Tumors employ a variety of stratagems to evade cancer treatments. Glioblastomas—a particularly aggressive form of brain cancer—are no exception. Giorgio Seano and colleagues have recently identified one of these resistance mechanisms, paving the way for new therapeutic approaches.
Glioblastomas are the most common form of brain cancer. Aggressive and highly resistant to radiotherapy and chemotherapy, they remain poorly understood. This resistance to chemotherapy is primarily due to the difficulty in crossing the blood-brain barrier, an impermeable layer that protects the brain from external attacks. Glioblastomas are highly vascularized and one of the main ways in which they spread is through the development of new blood vessel networks. This phenomenon, known as “angiogenesis”, involves the growth factor VEGF. Anti-VEGF treatments have been developed, but some gliomas become resistant to these agents. Understanding the underlying mechanisms of this resistance is one of the major challenges in the fight against brain cancer.
This form of brain cancer is particularly heterogeneous. Giorgio Seano, currently Team Leader of the Tumor Microenvironment Laboratory (CNRS/INSERM/Institut Curie), studied this aspect during his post-doctorate at Harvard Medical School, in collaboration with the University of California. His work focused in particular on the marker OLIG2, which is known to be a key regulator of the fate of glial cells during both their development and tumorigenesis. Using laboratory tumor models, he and his colleague, Amelie Griveau, noticed that OLIG2+ and OLIG2- gliomas (those carrying or not the OLIG2 gene, respectively), used different strategies to reach the vasculature. While OLIG2- cells promoted angiogenesis, OLIG2+ cells could use vascular co-option, a mechanism that enables tumor cells to migrate along pre-existing blood vessels.
In addition to this discovery, the team identified that the Wnt signaling pathway and, more specifically, one of its molecules, Wnt7, are involved in the phenomenon of vascular co-option by OLIG2+ cells. Interestingly, during anti-VEGF treatment, Wnt expression and co-option increase. In other words, during treatment designed to prevent angiogenesis, the tumor changes strategy: since it can no longer invade the brain via the creation of new blood vessels, it uses existing ones instead. Developing drugs that block Wnt signaling could therefore be a new therapeutic option. This might involve treatment with LGK974, which inhibits Wnts secretion.
The researchers also found that with OLIG2+ tumor cells, i.e. those that use the co-option mechanism, the blood-brain barrier remained impermeable, while with OLIG2- tumor cells, it became permeable. Preventing Wnt7 signaling and therefore co-option could thus enable chemotherapy agents to better penetrate the brain.
Additional research is now needed to understand the potential benefits of anti-Wnt signaling approaches in the fight against glioblastomas.
A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment
David H. Rowitch & al., Cancer Cell (May 14, 2018)