MECHANISIMS OF BLADDER CANCER PROGRESSION

Project: Research project

Project Details

Description

DESCRIPTION: (adapted from the investigator's abstract) Two critical
factors that affect the prognosis of bladder cancer patients are high-grade
invasive tumors and the high rate of tumor recurrence. Hyaluronidase is an
enzyme that degrades hyaluronic acid (HA), a glycosaminoglycan, into small
angiogenic fragments. Two hyaluronidases have been identified as potential
"molecular markers" of high-grade bladder tumors (BT). The long-term
objectives of this proposal are to elucidate functions of these
hyaluronidases in BT progression and to develop a simple, non-invasive and
accurate test for early detection and post-therapy surveillance of bladder
cancer.

To test the hypothesis that BT-derived hyaluronidases are structurally
distinct from other known hyaluronidases and are expressed in a tumor,
tissue, or cell specific manner, BT-derived hyaluronidases will be isolated,
purified, cDNA cloned and sequenced (Aim 1). These enzymes will be
characterized for substrate specificity and sensitivity to inhibitors and
their expression will be examined at protein and mRNA levels in normal
tissues, tumor tissues, and tumor cells (Aim 2). To test whether elevated
BT-derived hyaluronidase levels confer metastatic phenotype to otherwise
indolent BT cells, low-grade BT cells will be transfected with cDNAs of
these enzymes and following orthotopic implantation in nude mice metastasis
will be examined. In addition, the role of angiogenic HA fragments on
functions of BT cells and BT-derived endothelial cells which regulate BT
progression will be examined (Aim 3). Urinary HA levels are elevated in BT
patients and urinary hyaluronidase levels are elevated in patients with
high-grade BT. To test whether a HA-hyaluronidase test can detect bladder
tumor recurrence and indicate its malignant potential, urinary
HA-hyaluronidase levels in 150 BT patients will be measured at scheduled
surveillance visits and results will be compared with cystoscopic or urine
cytology findings (Aim 4).

The proposed study could result in identifying and functionally
characterizing a new marker of high-grade BT which could improve diagnosis
and treatment of bladder cancer.
StatusNot started