The goal of this proposal is to develop a prospective brain tumor model originating in PDGF over-expressing hES cells, and to utilize this model for physiological investigations of tumors and their interactions with non-tumor neighbors. We will study this model using the same techniques used on neural stem and progenitor cells. Gliomas often present clinically as seizure, and epileptic foci are found adjacent to experimental gliomas. Tumor cells, even if non-excitable, may interact reciprocally with electrically active neighbors. These questions are almost completely unexplored. Because we are exploring a novel concept, federal funding seems unlikely at this stage.
This project is composed of three parts:
Part I. Construct hES cell lines over expressing platelet-derived growth factor (PDGF) under control of the nestin promoter, and matched control lines. Over expression of platelet-derived growth factor (PDGF) can initiate brain tumor formation, and CNS gliomas often express PDGF.
Part II. Transplant PDGF-over expressing hES cells into developing mouse brain, and follow emergence tumors. Other groups have reported that undifferentiated hES cells, transplanted into the ventricles of embryonic mice, will migrate from the ventricles into the brain parenchyma, differentiate, and integrate into the host environment. No evidence of teratoma or immune rejection was seen. In this model only a small number of cells relative to the total population of the brain will be of human origin.
Part III. Study physiological reactions to the tumor and mechanisms by which host brain cells may be recruited by PDGF-overexpressing hES cells. Our hypothesis is that the tumor and surrounding cells are recapitulating in part the interactions between neuroprogenitor cells and their more differentiated surround. We will determine the extent to which the physiological characteristics and cell-cell signaling mechanisms of PDGF-secreting hES cells, neighboring naïve hES cells, and adjacent mouse neurons and non-neuronal cells reflect those seen during migration and differentiation of neural progenitors. Our ultimate goal is to look at recruitment and possible transformation of cell neighbors into the tumor, and ask if disruption of synchronous activity and/or blockade of transmitter systems disrupt tumor or surrounding cell migration, proliferation or recruitment.
Glioma is among the most intractable cancers, in part because invasion of the normal brain by tumor cells makes surgery only palliative. Tumor progenitor cell birth and migration is similar to normal brain development. We propose to create and study a model in which a small number in human ES cell-derived neuroprogenitor cells resident in mouse brain will express genes that will induce them to become tumors. We will then investigate them as we do normally developing cells, essentially considering the tumor as a developing tissue. Our hope is that this novel approach will yield unique insights leading to potential therapies. Any progress towards reducing the virulence of glioma will be of immense benefit to the State of California and its citizens.