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Ionizing radiation in glioblastoma initiating cells.

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.

SUBMITTER: Rivera M

PROVIDER: S-EPMC3619126 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Ionizing radiation in glioblastoma initiating cells.

Rivera Maricruz M Sukhdeo Kumar K Yu Jennifer J

Frontiers in oncology 20130408

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 mechanism ...[more]

PMID: 23579692

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Project description:Despite optimal clinical treatment, glioblastoma multiforme (GBM) inevitably recurs. Standard treatment of GBM, exposes patients to radiation which kills tumor cells, but also modulates the molecular fingerprint of any surviving tumor cells and the cross-talk between those cells and the host. Considerable investigation of short-term (hours to days) post-irradiation tumor cell response has been undertaken, yet long-term responses (weeks to months) which are potentially even more informative of recurrence, have been largely overlooked. To better understand the potential of these processes to reshape tumor regrowth, molecular studies in conjunction with in silico modeling were used to examine short- and long-term growth dynamics. Despite survival of 2.55% and 0.009% following 8 or 16Gy, GBM cell populations in vitro showed a robust escape from cellular extinction and a return to pre-irradiated growth rates with no changes in long-term population doublings. In contrast, these same irradiated GBM cell populations injected in vivo elicited tumors which displayed significantly suppressed growth rates compared to their pre-irradiated counterparts. Transcriptome analysis days to weeks after irradiation revealed, 281 differentially expressed genes with a robust increase for cytokines, histones and C-C or C-X-C motif chemokines in irradiated cells. Strikingly, this same inflammatory signature in vivo for IL1A, CXCL1, IL6 and IL8 was increased in xenografts months after irradiation. Computational modeling of tumor cell dynamics indicated a host-mediated negative pressure on the surviving cells was a source of inhibition consistent with the findings resulting in suppressed tumor growth. Thus, tumor cells surviving irradiation may shift the landscape of population doubling through inflammatory mediators interacting with the host in a way that impacts tumor recurrence and affects the efficacy of subsequent therapies. Clues to more effective therapies may lie in the development and use of pre-clinical models of post-treatment response to target the source of inflammatory mediators that significantly alter cellular dynamics and molecular pathways in the early stages of tumor recurrence.

Dataset Information

Ionizing radiation in glioblastoma initiating cells.

Publications

Ionizing radiation in glioblastoma initiating cells.

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