GLIOBLASTOM - Anni Hofmann Stiftung

Title: Glioma‐associated mesenchymal stem cells indicate new avenues for brain tumor therapy

Information on the applicants: Prof. Dr. Rainer Glass, PI Neurosurgical Research, University Clinics Munich

State of the art. A significant barrier for therapeutic treatment of malignant brain tumours (gliomas) is built-up by the tumour-host interface1, which supports invasion, angiogenesis and resistance to anti-angiogenesis. In order to effectively treat this disease, we need to fully understand the basic biology behind its development and progression, including the effects of various cells in the tumor microenvironment. Previously, we showed that different glioma-associated parenchymal cells have very profound effects on glioma progression2, 3. For example, gliomas manipulate the immune-phenotype of brain specific macrophages (termed microglial cells) to propel tumor cell invasion4-8. Furthermore, we have shown that some cells of the tumor microenvironment can have efficient anti-tumorigenic effects, which can be exploited for clinical use3, 9. Altogether, our data showed that brain tumor parenchymal cells can indicate new tumor therapies or can be a new target for adjuvans therapies against gliomas.

Recent data from a range of research groups, including our laboratory, indicate that mesenchymal stem cells (MSCs) are also a pathologically important component of the glioma microenvironment. The molecular pathways used by MSCs to modulate glioma progression are not known, but profound pro- and anti-tumorigenic effects mediated by MSCs were observed10, 11, which include inhibition of tumor cell migration12 or induction of glioma cell-death13, 14.  The anti-tumorigenic factors released from MSCs are highly interesting as they hold the key for new glioma therapies: the MSC-derived molecules (or pharmacological compounds mimicking the anti-tumor action of MSC-derived factors) can be used to induce glioma cell-death.

Our pilot studies
show that MSCs, (A) can exert anti-tumor effects against primary human glioma cells and against human glioma cell lines in vitro. (B) Interestingly, a shift in the culture conditions converted the tumor-suppressive functions into pro-tumorigenic actions.

Current research: Now we will use our newly discovered cell culture model to uncover (A) those anti-tumor factors that are released from MSCs. Importantly, we have determined that the MSC-mediated tumor suppression is molecularly distinct from the NPC-mediated cell-death induction in gliomas. Hence, we can discover a new tumor-suppressive factor, which is released from endogenous cells in humans and which should therefore be tolerated by glioma patients after exogenous application. (B) We aim to uncover new targets for stroma-directed adjuvans therapies in gliomas. We will explore the molecular factors that are responsible for the tumor supporting role of MSCs in an environment that may otherwise be unfavorable for glioma cells. These MSC-specific factors may have prognostic power and can also constitute a target for adjuvans treatments, which are suited to reduce invasion or therapeutic resistance in gliomas.

Work packages: We will perform (1.) genetic and (2.) proteomic assays to explore the MSC-derived molecular factors that are responsible for mediating the pro- and anti-tumor effects on glioma cells. (3.) We will use molecular modeling, genetic and pharmacological approaches to validate candidate MSC-derived factors that can suppress or support gliomas. (4.) We will determine the power of the newly discovered MSC-specific molecules as prognostic markers for glioma patients.

In scientific cooperations we will explore MSCs as a target for adjuvans therapies in more detail: MSCs have pro-tumorigenic effects under stressful environmental conditions and may then support the metabolism of gliomas (investigated together with Katrin Lamszus, UKE, Hamburg). Together with Christel Herold-Mende we will investigate the immune-modulatory effects of MSCs (which have been described for tumor-free conditions) in the context of gliomas.

The full description you will find here.

References

1.    Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H: The brain tumor microenvironment, Glia 2011, 59:1169-1180
2.    Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H: The brain tumor microenvironment, Glia 2011,
3.    Chirasani SR, Sternjak A, Wend P, Momma S, Campos B, Herrmann IM, Graf D, Mitsiadis T, Herold-Mende C, Besser D, Synowitz M, Kettenmann H, Glass R: Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells, Brain : a journal of neurology 2010, 133:1961-1972
4.    Markovic DS, Glass R, Synowitz M, Rooijen N, Kettenmann H: Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2, J Neuropathol Exp Neurol 2005, 64:754-762
5.    Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kalin R, van Rooijen N, Holmbeck K, Heppner FL, Kiwit J, Matyash V, Lehnardt S, Kaminska B, Glass R, Kettenmann H: Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion, Proceedings of the National Academy of Sciences of the United States of America 2009, 106:12530-12535
6.    Markovic DS, Vinnakota K, van Rooijen N, Kiwit J, Synowitz M, Glass R, Kettenmann H: Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression, Brain Behav Immun 2011, 25:624-628
7.    Sliwa M, Markovic D, Gabrusiewicz K, Synowitz M, Glass R, Zawadzka M, Wesolowska A, Kettenmann H, Kaminska B: The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A, Brain : a journal of neurology 2007, 130:476-489
8.    Synowitz M, Glass R, Farber K, Markovic D, Kronenberg G, Herrmann K, Schnermann J, Nolte C, van Rooijen N, Kiwit J, Kettenmann H: A1 adenosine receptors in microglia control glioblastoma-host interaction, Cancer research 2006, 66:8550-8557
9.    Stock K, Kumar J, Synowitz M, Petrosino S, Imperatore R, Smith ESJ, 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 via stimulation of TRPV1, Nature Medicine 2012, 18:1232-1238
10.    Ho IA, Toh HC, Ng WH, Teo YL, Guo CM, Hui KM, Lam PY: Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis, Stem Cells 2013, 31:146-155
11.    Kong BH, Shin HD, Kim SH, Mok HS, Shim JK, Lee JH, Shin HJ, Huh YM, Kim EH, Park EK, Chang JH, Kim DS, Hong YK, Lee SJ, Kang SG: Increased in vivo angiogenic effect of glioma stromal mesenchymal stem-like cells on glioma cancer stem cells from patients with glioblastoma, International journal of oncology 2013, 42:1754-1762
12.    Dasari VR, Kaur K, Velpula KK, Gujrati M, Fassett D, Klopfenstein JD, Dinh DH, Rao JS: Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway, PloS one 2010, 5:e10350
13.    Jiao H, Guan F, Yang B, Li J, Song L, Hu X, Du Y: Human amniotic membrane derived-mesenchymal stem cells induce C6 glioma apoptosis in vivo through the Bcl-2/caspase pathways, Molecular biology reports 2012, 39:467-473
14.    Kang SG, Jeun SS, Lim JY, Kim SM, Yang YS, Oh WI, Huh PW, Park CK: Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells, Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2008, 24:293-302