Download effects of radiation exposure on lung carcinogenesis

EFFECTS OF RADIATION EXPOSURE ON LUNG CARCINOGENESIS
Oliver Delgado, Ph.D.
The University of Texas Southwestern Medical Center at Dallas, 2009
Supervising Professor: Jerry W. Shay, Ph.D.
Full PDF available after 12/1/2012
Keywords: radiation; lung; cancer; stem cells; progresson
Lung cancer is one of the most prevalent forms of cancer in both men and women with
over 1.3 million annual related deaths worldwide. Analysis of several human populations
exposed to radiation reveals that the lung is remarkably susceptible to the carcinogenic effects
of radiation exposure. The considerable lung surface area and slow rate of epithelial turnover
may have causal roles in this vulnerability. This may be due to the increased probability that a
progenitor cell of the lung, which is proposed to be the cancer-initiating cell, may acquire
multiple carcinogenic alterations from radiation exposure. Currently, the lung is believed to
have several facultative progenitor cells, situated throughout the lung epithelium, that are
regionally restricted in their regenerative capacity. Normal human bronchial epithelial cells
(HBECs), immortalized through the expression of Cdk4 and hTERT, provide a sustainable cell
reagent for the evaluation of the radiation effects in vitro. These HBECs retain a novel
multipotent capacity in vitro (capable of differentiating into both central and peripheral lung
cell types) and thus may represent an unrestricted progenitor of the adult lung that resembles
an embryonic progenitor. Studies to determine whether the differentiation state influences
radiation exposure effects, such as DNA damage and repair, are ongoing. As cellular
responses change upon the acquisition of oncogenic mutations, the effects of fractionated or
acute radiation exposure on lung carcinogenesis in vivo were determined utilizing the
transgenic LA1 K-ras mouse model of lung cancer compared to wildtype littermates.
Radiation-induced carcinogenesis is a major concern not only for cancer patients being treated
with therapeutic radiation but also for astronauts on long-term space missions. X-ray
radiation did not affect the incidence or progression of lung carcinogenesis in this mouse
model of lung cancer. High-energy 56Fe- particle irradiation (a type of radiation present in
deep space), however, significantly increased the incidence of invasive carcinoma when
administered as a fractionated dose but not as a single acute dose. These results demonstrate
that pre-initiated lesions may be more susceptible to malignant transformation upon exposure
to radiation. Thus, radiation may have an impact on both lung cancer initiation and
progression.