Interaction between glioma cells and intrinsic brain cells
MinChi Ku, Feng Hu, Petya Georgieva, Frank Szulzewsky, Darko Markovic, Susanne Wolf
Malignant gliomas are the most common primary brain tumors. Glioma are highly infiltrated by microglial cells and in the tumor environment, these cells aquire a pro-tumorigenic phenotype. We have previously shown (Markovic et al., 2005, 2009) that glioma cells release soluble factors which induce expression of membrane type 1 matrix metalloprotease (MT1-MMP) in tumor associated microglia and subsequently exploit MT1-MMP mediated extracellular matrix degradation for invasion into the brain parenchyma. This proves to be a major impediment to effective treatment of aggressive gliomas via surgery, chemotherapy or radiation therapy.
We studied the role of the broad spectrum antibiotic and inhibitor of microglia activation, minocycline, in hindering microglia mediated glioma growth and invasion. We could show that minocycline blocked the increase in MT1-MMP gene expression and activity in primary microglia stimulated with glioma conditioned medium. Minocycline also lead to reduction of glioma growth ex vivo within organotypic brain slices containing microglia. Moreover, we found that in vivo minocycline administration to glioma-bearing mice attenuated not only the MT1-MMP expression in glioma-associated microglia, but also resulted in diminished glioma growth as compared to untreated controls. In summary, this study indicated that the clinically approved minocycline is a promising new candidate for adjuvant therapy against malignant gliomas.
Minocycline abrogates MT1-MMP expression in glioma-associated microglia and also reduces glioma expansion in vivo.
Microglia cells labeled for Iba1 (red) aggregated less at the tumor boundary after Minocycline treatment. MT1-MMP labeling shown in brown is less intense in microglia cells associated with gliomas in Minocycline administered mice. A representative picture of the immunolabeling from the experimental and control mice is shown above. Scale bar is 500 μm.
Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1
Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Neural precursor cells with somatic mutations likely are the source for those primary high-grade brain tumors like high-grade astrocytomas. In extension to this concept, we have previously shown that physiological neural precursor cells migrate towards and mediate paracrine tumor suppressive effects against high-grade astrocytomas. Here, we studied the molecular nature of the anti-tumorigenic factors that are released from neural precursor cells. We found that neural precursor cells release endovanilloids which can stimulate the vanilloid receptor (TRPV1) on cultured human and mouse high-grade astrocytoma cells and thereby mediate specific tumor-suppressive effects. Cultured glioblastoma cells express functional vanilloid receptors and their activation by endogenous and synthetic TRPV1 agonists triggers calcium transients. The application of vanilloids results in cell death mediated by TRPV1 via the activating transcription factor-3 (ATF3)-controlled branch of the endoplasmic reticulum stress pathway. However, the anti-tumorigenic response of neural precursor cells is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil. The administration of arvanil to ex vivo organotypic brain slices inoculated with high-grade astrocytoma cells decreased tumor expansion. Furthermore, application of arvanil mediated a significant improvement of survival in an in vivo glioma mouse model. Overall, our data imply that NPCs utilize vanilloids as endogenous paracrine tumor suppressors which could be clinically exploited as a new strategy for brain tumor therapy.
Stock K, Kumar J, Synowitz M, Petrosino S, Imperatore R, Smith ES, Wend P, Purfürst B, Nuber UA, Gurok U, Matyash V, Wälzlein JH, Chirasani SR, Dittmar G, Cravatt BF, Momma S, Lewin GR, Ligresti A, De Petrocellis L, Cristino L, Di Marzo V, Kettenmann H, Glass R. Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1.
Nat Med. 2012 Jul 22. doi: 10.1038/nm.2827.