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An integrated computational/experimental model of lymphoma growth.

ABSTRACT: Non-Hodgkin's lymphoma is a disseminated, highly malignant cancer, with resistance to drug treatment based on molecular- and tissue-scale characteristics that are intricately linked. A critical element of molecular resistance has been traced to the loss of functionality in proteins such as the tumor suppressor p53. We investigate the tissue-scale physiologic effects of this loss by integrating in vivo and immunohistological data with computational modeling to study the spatiotemporal physical dynamics of lymphoma growth. We compare between drug-sensitive E?-myc Arf-/- and drug-resistant E?-myc p53-/- lymphoma cell tumors grown in live mice. Initial values for the model parameters are obtained in part by extracting values from the cellular-scale from whole-tumor histological staining of the tumor-infiltrated inguinal lymph node in vivo. We compare model-predicted tumor growth with that observed from intravital microscopy and macroscopic imaging in vivo, finding that the model is able to accurately predict lymphoma growth. A critical physical mechanism underlying drug-resistant phenotypes may be that the E?-myc p53-/- cells seem to pack more closely within the tumor than the E?-myc Arf-/- cells, thus possibly exacerbating diffusion gradients of oxygen, leading to cell quiescence and hence resistance to cell-cycle specific drugs. Tighter cell packing could also maintain steeper gradients of drug and lead to insufficient toxicity. The transport phenomena within the lymphoma may thus contribute in nontrivial, complex ways to the difference in drug sensitivity between E?-myc Arf-/- and E?-myc p53-/- tumors, beyond what might be solely expected from loss of functionality at the molecular scale. We conclude that computational modeling tightly integrated with experimental data gives insight into the dynamics of Non-Hodgkin's lymphoma and provides a platform to generate confirmable predictions of tumor growth.

SUBMITTER: Frieboes HB

PROVIDER: S-EPMC3610621 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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An integrated computational/experimental model of lymphoma growth.

Frieboes Hermann B HB Smith Bryan R BR Chuang Yao-Li YL Ito Ken K Roettgers Allison M AM Gambhir Sanjiv S SS Cristini Vittorio V

PLoS computational biology 20130328 3

Non-Hodgkin's lymphoma is a disseminated, highly malignant cancer, with resistance to drug treatment based on molecular- and tissue-scale characteristics that are intricately linked. A critical element of molecular resistance has been traced to the loss of functionality in proteins such as the tumor suppressor p53. We investigate the tissue-scale physiologic effects of this loss by integrating in vivo and immunohistological data with computational modeling to study the spatiotemporal physical dy ...[more]

PMID: 23555235

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An integrated computational/experimental model of lymphoma growth.

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An integrated computational/experimental model of lymphoma growth.

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