Mathematical Modeling of the Role of Survivin on Dedifferentiation and Radioresistance in Cancer

Rhodes, Adam; Hillen, Thomas

doi:10.1007/s11538-016-0177-x

Cited by 17 publications

(11 citation statements)

References 51 publications

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“…The survivin effect is then controlled by administration of YM155. In (Rhodes and Hillen 2016) a mathematical model was developed to investigate the combination of YM155 administration and radiation therapy on the CSC dynamics.…”

Section: Introductionmentioning

confidence: 99%

Feedback Regulation in a Cancer Stem Cell Model can Cause an Allee Effect

2016

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The exact mechanisms of spontaneous tumor remission or complete response to treatment are phenomena in oncology that are not completely understood. We use a concept from ecology, the Allee effect, to help explain tumor extinction in a model of tumor growth that incorporates feedback regulation of stem cell dynamics, which occurs in many tumor types where certain signaling molecules, such as Wnts, are upregulated. Due to feedback and the Allee effect, a tumor may become extinct spontaneously or after therapy even when the entire tumor has not been eradicated by the end of therapy. We quantify the Allee effect using an ‘Allee index’ that approximates the area of the basin of attraction for tumor extinction. We show that effectiveness of combination therapy in cancer treatment may occur due to the increased probability that the system will be in the Allee region after combination treatment versus monotherapy. We identify therapies that can attenuate stem cell self-renewal, alter the Allee region and increase its size. We also show that decreased response of tumor cells to growth inhibitors can reduce the size of the Allee region and increase stem cell densities, which may help to explain why this phenomenon is a hallmark of cancer.

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Section: Introductionmentioning

confidence: 99%

Feedback Regulation in a Cancer Stem Cell Model can Cause an Allee Effect

2016

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“…This is confirmed by preliminary simulations that combine a spatial extension of the model in ref. 46, which accounts for the reprogrammingpromoter survivin and its inhibitor YM155, with the multispecies model presented here (results not shown). A complete study will be presented in future work.…”

Section: Discussionmentioning

confidence: 98%

“…When combined with AM therapies (chemo-and radio-), these combinatorial treatments can eradicate the tumor by the time treatment has ended. When reprogramming of GBM-differentiated cells into GSCs is considered, anti-reprogramming therapies might also be required in the combinatorial treatments to eradicate the tumor (46). However, if the reprogramming rates are sufficiently small, our proposed combination strategy should still be effective.…”

Section: Discussionmentioning

confidence: 99%

3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.

Bota

Yan

Romero-López

et al. 2017

JCO

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e13535 Background: Glioblastoma (GBM), the most aggressive brain tumor in human patients, is highly heterogeneous and intensively vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and by promoting resistance to therapy. Recently, crosstalk between GSCs and vascular endothelial cells that line capillaries has been shown to considerably promote GSC self-renewal and tumor progression. GSCs have been shown to also transdifferentiate into bona-fide vascular endothelial cells (GEC). GECs inherit mutations present in GSCs and are resistant to traditional anti-angiogenic therapies. Methods: We develop a multispecies mathematical model to investigate the 3D spatiotemporal dynamics of vascularized GBM progression and response to cancer therapies. Results: The model predicts GSCs drive invasive fingering and that GECs spontaneously form a network within the hypoxic core, consistent with published experimental findings. We demonstrate that standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies reduce GBM tumor sizes but increase invasiveness. Anti-GEC treatments block the GEC support of GSCs and reduce tumor sizes but can lead to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduce tumor invasiveness and sizes, but are ultimately limited in reducing tumor sizes because GECs can maintain GSCs. Anti-GEC therapies are required to remove the tumor completely. Conclusions: Our results suggest that a combinatorial regimen targeting the vasculature, GSCs and GECs, using drugs already approved by the FDA, can reduce both tumor sizes and invasiveness and could lead to tumor eradication without recurrence when the treatment is stopped.

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“…It is expressed in ~60 different human tumor types, with the highest levels of expression observed in breast and lung cancer cell lines (47)(48)(49). The survivin protein inhibits caspase activation, thereby leading to negative regulation of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Anticancer effects of β-elemene with hyperthermia in lung cancer cells

Wang²,

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. β-elemene is a novel, plant-derived anticancer drug, which has been used to target multiple solid tumor types. Hyperthermia is an adjuvant therapeutic modality to treat cancer. However, the underlying mechanisms associated with the efficacy of these two treatments are largely unknown. The aim of the present study was to evaluate the effects of β-elemene combined with hyperthermia in lung cancer cell lines. An MTT assay was used to determine cell viability. The cell cycle and apoptosis were analyzed using flow cytometry. The morphology of cells during apoptosis was determined using a transmission electron microscope. The expression levels of P21, survivin, caspase-9, B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) mRNA were detected using quantitative polymerase chain reaction. β-elemene with hyperthermia treatment significantly inhibited the viability and increased the apoptosis rate of A549 cells compared with β-elemene treatment alone (P<0.01), and significantly decreased the proportion of cells in S phase compared with the control (P<0.01). Morphological observation using transmission electron microscopy indicated cross-sectional features of apoptosis: Chromatin condensation, reduced integrity of the plasma membrane, increased cellular granularity, nuclear collapse and the formation of apoptotic bodies. β-elemene with hyperthermia treatment significantly promoted P21 and Bax mRNA expression (P<0.01) and significantly decreased caspase-9, Bcl-2 and survivin mRNA expression (P<0.01) in A549 cells. In conclusion, β-elemene with hyperthermia has a significant inhibitory effect on A549 cells. This occurs through reducing S phase and inducing apoptosis, via an increase in P21 and Bax expression and a decrease in caspase-9, Bcl-2 and survivin expression.

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Mathematical Modeling of the Role of Survivin on Dedifferentiation and Radioresistance in Cancer

Cited by 17 publications

References 51 publications

Feedback Regulation in a Cancer Stem Cell Model can Cause an Allee Effect

Feedback Regulation in a Cancer Stem Cell Model can Cause an Allee Effect

3D Mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells promote resistance to current standard-of-care therapy.

Anticancer effects of β-elemene with hyperthermia in lung cancer cells

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