Pluripotent state and its relationship to cancer stem cells in human gliomas
Glioblastomas are the most common and lethal form of intracranial tumors. They account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The median age of patients at the time of diagnosis is 64 years. Despite optimal treatment, and improving standard of care the median survival is only 12 to 15 months for patients with glioblastomas.
Glioblastoma multiforme (GBM), the most malignant of all brain tumors resuls from the sequential accumulation of genetic aberrations. To understand the role of some or all of the altered genes found in the human gliomas, we have recently used a novel method of using viral vectors to introduce the mutated genes directly into the specific part or cells in the brain. Remarkably we are able to completely recapture the disease of GBM, found in humans. Thus we have an excellent model system to understand and mechanistically decipher the formation of cancer stem cells. In our mouse model systems and xenotransplantation with human GBM cells, as few as 10 cells can lead to the formation of gliomas. Thus on principle every GBM cell is potentially a cancer initiating stem cell. To understand the role of cancer stem cells in glioblastomas, in the next three years we would like to first recapitulate the genetic traits of human GBM in mouse models. We would then like to pursue the time course in which brain tumors develop to get an idea of how soon the tumors grow and more importantly if the different regions of the brain form the same or different tumors. Another important property of the GBMs is that they have very extensive blood supply; therefore it is a good candidate for treatment with drugs that inhibit blood vessel formation. Interestingly, the tumor cells have learned to transdifferentiate into cells that line the walls of blood vessels, thereby rendering the drugs effecting formation of blood vessels ineffective. Finally, since as few as 10-100 GBM tumor cells are capable of initiating new tumors, they offer an excellent opportunity to study the pluripotency of GBMs and their relationship to cancer stem cells
We believe that the proposed experiments provide an excellent opportunity to help us understand the molecular mechanisms of formation of GBM and its relationship to formation of pluripotent cancer stem cells.
There is a growing body of scientific literature which suggests that many cancers have stem cells which, like pluripotent stem cells, have the ability to replicate and differentiate into specific cancer phenotypes. The clinical implications are that unless such cancer stem cells are not eliminated, tumors will grow back again leading to a relapse. The actual percentage of the stem cells in different types of tumors varies quite a bit. Our results, albeit preliminary, indicate that in glioblastoma multiforme (GBM)—one of the most devastating brain tumors with a life expectancy of just over 12-15 months—every tumor cell has the potential to induce gliomas. Moreover these gliomas undergo transdifferentiation to endothelial cells, lining the blood vessels, thus frustrating the use of anti-angiogenic drugs. The work proposed here in our CIRM Basic Biology Awards II application has the potential to not only identify the mechanism of gliomogenesis, but offers an excellent opportunity to generate therapeutic entities.
The State of California has excellent academic and biotechnology institutions that will be very glad to further develop some of the genes that we identify in our pursuit to understand the mechanism of GBM formation. Cancer is a very big health burden on the state budget and takes a major toll on the families of cancer patients, especially something as malignant as GBM. Ever more, we need to spend state resources wisely, and finding ways to reduce the continually increasing cost of long-term medical care is critical. The work proposed here seeks to do just that by creating outright cures for diseases that if left untreated require substantial and prolonged medical expenditures and incredible suffering for the patients and their families. In other regards keeping the State of California at the forefront of medical breakthroughs and strengthening our biomedical and biotechnology industries. We are a leading force in these fields, not only across the nation but also worldwide.