© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 219-227, Copyright © 1997 by Oxford University Press
GD Grossfeld, DA Ginsberg, JP Stein, BH Bochner, D Esrig, S Groshen, M Dunn, PW Nichols, CR Taylor, DG Skinner and RJ Cote
BACKGROUND: Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an
important component of the extracellular matrix and is known to be a potent
inhibitor of angiogenesis (i.e., formation of new blood vessels) both in
vitro and in vivo. Several reports suggest that TSP possesses tumor
suppressor function, possibly through its ability to inhibit tumor
neovascularization. It has recently been shown that TSP expression is
enhanced by the product of the p53 gene (also known as TP53). PURPOSE: We
examined the role of TSP expression in tumor recurrence and overall
survival in patients with invasive bladder cancer. We also examined the
relationship between alterations in p53 protein expression, TSP expression,
and tumor angiogenesis. METHODS: Tumors from 163 patients (with a median
follow-up of 7.7 years) who underwent radical cystectomy for invasive
transitional cell carcinoma of the bladder (63 patients with organ-confined
disease and no lymph node involvement, 48 patients with extravesical
extension of the disease and no lymph node involvement, and 52 patients
with metastasis to regional lymph nodes) were examined for TSP expression
by immunohistochemistry, utilizing monoclonal antibody MA-II, which
recognizes an epitope in the amino-terminal region of TSP. For each tumor,
microvessel density counts and p53 protein expression status (via
immunohistochemistry) were also determined. TSP expression was graded as
low, moderate, or high without knowledge of clinical outcome, p53 status,
and microvessel density count; tumors with moderate and high TSP levels
were considered as one group. Groups of patients were compared by
Kaplan-Meier product limit estimates of overall survival, the complement of
cumulative incidence curves for recurrence-free survival, and the
stratified logrank test. Reported P values are two- sided. RESULTS: TSP
expression was significantly associated with disease recurrence (P = .009)
and overall survival (P = .023). Patients with low TSP expression exhibited
increased recurrence rates and decreased overall survival. TSP expression
was an independent predictor of disease recurrence (P = .002) and overall
survival (P = .01) after stratifying for tumor stage, lymph node status,
and histologic grade, but it was not independent of p53 status. TSP
expression was significantly associated with p53 expression status (P =
.001) and microvessel density counts (P = .001). Tumors with p53
alterations were significantly more likely to demonstrate low TSP
expression, and tumors with low TSP expression were significantly more
likely to demonstrate high microvessel density counts. Results of an
analysis of variance were compatible with the hypothesis that p53 affects
tumor angiogenesis by regulating the level of TSP expression. CONCLUSIONS
AND IMPLICATIONS: These data support the concept that TSP may possess a
tumor-inhibitory function. TSP may act, in part, through the regulation of
tumor neovascularity. These results may also provide insight into one
mechanism by which p53 exerts its tumor suppressor effects, i.e., through
the control of tumor angiogenesis.
ARTICLES
Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
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