Details of Blood Vessel Formation in Breast Tumors Uncovered
In a new study published in Nature Communications, researchers identify a critical factor that activates growth of these vessels in breast cancers that have metastasized.
Tumor growth requires angiogenesis, the formation of blood vessels that provide oxygen and nutrients to tumor cells. Blood vessel growth adjacent to tumors is thought to occur through the elongation of pre-existing vessels that secrete the vascular endothelial growth factor (VEGF). Now, in a new study published in Nature Communications, researchers identify a critical factor that activates growth of these vessels in breast cancers that have metastasized.1
The DOCK4 protein, discovered by Georgia Mavria, PhD, a senior research fellow at the University of Leeds in the United Kingdom and colleagues, is critical for forming the inside of blood vessels, called the lumen, in tumors and is necessary for the migration of the vessels to tumors. Inhibiting DOCK4 (dedicator of cytokinesis 4) in mouse models of breast cancer resulted in a lack of blood vessel lumen formation and slowed the rate of tumor growth.2
When DOCK4 is missing, tumors cannot grow as efficiently due to a lack of a blood supply, the study showed.
This is the first time that DOCK4 has been implicated in angiogenesis, Dr. Mavria told OncoTherapy Network. “This is a relatively new signaling pathway and totally unappreciated in the context of angiogenesis. The work could lead to new approaches to prevent blood supply to tumors and metastases. Moreover, prognostic or predictive potential would have the potential to inform diagnosis and clinical decisions.”
The researchers also found that mouse models missing the DOCK4 protein also prevented blood vessel lumen formation in colorectal tumors. “The mechanism is likely to be important for other tumor types,” said Dr. Mavria.
Dr. Mavria and colleagues, including those from the Lunenfeld-Tanenbaum Research Institute in Toronto, searched for specific enzymes that could be involved in the angiogenesis process. This search uncovered the DOCK4 gene as a key factor in angiogenesis and formation of the projections at the leading edge of vessels during their migration and organization of the inside of blood vessels. The researchers also uncovered a pathway that starts with VEGF signaling and leads to the activation of DOCK4 necessary for vessel migration to tumors.
“Our study reveals new insights into how the complex process of forming blood vessels is controlled. This knowledge could lead to new approaches to preventing the blood supply to tumors and metastases. If we can find new ways to reduce the blood supply to tumors, we might be able to find new ways to slow cancer growth in future,” said study author Chris Marshall, Professor of Cell Biology at The Institute of Cancer Research, London in a statement.
Future studies, noted Dr. Mavria, will focus on a more detailed understanding of the role of DOCK4 in spontaneous human cancer models including how blood vessels will develop in the absence of DOCK4. “We are also investigating the prognostic and predictive potential of DOCK4 in breast cancer and various treatment settings,” added Mavria.
References:
- Abraham S, Scarcia M, Bagshaw RD, et al. (2015). A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis. Nature Communications, Jul 1;6:7286.
- University of Leeds. (2015). How removing a protein slows blood vessel growth in tumours
