Malignant brain cancer is a devastating disease and it’s estimated that more than 16,000 patients will die of it this year. One of the most aggressive forms of brain cancer is gliomas, which originate from the support cells in the brain or spine that keep nerve cells happy and functioning. Unfortunately, there is no cure for gliomas and common treatments involving surgery, radiation and chemotherapy are not effective in fully eradicating these tumors.
In hopes of finding a cure, scientists have turned to animal models and human cell models derived from tumor biopsies or fetal tissue, to gain understanding of how gliomas form and what makes these type of tumors so deadly and resistant to normal cancer treatments. These models have their limitations, and scientists continue to develop more relevant models in hopes of identifying new potential treatments for brain cancer.
Speaking of which, a CIRM-funded research team from the Salk Institute recently reported a new human stem cell-based model for studying gliomas in Nature Communications. The team figured out how to transform human induced pluripotent stem cells (iPS cells) into glioma tumor-initiating cells (GTICs) that they used to model how gliomas develop and to screen for drugs that specifically target this deadly form of cancer.
Making the Model
One theory for how gliomas form is that neural progenitor cells (brain stem cells) can transform and take on new properties that turn them into glioma tumor-initiating cells or GTICs, which are a subpopulation of cancer stem cells that are really good at staying alive and reproducing themselves into nasty tumors.
The Salk team created a stem cell model for glioma by generating GTICs in a dish from human iPS cells. They genetically manipulated brain progenitor cells (which they called induced neural progenitor cells or iNPCs) derived from human iPS cells to look and behave like GTICs. Building off of previous studies reporting that a majority of human gliomas have genetic mutations in the p53 and Src-family kinase (SFK) genes, they developed different iNPC lines that either turned off expression of p53, a potent tumor suppressor, or that ramped up expression of SFKs, whose abnormal expression are associated with tumor expansion.
The team then compared the transformed iNPC lines to primary GTICs isolated from human glioma tissue. They found that the transformed iNPCs shared many similar characteristics to primary GTICs including the surface markers they expressed, the genes they expressed, and their metabolic profiles.
Their final test of their stem cell model determined whether transformed iNPCs could make gliomas in an animal model. They transplanted normal and transformed iNPC lines into the brains of mice and saw aggressive tumors develop only in mice that received transformed cells. When they dissected the gliomas, they found a mixture of GTICs, more mature brain cells produced from GTICs, and areas of dead cells. This cellular makeup was very similar to that of advanced grade IV primary glioblastomas.
Screening for drugs that target glioma initiating cells
Now comes the applied part of this study. After developing a new and relevant stem cell model for glioma, the team screened their transformed iNPC lines with a panel of 101 FDA-approved anti-cancer drugs to see if any of them were effective at stopping the growth and expansion of GTICs. They identified three compounds that were able to target and kill both transformed iNPCs and primary GTICs in a dish. They also tested these compounds on living brain slices that were injected with GTICs to form tumors and saw that the drugs worked well at reducing tumor size.
The authors concluded that their transformed iNPCs are appropriate for modeling certain features of how GTICs develop into adult gliomas. Their hope is that this model will be useful for developing new targeted therapies for aggressive forms of brain cancer.
“Our results highlight the potential of hiPSCs for studying human tumourigenesis. Similar to conventional disease modeling strategies based on the use of hiPSCs, the establishment of hiPSC cancer models might facilitate the future development of novel therapeutics.”