor immunity. However, there are no published reports in this regard.

We have spent that past 3 years researching the role of DC2 and DC1 in ovarian cancer. In our work, we have found an unusual dendritic cell distribution in malignant tumors of patients with ovarian carcinoma: high levels of DC2 exist while no DC1 are present. Our data demonstrate that tumor derived chemokine SDF-1 not only attracts DC2, but also protect them from death. More strikingly, these DC2 were found to release angiogenic factors, and synergize the angiogenic effects of tumor SDF-1, thereby inducing tumor angiogenesis. This is significant because DC2 studied in blood, rather than in tumors, showed none of these characteristics. Therefore, tumor DC2 appear to be beneficial, rather than detrimental to tumor development. Further research to continue our understanding of the role of tumor DC2 will help to determine if the hypothesis ¿ that tumors manipulate DC1 and DC2 distribution and function to support tumor angiogenesis ¿ is valid.

A manuscript has been published in Nature Medicine, one of the top-impact scientific journals in the world, testifying to the novelty and originality of these observations, and the significance of his further research on this project. The continued research will focus on defining 1) the in vivo capacity for tumor SDF-1 and tumor DC2 to induce tumor angiogenesis, 2) the specific mechanisms that cause this induction, and 3) the small antagonist that block their tumor angiogenesis.

In terms of pathology, this proposal will provide a model to demonstrate the significance of DC2 in ovarian carcinoma by showing how tumors induce tumor angiogenesis by attracting and protecting detrimental DC2, and prevent the accumulation of DC1 in the tumor, which would otherwise provide anti-angiogeneic effects. Ovarian carcinoma will be the focus of the study, but this process is expected to relate to other tumor types as well. In terms of therapy, the research has been designed to generate information and tools that will be of immediate interest to the clinical management of ovarian cancer. Once completed, the results will demonstrate how human tumor angiogenesis can be induced by tumor SDF-1 and its target DC2 in the tumor micro-environment. Therefore, modification of DC2 migration to the tumor would be a novel strategy for treating cancer patients.