Increased cancer risk of augmentation cystoplasty: Possible role for hyperosmolal microenvironment on DNA damage recognition

Abstract

Patients who have had surgical bladder augmentation have an increased risk of bladder malignancy, though the mechanism for this increased risk is unknown. Hyperosmolal microenvironments such as the bladder may impair DNA damage signaling and repair; this effect may be more pronounced in tissues not normally exposed to such conditions. Comparing gastric and colon epithelial cell lines to transitional epithelial cell lines gradually adapted to an osmolality of 600mOsm/kg with either sodium chloride or urea, cell lines of gastrointestinal origin were inhibited in their ability to activate ATM and downstream effectors of DNA damage signaling and repair such as p53, Nbs1, replication protein A (RPA), and γH2AX following the induction of DNA damage with etoposide. In contrast, bladder cell lines demonstrated a preserved ability to phosphorylate ATM and its effectors under conditions of hyperosmolal urea, and to a lesser extent with sodium chloride. The bladder cell lines' ability to respond to DNA damage under hyperosmolal conditions may be due in part to protective mechanisms such as the accumulation of intracellular organic osmolytes and the uroplakincontaining asymmetric unit membrane as found in transitional epithelial cells, but not in gastrointestinal cells. Failure of such protective adaptations in the tissues used for augmentation cystoplasties may place these tissues at increased risk for malignancy.

Expression of P53, HER2 and Ki67 proteins in rats subjected to bladder augmentation with stomach, colon and ileum

“…The significant increase of cell proliferation in gastrocystoplasties in relation to the groups which were used colon and ileum confirm the findings described that show greater gene instability in these patients 26 . The changes found strengthen the studies that suggest that these kind of surgical procedures is unquestioned and will contribute to a better quality of life and survival of patients who require the achievement of cystoplasties.…”

Src kinase pathway is involved in NFAT5-mediated S100A4 induction by hyperosmotic stress in colon cancer cells

“…The pro-survival function of S100A4 induction might be critical for protection of epithelial cells from apoptosis and adaptation to the environment; however, chronic exposure to hyperosmotic stress may have adverse effects. Impaired DNA repair pathways and formation of DNA strand breaks appear in cells adapted to hyperosmotic stress (10), which could lead to accumulation of DNA mutations by exposure to a hyperosmolar microenvironment (9). In this respect, the sustained S100A4 induction by hyperosmotic stress further provides the survival advantage and increases the risk of genomic instability.…”

Unique clinicopathologic and molecular characteristics of urinary bladder tumors in children and young adults

“…Gastrointestinal epithelial cells are not normally exposed to the hyper-osmolal microenvironmental conditions of the urinary tract. As such, Dixon et al find that the gastrointestinal epithelial cells in this setting may be less able to respond to DNA damage and undergo apoptosis, in contrast to the urothelial cells, which appear to be more tolerant to such conditions [31].…”