Integration of Principles of Systems Biology and Radiation Biology: Toward Development of in silico Models to Optimize IUdR-Mediated Radiosensitization of DNA Mismatch Repair Deficient (Damage Tolerant) Human Cancers

Abstract

Over the last 7 years, we have focused our experimental and computational research efforts on improving our understanding of the biochemical, molecular, and cellular processing of iododeoxyuridine (IUdR) and ionizing radiation (IR) induced DNA base damage by DNA mismatch repair (MMR). These coordinated research efforts, sponsored by the National Cancer Institute Integrative Cancer Biology Program (ICBP), brought together system scientists with expertise in engineering, mathematics, and complex systems theory and translational cancer researchers with expertise in radiation biology. Our overall goal was to begin to develop computational models of IUdR- and/or IR-induced base damage processing by MMR that may provide new clinical strategies to optimize IUdR-mediated radiosensitization in MMR deficient (MMR−) “damage tolerant” human cancers. Using multiple scales of experimental testing, ranging from purified protein systems to in vitro (cellular) and to in vivo (human tumor xenografts in athymic mice) models, we have begun to integrate and interpolate these experimental data with hybrid stochastic biochemical models of MMR damage processing and probabilistic cell cycle regulation models through a systems biology approach. In this article, we highlight the results and current status of our integration of radiation biology approaches and computational modeling to enhance IUdR-mediated radiosensitization in MMR− damage tolerant cancers.

Clinical value of MLH1-negative circulating tumor cells in lung cancer patients

“…Previous research has shown that MLH1 expression loss may be responsible for platinum resistance and worse prognosis in lung cancer. [6,10,28,29] In contrast, the loss of MLH1 expression was associated with significantly improved survival compared to normal MLH1 expression in Mario Scartozzia's study. [25] However, Cooper and his group found that MLH1 expression had no relationship with lung cancer patient prognosis.…”

“…Many studies suggest that the loss of MLH1 expression may lead to platinum resistance and worse outcomes. [6,10] Other studies have reported no link between MLH expression and outcome in lung cancer patients. [11–13] Therefore, we explored MLH1 expression and its clinical significance in lung cancer in a larger number of patients by summarizing data from bioinformatic websites.…”

A Pan-Cancer Analysis on the Systematic Correlation of MutS Homolog 2 (MSH2) to a Malignant Tumor

“…This protein helps repair errors arising when DNA is replicated for cell division proteins (the MSH2 protein binds to one of the MSH6 or MSH3 (each produced by a different gene)) to form a dimer of the two-protein complex [ 1 ], which recognizes the error-occurring sites on DNA that begets in the course of DNA replication. The MLH1-PMS2 dimer is formed with another set of proteins, which subsequently combine with the MSH2 dimer to initiate the process of error repair by removing mismatched DNAs and replicating a new fragment [ 2 , 3 ]. DNA damage is an inducement of cancer genesis; hence, the defection of DNA repair genes is primarily responsible for many cancers' initiation and development [ 4 , 5 ].…”

Electromagnetic Fields, Genomic Instability and Cancer: A Systems Biological View

“…This review discusses systems biology of electromagnetic fields, covering frequencies from extremely low frequencies (ELF; <300 Hz) to radiofrequencies (RF; up to 300 GHz). While several articles have applied various systems biology approaches to the biological effects of ionizing radiation [4,5,6,7,8,9] and chemicals [10,11], systems biological approaches to biological effects of electromagnetic fields have been discussed, to the best of our knowledge, in only one book [12]. We focus particularly on induced genomic instability and its role in cancer as cancer is a major issue in the discussion of the health effects of electromagnetic fields (and in general in environmental health).…”