Abstract
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.
Highlights
The standard of care for newly diagnosed glioblastoma multiforme (GBM) is a multi-modality strategy beginning with maximal surgical resection followed by fractionated radiotherapy, (60Gy, 30–33 fractions of 1.8–2.0Gy) with temozolomide given during and after the irradiation [1]
Following high-dose radiation exposure, long-term GBM cell population growth dynamics show an escape from extinction and restoration of the dynamics existing in the pre-irradiated state
Recurrent GBM after irradiation maintaining reproductive integrity were measured as cells undergoing two or more cellular divisions decreasing the PKH-26 fluorescent intensity (FL2-low)
Summary
The standard of care for newly diagnosed glioblastoma multiforme (GBM) is a multi-modality strategy beginning with maximal surgical resection followed by fractionated radiotherapy, (60Gy, 30–33 fractions of 1.8–2.0Gy) with temozolomide given during and after the irradiation [1]. In clinical trials, this strategy increased the median survival of GBM patients from 12.1 to 14.6 months, as well as increased the two-year survival rate from 10.4% to 26.5%. To treat recurrent brain tumors, stereotactic radiosurgery is an option used for previously irradiated primary brain tumors as well as brain metastases This therapy uses high, single fraction doses of ionizing radiation (IR) to target the tumor volume. The maximum tolerated single fraction dose for radiosurgery is recommended as 15Gy for tumors 31-40mm, 18Gy for tumors 21-30mm, and 24Gy for tumors less than 20mm in diameter [4]
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