Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition
Abstract Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthe...
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doaj-3ef55534139140c0b7f180eeda0e91432020-11-25T03:40:11ZengBMCBMC Bioinformatics1471-21052019-10-0120111510.1186/s12859-019-3098-5Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibitionEmile P. Chen0Roy S. Song1Xueer Chen2Computational Sciences, GlaxoSmithKlineComputational Sciences, GlaxoSmithKlineDepartment of Biomedical Informatics, University of PittsburghAbstract Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthermore, there are inconsistent reports of hypoxia-induced kinase activities in different cancer cell-lines, where increase, decreases, or no change has been observed. Thus, we asked, why are there widely contrasting results in kinase activity under hypoxia in different cancer cell-lines and how does hypoxia play a role in anti-cancer drug sensitivity? Results We took a modeling approach to address these questions by analyzing the model simulation to explain why hypoxia driven signals can have dissimilar impact on tumor growth and alter the efficacy of anti-cancer drugs. Repeated simulations with varying concentrations of biomolecules followed by decision tree analysis reveal that the highly differential effects among heterogeneous subpopulation of tumor cells could be governed by varying concentrations of just a few key biomolecules. These biomolecules include activated serine/threonine-specific protein kinases (pRAF), mitogen-activated protein kinase kinase (pMEK), protein kinase B (pAkt), or phosphoinositide-4,5-bisphosphate 3-kinase (pPI3K). Additionally, the ratio of activated extracellular signal-regulated kinases (pERK) or pAkt to its respective total was a key factor in determining the sensitivity of pERK or pAkt to hypoxia. Conclusion This work offers a mechanistic insight into how hypoxia can affect the efficacy of anti-cancer drug that targets tumor signaling and provides a framework to identify the types of tumor cells that are either sensitive or resistant to anti-cancer therapy.http://link.springer.com/article/10.1186/s12859-019-3098-5Mathematical tumor modelHypoxia tumor signalingTumor signalingTumor growth model |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Emile P. Chen Roy S. Song Xueer Chen |
spellingShingle |
Emile P. Chen Roy S. Song Xueer Chen Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition BMC Bioinformatics Mathematical tumor model Hypoxia tumor signaling Tumor signaling Tumor growth model |
author_facet |
Emile P. Chen Roy S. Song Xueer Chen |
author_sort |
Emile P. Chen |
title |
Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition |
title_short |
Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition |
title_full |
Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition |
title_fullStr |
Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition |
title_full_unstemmed |
Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition |
title_sort |
mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition |
publisher |
BMC |
series |
BMC Bioinformatics |
issn |
1471-2105 |
publishDate |
2019-10-01 |
description |
Abstract Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthermore, there are inconsistent reports of hypoxia-induced kinase activities in different cancer cell-lines, where increase, decreases, or no change has been observed. Thus, we asked, why are there widely contrasting results in kinase activity under hypoxia in different cancer cell-lines and how does hypoxia play a role in anti-cancer drug sensitivity? Results We took a modeling approach to address these questions by analyzing the model simulation to explain why hypoxia driven signals can have dissimilar impact on tumor growth and alter the efficacy of anti-cancer drugs. Repeated simulations with varying concentrations of biomolecules followed by decision tree analysis reveal that the highly differential effects among heterogeneous subpopulation of tumor cells could be governed by varying concentrations of just a few key biomolecules. These biomolecules include activated serine/threonine-specific protein kinases (pRAF), mitogen-activated protein kinase kinase (pMEK), protein kinase B (pAkt), or phosphoinositide-4,5-bisphosphate 3-kinase (pPI3K). Additionally, the ratio of activated extracellular signal-regulated kinases (pERK) or pAkt to its respective total was a key factor in determining the sensitivity of pERK or pAkt to hypoxia. Conclusion This work offers a mechanistic insight into how hypoxia can affect the efficacy of anti-cancer drug that targets tumor signaling and provides a framework to identify the types of tumor cells that are either sensitive or resistant to anti-cancer therapy. |
topic |
Mathematical tumor model Hypoxia tumor signaling Tumor signaling Tumor growth model |
url |
http://link.springer.com/article/10.1186/s12859-019-3098-5 |
work_keys_str_mv |
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