Resistance of Glioblastoma-Initiating Cells to Radiation Mediated by the Tumor Microenvironment Can Be Abolished by Inhibiting Transforming Growth Factor-beta
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 indicate that although GIC are sensitive, the response is mediated by undefined factors in the microenvironment. GBM produce abundant transforming growth factor-β (TGF-β), 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 by approximately 25% when treated with LY364947, a small-molecule inhibitor of TGF-β type I receptor kinase, before irradiation. Mice bearing GL261 flank tumors treated with 1D11, a pan-isoform TGF-β neutralizing antibody, exhibited significantly increased tumor growth delay following IR. GL261 neurosphere cultures were used to evaluate GIC. LY364947 had no effect on the primary or secondary neurosphere-forming capacity. IR decreased primary neurosphere formation by 28%, but did not reduce secondary neurosphere formation. In contrast, LY364947 treatment before IR decreased primary neurosphere formation by 75% and secondary neurosphere formation by 68%. Notably, GL261 neurospheres produced 3.7-fold more TGF-β per cell compared with conventional culture, suggesting that TGF-β production by GIC promotes effective DNA damage response and self-renewal, which 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 TGF-β inhibitors with radiation to improve therapeutic response in patients with GBM.
- SourceAvailable from: Yonghyun Kim
[Show abstract] [Hide abstract]
- "Galli et al. similarly demonstrated that glioblastoma cell lines possess molecular, cytologic, and histologic characteristics similar to neural stem cells (NSCs) . Like other CSCs, GSCs are especially endowed with the ability to resist radiation therapy    . For example, GSCs were shown to possess higher capacity to activate DNA damage checkpoint proteins and thereby are more radiation resistant than non-GSCs . "
ABSTRACT: Glioblastoma multiforme (GBM) is the most malignant form of central nervous system tumor, and current therapies are largely ineffective at treating the cancer. Developing a more complete understanding of the mechanisms controlling the tumor is important in order to explore new possible treatment options. It is speculated that the presence of glioblastoma stem or stem-like cells (GSCs), a rare type of pluripotent cancer cell that possesses the ability to self-renew and generate tumors, could be an important factor contributing to the resistance to treatment and deadliness of the cancer. A comprehensive knowledge of the mechanisms controlling the expression and properties of GSCs is currently lacking, and one promising area for further exploration is in the influence of basic fibroblast growth factor (FGF-2) on GSCs. Recent studies reveal that FGF-2 plays a significant part in regulating GBM, and the growth factor is commonly included as a supplement in media used to culture GSCs in vitro. However, the particular role that FGF-2 plays in GSCs has not been as extensively explored. Therefore, understanding how FGF-2 is involved in GSCs and in GBMs could be an important step towards a more complete comprehension of the managing the disease. In this review, we look at the structure, signaling pathways, and specific role of FGF-2 in GBM and GSCs. In addition, we explore the use of FGF-2 in cell culture and using its synthetic analogs as a potential alternative to the growth factor in culture medium.Cancer letters 12/2013; 346(1). DOI:10.1016/j.canlet.2013.12.003 · 5.62 Impact Factor
[Show abstract] [Hide abstract]
- "IR induction of NOTCH activation results in an expansion of GICs (Wang et al., 2010). Combining TGF-β inhibition and IR failed to induce the DDR and NOTCH activation, underlining the interplay between the DDR and NOTCH signaling pathways (Hardee et al., 2012). In vitro studies of glioma cells with γ-secretase inhibitors (GSIs) decreased cell proliferation, viability , and percentage of CD133-positive cells, while inducing cell death exclusively in GICs (Fan et al., 2010; Hovinga et al., 2010). "
ABSTRACT: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12-15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem cell-like properties termed GBM initiating cells (GICs). Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of GBM. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies.Frontiers in Oncology 04/2013; 3:74. DOI:10.3389/fonc.2013.00074
[Show abstract] [Hide abstract]
- "Recent studies demonstrate that TGFí µí»½ inhibitors are able to block the toxicity associated with radiation-mediated fibrosis , increase the therapeutic efficacy of radiation therapy in murine models  , and synergize with immunotherapy . These data suggest that the key regulators of inflammatory resolution are potential targets to increase the efficacy of radiation therapy. "
ABSTRACT: Radiation therapy is showing potential as a partner for immunotherapies in preclinical cancer models and early clinical studies. As has been discussed elsewhere, radiation provides debulking, antigen and adjuvant release, and inflammatory targeting of effector cells to the treatment site, thereby assisting multiple critical checkpoints in antitumor adaptive immunity. Adaptive immunity is terminated by inflammatory resolution, an active process which ensures that inflammatory damage is repaired and tissue function is restored. We discuss how radiation therapy similarly triggers inflammation followed by repair, the consequences to adaptive immune responses in the treatment site, and how the myeloid response to radiation may impact immunotherapies designed to improve control of residual cancer cells.Clinical and Developmental Immunology 04/2013; 2013:281958. DOI:10.1155/2013/281958 · 2.93 Impact Factor