Sponsored by
Cancer Res. 2012 Jun 12. [Epub ahead of print]
Resistance of glioblastoma initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β (TGFβ).
Hardee ME, Marciscano AE, Medina-Ramirez CM, Zagzag D, Narayana A, Lonning S, Barcellos-Hoff MH.
Source
Radiation Oncology, New York University School of Medicine.
Abstract
The poor prognosis of glioblastoma (GBM) routinely treated with ionizing radiation (IR) has been attributed to the relative radioresistance of glioma initiating cells (GIC). Other studies suggest that GIC are sensitive but the response is mediated by undefined factors in the microenvironment. GBM produce abundant transforming growth factor-β (TGFβ), a pleotropic cytokine that promotes effective DNA damage response. Consistent with this, radiation sensitivity, as measured by clonogenic assay, of cultured murine (GL261) and human (U251, U87MG) glioma cell lines, increased approximately 25% when treated with LY364947, a small molecule inhibitor of TGFβ type I receptor kinase, prior to irradiation. Mice bearing GL261 flank tumors treated with 1D11, a pan-isoform TGFβ neutralizing antibody, exhibited significantly increased tumor growth delay following IR. GL261 neurosphere cultures were used to evaluate GIC. LY364947 had no effect on primary or secondary neurosphere-forming capacity. IR decreased primary neurosphere formation by 28%, but did not reduce secondary neurosphere formation. In contrast, LY364947 prior to IR decreased primary neurosphere formation by 75% and secondary neurosphere formation by 68%. Notably, GL261 neurospheres produced 3.7-fold more TGFβ per cell compared to traditional culture, suggesting that TGFβ production by GIC promotes the DNA damage response and self-renewal and creates microenvironment mediated resistance. Consistent with this, LY364947 treatment in irradiated GL261 neurosphere-derived cells decreased DNA damage responses, H2AX and p53 phosphorylation, and induction of self-renewal signals, Notch1 and CXCR4. These data motivate the use of TGFβ inhibitors with radiation to improve therapeutic response in GBM patients.
PMID: 22693253 [PubMed - as supplied by publisher]
2. Magn Reson Med. 2012 Jun 12. doi: 10.1002/mrm.24368. [Epub ahead of print]