SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M
VINATA B. LOKESHWAR, PH.D.
Associate Professor of Urology
DESCRIPTION OF RESEARCH
Dr. Lokeshwar’s research focuses on understanding
the mechanism of cancer progression
and tumor angiogenesis. Recent advances in
cancer research have elucidated that the components
of extracellular matrix (ECM) and ECMdegrading
enzymes play a crucial role in
regulating both the metastatic progression of localized
tumors and tumor angiogenesis. Using
bladder and prostate cancer model systems, she
and her colleagues are trying to understand how
ECM affects tumor metastasis and angiogenesis.
Work in Dr. Lokeshwar’s laboratory demonstrates
that an ECM component, hyaluronic acid
(HA, which is a glycosaminoglycan), and its degrading
enzyme, hyaluronidase (HAase), are
closely associated with the biology of cancers of
the bladder and prostate. They observed that elevated
urinary HA and HAase levels are diagnostic
indicators of bladder cancer and its grade,
respectively. This finding has led to the development
of a simple, noninvasive, highly sensitive,
and specific urine test (HA-HAase test; 90 percent
accuracy) for detecting bladder cancer and
monitoring its recurrence.
Dr. Lokeshwar’s research on prostate cancer
showed that immunohistochemical localization
of both HA and HAase in prostate cancer tissues
is greater than 85 percent accurate in predicting
prognosis for prostate cancer patients and is
better than CD44v6 and microvessel density.
Furthermore, both HAase and the HA-HAase
combination are independent predictors of
prognosis. Thus, use of these markers in biopsy
specimens may help clinicians to make individualized
treatment decisions and improve patients’
prognosis.
In their efforts to understand the function of
tumor-derived HAase, the researchers purified
and cloned the first tumor-derived HAase. They
have demonstrated that this tumor-derived
HAase degrades tumor-associated HA into small
angiogenic fragments, which then interact with a
HA receptor, RHAMM, on endothelial cells. The
HA fragments and RHAMM interaction on the
cell surface induces signaling events, resulting in
the stimulation of endothelial cell functions such
as proliferation through the mitogen-activated
protein kinase (MAPK). Endothelial cell proliferation
is of key importance in tumor angiogenesis.
Their recent work, using an antisense cDNA
transfection strategy, demonstrates that tumorderived
HAase is necessary for tumor growth and
muscle invasion of bladder tumors. This is an
important finding since 60 percent of bladder
cancer patients with muscle invasive disease die
within five years.
Currently, Dr. Lokeshwar’s research efforts
focus on the following areas. First, researchers are
comparing the efficacy of the HA-HAase test
with other FDA-approved bladder tumor markers
for monitoring bladder cancer recurrence. Second,
they are testing the potential of HAase and
HA-HAase to predict prognostic potential using
prostate biopsy specimens. Thirdly, they are
investigating the functions of HAase and HAsynthase
enzymes in bladder and prostate cancer
growth and progression.
SELECTED PUBLICATIONS
2002
Lokeshwar, VB and Soloway, MS. Re: Urine
based markers of urological malignancy. Journal
of Urology 167:1406-07, 2002.
Lokeshwar, VB , Schroeder, GL, Selzer, MG,
Hautmann, SH, Posey, JT, Duncan, RC, Watson,
R, Rose, L, Markowitz, S, and Soloway, MS.
Bladder tumor markers for monitoring recurrence
and screening comparison of hyaluronic
acid-hyaluronidase and BTA-Stat tests. Cancer
95:61-72, 2002.
Ekici, S and Lokeshwar, VB . Mesane tumoru
belirleyicileri ve HA-HAase testi. Uroloji Bulteni
13:133-40, 2002.
UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 47