Tumor Microenvironment, Tumor Angiogenesis, Vascular Stem Cells
|Figure 1. A lung metastasis infiltrated by bone marrow-derived stem cells (green). Blood vessels are stained red and cell nuclei are stained blue.
Solid tumors resemble dysfunctional “organs” complete with their own vascular network that supplies blood, oxygen and nutrients. Tumor vessels also form conduits for the dissemination of tumor cells throughout the body. Thus, some cancers may be reversible or made dormant by specific elimination of the blood vessels feeding them. Generally, three “ingredients” are needed to make a tumor blood vessel: endothelial cells form lumens, mesenchymal cells form perivascular cells and hematopoietic cells guide and unite nascent vessel sprouts. Some of these vascular-forming cells are conscripted by tumors from nearby tissue and some are from bone marrow. Our lab seeks to understand how tumors make new blood vessels in order to better design and implement the anti-angiogenic therapies that can destroy them.
We currently have three projects in the lab:
1) To determine the role of bone marrow-derived cells during tumor growth and angiogenesis
Most tumors hijack a heterogeneous population of stromal cells from nearby tissue and from the circulation. Some of these stromal cells are vascular progenitors used as building blocks for tumor blood vessels. We are using transgenic mice to genetically mark mesodermal stem cells (MPC) in the bone marrow. This model will help us determine the kinetics of MPC mobilization, fate and differentiation once recruited to growing tumors.
2) Developing in vivo models of tumor vascular networks
Tumor vessels are poorly formed, leaky and dysfunctional. These abnormalities can contribute to tumor progression. For example, leaky vessels may facilitate metastasis while “activated” tumor endothelium may enable the recruitment of leukocytes that create a permissive environment for tumor growth. We are using isolated cultures of tumor endothelial cells to re-create tumor vascular networks in mice. Our goal is to identify tumor endothelial cell-derived paracrine factors that control leukocyte tropism and differentiation in tumors.
3) Understanding resistance to anti-angiogenic therapies
Anti-angiogenic therapies have not produced a sustained benefit in cancer patients. Most patients on anti-angiogenic drugs experience brief tumor stasis followed by tumor rebound. An unexpected finding is that some tumor cells may acquire properties of vascular cells (often termed “vasculogenic mimicry”). We are using mouse models to identify tumor cells with properties of vascular cells and determine their role in mediating resistance to anti-angiogenic therapies.