The role of platelet-derived growth factor in radiation injury to the lower urinary tract

Abstract

Approximately half of all patients diagnosed with cancer will receive radiotherapy as a part of the management of their tumours. Radiotherapy allows organ sparing treatment but it is associated with a number of acute and late unwanted effects. Radiotherapy has a crucial role to play in the treatment of urothelial malignancies. However, the late non-tumoricidal consequences cause significant morbidity, particularly in relation to fibrosis of the pelvic structures. The unwanted effects of radiotherapy were originally though to be due to the result of direct cell injury, cell death and subsequent fibroatrophic changes. It is now clear that radiation initiates a series of events in cells and tissues that is primarily based upon the release of cytokines, including growth factors, which lead to the development of late radiation injury. This study investigates the changes that occur in the lower urinary tract after radiotherapy and looks for a possible role for platelet derived growth factor (PDGF) in this process. Fifty-six cystectomy specimens were retrieved from the archives of the Pathology Department of patients who had been treated with a similar schedule of radiotherapy for bladder cancer. Morphological changes were identified by routine light microscopy, focussing mainly on the bladder and prostate gland. The degree of fibrosis was measured using an image analysis system and this was related to time since irradiation. Immunohistochemistry for fibronectin, PDGFs and PDGF receptors was performed and the expression assessed by a semiquantitative scoring method. The results were compared to non-irradiated control bladders, either with or without tumours. A range of histological changes were identified including inflammatory, epithelial, stromal, vascular and neural alterations. These were either more commonly seen in the irradiated group or the normal age/physiological changes usually encountered in these organs were exaggerated in this group after irradiation. Predictably, fibrosis and fibronectin production was more obvious in the irradiated group, and this increased with time since irradiation for period of study. PDGFs and their receptors were expressed after irradiation and the levels were higher than in the non-irradiated group. The histological basis for the unwanted side effects of irradiation is described in this study. The fibrosis is progressive, with accumulation of connective tissue long after the radiation dose has been delivered. It is likely, from these results, that PDGF and its 11 receptors play a role in this process. These results pave the way for manipulation of growth factors and/or their receptors, including PDGF, in the future management of patients who are symptomatic with radiation injury.