ABSTRACT: Tumor angiogenesis- TGF-β in angiogenesis
Tumors have unique and high metabolic demands, and they produce excessive waste and toxins that must be eliminated. Therefore, tumors need a blood supply in order to survive and grow. Angiogenesis is the orchestrated process by which new blood vessels are formed from pre-existing blood vessels. Angiogenesis is such an important process in tumor development that it is denoted a ‘Hallmark of Cancer’. Anti-angiogenic drugs have been in use against cancer for around fifteen years. I performed research for over two years in a laboratory that sought to further understand the role of angiogenesis in cancer. Our group was particularly interested in a protein called Endoglin. Endoglin is a cell surface co-receptor for ligands of the TGF-β superfamily. I was involved in multiple projects in this laboratory, and my contributions led to the authorship of three peer-reviewed research articles related to Endoglin. These works characterize the mechanisms by which Endoglin modulates TFG-β signaling in order to orchestrate the angiogenic process.
Panel 1 of the figure depicts the process by which Endoglin inhibits proliferation by sequestering β-arrestin and preventing CyclinD1 activation and cMyc expression. This process is an important regulatory step in angiogenesis because by slowing proliferation, the collagen matrix required to confer strength to the endothelial basement membrane can be produced. Panel 2 depicts a mechanism of endothelial cell survival that is mediated by Endoglin. Since angiogenesis exists as a process to deliver nutrients to areas in need, it is intuitive to think that endothelial cells must be able to survive in nutrient poor environments. Endothelial cells turn to the process of autophagy to supply the cells with the resources to grow in such environments. We showed that Endoglin is critical for initiating autophagy in endothelial cells. Panel 3 describes a mechanism by which a pharmaceutical agent acts on Endoglin. Since Endoglin is highly activated in the tumor vasculature, it is an enticing target for anti-cancer therapy. The drug, Tracon105 was developed to target Endoglin. Our group elucidated an anti-angiogenic mechanism of this action of this drug. Tracon105 couples Endoglin to Matrix Metalloprotease 14, which sheds Endoglin into the extracellular matrix. Without this necessary pro-angiogenic protein on the endothelial cell surface, angiogenesis cannot take place.