Cancer is a highly complex disease, characterized by impairments in various biological pathways. Each of these pathways constitutes a potential therapeutic target in which manipulation of the pathway may halt disease progression. One key player in the development and metastasis of cancer is the blood vessel, which scientists believe feeds cancer cells with necessary nutrients as well as providing them with a way to spread throughout the body. Published in Developmental Cell, a new study by Hopkins researchers elucidates the molecular pathways by which brain blood vessel growth is regulated, setting the stage for development of more effective anti-cancer treatments.
The first step in the progression of cancer is the disruption of cellular machinery that modulates proliferation and survival. Normally, these pathways prevent cells from growing out of control, shutting down cells when they are dysfunctional and old. When these intracellular pathways are disturbed, cells multiply uncontrollably, leading to the formation of a tumor. Interestingly, abnormal growth of blood vessels have been found near tumor cells, suggesting that angiogenesis (blood vessel growth) plays a role in cancer by sustaining cancer cells with nutrients necessary for prolonged survival. Moreover, since the circulatory system is spread throughout the entire body, cancer cells are able to attack other regions of the body by first invading blood vessels.
Given the contribution of blood vessels to cancer growth, targeting tumor-related blood vessels emerges as an attractive therapeutic strategy. In order to exploit this strategy, however, we must learn about the molecules and signaling pathways that control angiogenesis. One potential candidate protein is tumor endothelial marker 5 (TEM5), which is overexpressed by blood vessels that grow toward tumor cells. However, the molecular mechanism by which TEM5 governs angiogenesis under normal conditions has not been explored.
Dr. Jeremy Nathans, a professor of molecular biology and genetics, neuroscience and ophthalmology at the Hopkins School of Medicine, and his graduate student, Yulian Zhou, investigated how TEM5 regulates angiogenesis by using cell cultures and mice genetically engineered to lack or overexpress certain genes. First, they found that TEM5 is activated by Wnt7a and Wnt7b, which are well-characterized signaling molecules that are known to be involved in early cerebral blood vessel development. More importantly, mutations in Wnt signaling genes have been found in human cancers, implying their importance in tumor pathogenesis.
In subsequent sets of experiments, Nathans and Zhou further explored the relationship between TEM5 and the Wnt signaling proteins. Previous studies showed that knocking out (or removing) TEM5 in mice causes defects in brain blood vessel growth during early development. When Nathans and Zhou activated Wnt signaling pathways in mice that lack TEM5, these impairments in angiogenesis were rescued, allowing the blood vessels to grow normally. This finding suggests that TEM5 controls angiogenesis through Wnt signaling pathways, suggesting the powerful therapeutic potential of targeting TEM5 and its associated molecular network to halt cancer progression.
Beyond cancer, these findings also have implications for other brain disorders. For instance, cerebral blood vessels play a critical role as the “garbage truck” of the brain, expelling waste from neurons to the outside of the central nervous system. Consequently, failure to move neuronal waste away from the brain has been hypothesized to cause buildup of protein plaques thought to be responsible for Alzheimer’s disease. Therefore, manipulation of angiogenesis through TEM5 may facilitate better removal of harmful protein plaques, which may slow down the development of neurodegenerative diseases.
