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predicted by the repair-dependent model for both ultraviolet and ionizing radiation. For the ultraviolet-
and ionizing radiation induced neoplastic transformation experiments that were analyzed, the
transformation frequency data can be fit with only the repair-dependent quadratic function, which
approaches being strictly quadratic in the low-dose limit, but has a sigmoidal shape over a wider range of
doses. Inclusion of data from the transition region in a traditional linear-quadratic analysis of neoplastic
transformation data can exaggerate the magnitude of, or create the appearance of, a linear component.
Quantitative analysis of survival and transformation data shows good agreement for ultraviolet radiation;
the shapes of the transformation components can be determined from survival data. For ionizing
radiations, both neutrons and X-rays, survival data overestimate the transforming ability for low to
moderate doses. The presumed cause of this difference is that, unlike UV photons, a single x-ray or
neutron may generate more than one lethal damage in a cell, so the distribution of such damages in not
accurately described by Poisson statistics. However, the complete sigmodial dose-response data for
neoplastic transformations can be fit using the repair-dependent functions with all parameters
determined only from transformation frequency data.
(PS4-08) An age-associated decline in fibroblast antioxidant capacity promotes epithelial cancer cell
proliferation. John T. Lafin; Ehab H. Sarsour; Wusheng Xiao; Amanda L. Kalen; and Prabhat C. Goswami
University of Iowa, Iowa City, IA
Age is a risk factor for both the incidence and progression of carcinomas. Recent evidence
suggests that the stroma is a significant factor that regulates cancer cell proliferation and therapy
response. Fibroblasts are the major non-cancerous stromal cell type that contribute to the synthesis and
remodeling of the extracellular matrix and the production of secretory and non-secretory factors that
influence cancer cell proliferation and progression to end stage disease. This study investigated the
hypothesis that an age-associated decline in antioxidant capacity of fibroblasts promotes the proliferation
of human head and neck squamous cancer cells. Total cellular RNA was isolated from normal human
fibroblasts of different age groups (3-d, 12-y, and 61-y). A quantitative RT-PCR assay was used to analyze
mRNA expression of selected oxidative stress response genes: SOD2, catalase, GPx1, GPx4, NOS2, PRDX3,
DUOX1, DUOX2, NOX4, and SEPP1. Old fibroblasts showed a significant decrease in mRNA levels of SOD2
(5 fold), GPx4 (2 fold) and catalase (1.6 fold), and an increase in mRNA levels of PRDX3 (1.6 fold), NOX4
(1.4 fold) and SEPP1 (1.7 fold). SOD2 reduces superoxide to hydrogen peroxide, which can be reduced to
water by catalase. GPx4 reduces lipid hydroperoxides. Because SOD2 and GPx4 are localized to the
mitochondria, an age-associated decrease in their expression is anticipated to shift the cellular redox-
state to a more oxidizing environment, resulting in mitochondrial injury. Additionally, fibroblasts from
aged donors were found to have approximately 40% more intracellular thiols compared to younger
donors. Results from co-culture studies showed an approximate 30% increase in cell number of Cal27
human head and neck cancer cells co-cultured with old fibroblasts compared to those co-cultured with
young fibroblasts. Similarly, FaDu cells cultured in media conditioned by old fibroblasts showed a faster
cell doubling time (31 h) compared to those cultured in media conditioned by young fibroblasts (36 h).
Taken together, these results demonstrate an age-associated decrease in the expression of mitochondria-
localized antioxidant enzymes correlates with aging fibroblast-induced increases in the proliferation of
human head and neck cancer cells. (Supported by NIH 2R01 CA111365 and NIH 5T32CA078586-13)
237 | P a g e
and ionizing radiation induced neoplastic transformation experiments that were analyzed, the
transformation frequency data can be fit with only the repair-dependent quadratic function, which
approaches being strictly quadratic in the low-dose limit, but has a sigmoidal shape over a wider range of
doses. Inclusion of data from the transition region in a traditional linear-quadratic analysis of neoplastic
transformation data can exaggerate the magnitude of, or create the appearance of, a linear component.
Quantitative analysis of survival and transformation data shows good agreement for ultraviolet radiation;
the shapes of the transformation components can be determined from survival data. For ionizing
radiations, both neutrons and X-rays, survival data overestimate the transforming ability for low to
moderate doses. The presumed cause of this difference is that, unlike UV photons, a single x-ray or
neutron may generate more than one lethal damage in a cell, so the distribution of such damages in not
accurately described by Poisson statistics. However, the complete sigmodial dose-response data for
neoplastic transformations can be fit using the repair-dependent functions with all parameters
determined only from transformation frequency data.
(PS4-08) An age-associated decline in fibroblast antioxidant capacity promotes epithelial cancer cell
proliferation. John T. Lafin; Ehab H. Sarsour; Wusheng Xiao; Amanda L. Kalen; and Prabhat C. Goswami
University of Iowa, Iowa City, IA
Age is a risk factor for both the incidence and progression of carcinomas. Recent evidence
suggests that the stroma is a significant factor that regulates cancer cell proliferation and therapy
response. Fibroblasts are the major non-cancerous stromal cell type that contribute to the synthesis and
remodeling of the extracellular matrix and the production of secretory and non-secretory factors that
influence cancer cell proliferation and progression to end stage disease. This study investigated the
hypothesis that an age-associated decline in antioxidant capacity of fibroblasts promotes the proliferation
of human head and neck squamous cancer cells. Total cellular RNA was isolated from normal human
fibroblasts of different age groups (3-d, 12-y, and 61-y). A quantitative RT-PCR assay was used to analyze
mRNA expression of selected oxidative stress response genes: SOD2, catalase, GPx1, GPx4, NOS2, PRDX3,
DUOX1, DUOX2, NOX4, and SEPP1. Old fibroblasts showed a significant decrease in mRNA levels of SOD2
(5 fold), GPx4 (2 fold) and catalase (1.6 fold), and an increase in mRNA levels of PRDX3 (1.6 fold), NOX4
(1.4 fold) and SEPP1 (1.7 fold). SOD2 reduces superoxide to hydrogen peroxide, which can be reduced to
water by catalase. GPx4 reduces lipid hydroperoxides. Because SOD2 and GPx4 are localized to the
mitochondria, an age-associated decrease in their expression is anticipated to shift the cellular redox-
state to a more oxidizing environment, resulting in mitochondrial injury. Additionally, fibroblasts from
aged donors were found to have approximately 40% more intracellular thiols compared to younger
donors. Results from co-culture studies showed an approximate 30% increase in cell number of Cal27
human head and neck cancer cells co-cultured with old fibroblasts compared to those co-cultured with
young fibroblasts. Similarly, FaDu cells cultured in media conditioned by old fibroblasts showed a faster
cell doubling time (31 h) compared to those cultured in media conditioned by young fibroblasts (36 h).
Taken together, these results demonstrate an age-associated decrease in the expression of mitochondria-
localized antioxidant enzymes correlates with aging fibroblast-induced increases in the proliferation of
human head and neck cancer cells. (Supported by NIH 2R01 CA111365 and NIH 5T32CA078586-13)
237 | P a g e
