Mathematical Modeling of PDGF-Driven Glioblastoma Reveals Optimized Radiation Dosing Schedules

Leder, Kevin; Pitter, Kenneth L.; LaPlant, Quincey; Hambardzumyan, Dolores; Ross, Brian D.; Chan, Timothy A.; Holland, Eric C.; Michor, Franziska

doi:10.1016/j.cell.2013.12.029

Cited by 252 publications

(264 citation statements)

References 61 publications

(81 reference statements)

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“…When mutations can be found in nearly all possible coding regions within a tumor, resistance to most drugs seems highly likely. Read et al (37) pointed out that aggressive strategies against cancerous cells are effective only in the absence of resistance at treatment and various strategies for administering drugs in the face of resistant clones have been proposed (38)(39)(40)(41)(42). Finally, a key feature of the non-Darwinian model is the rapidity with which mutations accrue.…”

Section: Discussionmentioning

confidence: 99%

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Ling

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

334

410

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The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 “polymorphic” SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model, MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors.

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Section: Discussionmentioning

confidence: 99%

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Ling

Yang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

334

410

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“…By use of a model that takes into account rates of proliferation and invasion in combination with imaging data, it has been proposed that IDH1 mutant tumors are actually less proliferative and more invasive (Baldock et al 2014). Clinically relevant parameters, such as identifying optimal radiation schedules, have also been modeled using genetically engineered mice (Leder et al 2014). Additionally, quantitative approaches have been developed to model the events leading to intertumoral and intratumoral heterogeneity in both human patient specimens (Sottoriva et al 2013) and mouse models (Cheng et al 2012).…”

Section: Reducing Complexity Through Mathematical Modelingmentioning

confidence: 99%

Cancer stem cells in glioblastoma

et al. 2015

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Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.

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“…32,89 Oligodendrogenesis relies on platelet-derived growth factor (PDGF); increased PDGF signaling has been demonstrated to cause abnormal NSC proliferation and glioma formation. 40,44,56 Putative CSCs selected using common NSC markers have demonstrated the ability to form orthotopic tumors in nude mice that more closely resemble human GBM than could isolated cells lacking these markers. 22,91,92 Compared with the remaining tumor cells, CSCs are thought to be metabolically unique because of data demonstrating epigenetic DNA changes and a role for microRNAs in regulating gene expression.…”

Section: Glioblastoma and Cancer Stem Cellsmentioning

confidence: 99%

The role of cancer stem cells in glioblastoma

Sundar

Hsieh

Manjila

et al. 2014

FOC

109

105

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G lioblastoma (GBM) is the most common primary malignant brain tumor. It is extremely aggressive, with a median overall survival (OS) of less than 15 months after diagnosis even with maximal therapy. 95 Survival rates are dismal, ranging from 26% to 33% for 2-year survival and less than 5% for 5-year survival. 49,53,96 The standard first-line treatment includes resection, if possible, followed by concurrent radio-and chemotherapy, typically temozolomide (TMZ), and then 6-12 months of adjuvant TMZ. 38,68 Despite treatment, recurrence is nearly universal. 96 Glioblastoma demonstrates a great deal of phenotypic, morphological, and cellular heterogeneity and is thought to contain a population of self-renewing cancer stem cells (CSCs) that contributes to tumorigenesis and treatment resistance. Both intratumoral heterogeneity and the presence of these CSCs may contribute to the treatment-resistant nature of GBM and its propensity to recur in patients. 15,70 History and DefinitionThe concept of CSCs originated in 1994 with the observation that a fraction of cells in human acute myeloid leukemia can self-renew and reconstitute both the leukemic cell hierarchy and the clinical disease state in vivo after xenotransplantation. 1,11,49,99 These self-renewing cells were later discovered to exist in various solid tumors as well, including those of the breast, colon, lung, brain, and liver. 1,20,71,81,92 The CSC hypothesis proposes that individual tumors comprise a cellular hierarchy. Cancer stem cells reside at the apex of the hierarchy and possess the ability to self-renew and to divide to give rise to the variety of cells that populate a tumor. As tumor cells differentiate, their ability to self-renew is reduced and they lose their "stemness." The hierarchy is dynamic with respect to cell type (CSCs, non-CSCs) and is maintained by the balance between self-renewal and differentiation. 43,107 Viewed in this light, tumors can be thought of as aberrant organs comprising heterogeneous cell types derived from CSCs rather than simply an accumulation of diverse neoplastic clones.Researchers who made the initial attempts to define CSCs described a qualitatively distinct population of pathological cells that was able to self-renew and ir- Recurrence in glioblastoma is nearly universal, and its prognosis remains dismal despite significant advances in treatment over the past decade. Glioblastoma demonstrates considerable intratumoral phenotypic and molecular heterogeneity and contains a population of cancer stem cells that contributes to tumor propagation, maintenance, and treatment resistance. Cancer stem cells are functionally defined by their ability to self-renew and to differentiate, and they constitute the diverse hierarchy of cells composing a tumor. When xenografted into an appropriate host, they are capable of tumorigenesis. Given the critical role of cancer stem cells in the pathogenesis of glioblastoma, research into their molecular and phenotypic characteristics is a therapeutic priority. In this review, the authors discuss...

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Mathematical Modeling of PDGF-Driven Glioblastoma Reveals Optimized Radiation Dosing Schedules

Cited by 252 publications

References 61 publications

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Cancer stem cells in glioblastoma

The role of cancer stem cells in glioblastoma

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