We are studying mechanistic similarities and differences of blood vessel formation (including angiogenic and vasculogenic aspects) in distinct tumors types (brain, breast, pancreas), and the functional consequences of neovascularization or inhibition of it on tumor behavior. Our laboratory also translates the knowledge gained into new therapeutic strategies with the goal to stop tumor growth and progression. Our specific interest lays in tumors that have relapsed to reveal adaptation mechanisms of tumors during the course of antiangiogenic therapy. We further are interested in the effects of the vascular niche on the maintenance and activation of tumor-initiating cells in tumors. Our laboratory combines genetics, pharmaco-genetics, cell and molecular biology studies with confocal imaging approaches in various transgenic and orthotopic mouse tumor models of gliomas, pancreatic islet carcinomas and mammary carcinomas to address various aspects in the neovascularization processes of tumors:

1. When do tumors utilize bone marrow cells to fuel new blood vessel growth? Recent studies have shown that neovascularization of tumors is not solely restricted to activation of differentiated endothelial cells but can also involve the recruitment of bone marrow-derived cells to active sites of vascular remodeling in tumors. These BMDCs include endothelial progenitor cells (EPC) and pericyte progenitor cells (PPC). While EPCs incorporate into the vasculature and differentiate into endothelial cells, PPCs envelop blood vessels and mature into pericytes. In addition, proangiogenic CD45+ cells of the monocytic lineage that function as vascular modulators, but are not physically part of the vasculature, present the biggest and most heterogeneous group. Recruitment of BMDC, specifically of EPC, can vary substantially between tumor types and stages but little is known about factors that dictate the mobilization of BMDC from the bone marrow into the blood stream and their recruitment and retention into the tumor. We found that hypoxia/HIF1 is a driving force in BMDC-dependent neovascularization of tumors and that BMDCs can play a critical role in this process. What is the nature of BMDC that are recruited and how do these different populations facilitate neovascularization? How significant is the contribution of BMDC in tumor vessel formation and is there a specific subpopulation from the bone marrow that is pivotal? Does hypoxia, due to vessel regression induced by antiangiogenic therapy, also enforce BMDC recruitment and thereby endorse an adaptation mechanism of tumors to overcome low oxygen tension?

2. Do vascular progenitor cells exist in tumors?
Since stem cells are present in most tissues and important for tissue repair, growth and maintenance, it is conceivable that the vasculature also harbors progenitor cells that become activated when new blood vessel formation is necessary. Vascular progenitor cells can be drafted from the bone marrow, differentiate then into endothelial cells and pericytes to form a new vasculature. We were one of the first who identified pericyte progenitors and demonstrated that these cells are capable of differentiating into mature pericytes and elicit survival factors to endothelial cells. More recently, we discovered a different, less committed vascular progenitor population in tumors that is not derived from the bone marrow but activated within the tumor when angiogenesis occurs. What is the exact nature and function of these cells? How are they recruited and activated? Which crucial signaling pathways dictate dormancy, self-renewal capacity and differentiation of these vascular progenitors? Can we target these populations in tumors to improve antiangiogenic therapy and utilize them therapeutically in ischemic conditions?

3. Does angiogenesis affect tumor invasion?
Glioblastoma multiformae (GBM) are very aggressive tumors that are fast and diffusely growing and highly angiogenic. While we found that angiogenesis via induction of VEGF, promotes tumor cell infiltration in which single cells migrate through the extracellular matrix, we demonstrated that glioblastomas deficient in angiogenic key factors including HIF-1a, VEGF or MMP-9 are unable to promote neovascularization and thereby switch to a solely perivascular invasive mode using the spaces that surround blood vessels as highways to journey deep into the brain tissue. Interestingly, VEGF itself and potentially other angiogenic factors might serve as brakes in this process. Addition of VEGF to tumor cells, or the generation of tumor cells that ectopically express high levels of VEGF, reduced the capacity of tumor cells to invade in vitro and in vivo. We therefore hypothesize that the mechanisms of tumor cell infiltration and perivascular invasion are very distinct. How does VEGF regulate tumor cell infiltration and perivascular tumor cell invasion? What are the underlying mechanisms that lead to perivascular tumor cell invasion? Does it require a similar molecular program including integrins and proteases, or do cells utilize distinct molecules to migrate along blood vessels? Can we identify key factors and target them to block this invasive pathway in the presence of antiangiogenic agents?