Functional role of tumor-associated glial cells (TAGs) in brain cancer progression

Flere studier har vist at vertsceller endres eller omprogrammers når de kommer i kontakt med kreftceller i en svulst. Disse endringene vil kunne påvirke og ofte fremme vekst av kreftceller. Vi har isolert vertsceller fra hjernesvulster, såkalte gliale celler og analysert forandringer i disse. De resultatene viser at gliale celler fra hjernesvulster uttrykker POU3F2 og SOX2, proteiner en vanligvis finner i umodne celler. I tillegg ser vi at gliale celler fra kreftceller prolifererer, i motsetning til gliale celler fra normal hjerne. De skiller også ut vekstfaktorer som kan virke tilbake på kreftcellene og fremme veksten av disse. Ved å overuttrykke POU3F2 eksperimentelt ser vi at også dette fremmer veksten i humane astrocytter. I humane biopsier ser vi også at uttrykket av POU3F2 korrelerer med aggressivitet. I modellsystemer har vi anvendt humane astrocytter med overuttrykk av POU3f2 og vist at disse kan promotere både migrasjon og proliferasjon av gliomceller. Vi er nå i gang med å fremavle en musestamme med kondisjonell knockout av SOX 2 for å se hvordan SOX2 knockout påvirker vekst av gliomer in vivo. Vi håper også å få satt i gang avl av mus med POU3F2 knockout.

Malignant gliomas are lethal cancers which infiltrate the surrounding brain extensively, making radical surgery impossible. Adjuvant treatments also have a limited effect, and new therapies are urgently needed. A major advance came with the recognition th at cancer-associated fibroblasts actively foster the growth of malignant cells in several tumor types. Glial cells in the central nervous system may have similar functions in brain tumors, and tumor-associated glial cells (TAGs) are phenotypically altered , frequently adopting a reactive phenotype. We therefore hypothesize that TAGs are major regulators of brain tumor progression, and will combine in vitro functional studies with animal experiments to characterize the TAG cell compartment. This will then g uide the selection of stromal targets for therapeutic validation. We have established fluorescence activated cell sorting protocols for isolating stromal cells from xenograft gliomas established in GFP-scid mice. These cells express predominantly immature and glial cell markers (TAGs), and proliferate in vitro. Co-implantation of TAGs with glioma cells in mice accentuates growth significantly, compared to implanting glioma cells only or together with normal glial cells. Microarray analysis has revealed ge ne clusters differentially expressed between TAGs and normal glial cells. Collectively, our data suggest that TAGs are reprogrammed to a mesenchymal, proliferative state that promotes angiogenesis and invasion through the release of angiogenic and proinva sive factors. Future experiments include functional studies to identify candidate signaling pathways mediating the TAG phenotype, and subsequent selection of TAG specific targets for therapeutic validation. Thus, the work outlined in this project presents an integrated approach for a detailed molecular characterization of TAGs, functional studies into the mechanisms that mediate their tumor-promoting effects, and validation of TAG markers as therapeutic targets