The prognostic significance of uPA, uPAR an d the cytokine IL-1-alpha in urinary bladder cancer
Author: Seddighzadeh, Maria
Date: 2002-04-12
Location: Radiumhemmets föreläsningssal, Karolinska Sjukhuset
Time: 9.30
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
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thesis.pdf (802.0Kb)
Abstract
Tumor invasion and metastasis are the major causes of cancer-related
death. Proteases are important for the invasive and metastatic
propensities of tumors. We have studied the mechanism underlying
endogenous expression of the serine protease urokinase plasminogen
activator (uPA) by human breast cancer cells. The expression of uPA mRNA
was found to be affected by manipulation of the activity of the MEK-ERK
signaling pathway. A minor portion of total ERK was phosphorylated (and
hence active) in the NMA-MB-231 breast cancer cell line. Decreased ERK
activity was associated with decreased uPA expression, whereas
stimulation of ERK activity did not lead to an increase in uPA
expression. In contrast, increased ERK activity was found to lead to
increased expression of the cyclin kinase inhibitor p21Cip1. These data
suggest that ERK activity in these cells is tuned to a level that allows
rapid cell proliferation and high levels of uPA expression
Urinary bladder carcinoma is heterogeneous in nature and can follow
distinct clinical courses. More than fifty percent of all patients with
muscle invasive bladder tumors that develop metastasis die from their
disease. It is important to identify factors that can predict the
prognosis of patients with muscle invasive tumors, both to be able to
offer a more individualized treatment strategy and also to be able to
develop therapeutic methods that can target these factors. In a
prospective study we found that the expression of uPA and its receptor
(uPAR) predict the outcome of patients with bladder cancer and that
elevated levels of uPAR were associated with an increased risk for
development of metastasis. Moreover, we observed that high uPA expression
was associated with an increased risk of death from cancer in the group
of patients with muscle invasive tumors. The risk associated with
elevated uPA was lower in cystectomized patients, suggesting that
treatment improved the prognosis. Elevated uPAR expression did not show
this pattern.
Interleukin-1-alpha (IL-1-alpha) is a multifunctional cytokine with many
potential roles in cancer. One such role is that of inducing expression
of uPA in the tumor stroma. IL-1-alpha has been shown to be expressed by
bladder cancer cell lines and has also been shown to inhibit cell
proliferation and angiogenesis in vitro. We observed that bladder tumor
cells produce IL-1-alpha but did not observe any correlation to uPA
expression. Interestingly, low IL-1-alpha expression was associated with
a relative risk of 1.76 for death in cancer in the group of patients with
muscle invasive tumors. The results indicate that uPA, uPAR and
IL-1-alpha can be used as markers for refined staging of tumors.
Inhibition of the uPA system and/or treatment of patients with IL-1-alpha
may be considered as future therapy of urinary bladder cancer.
List of papers:
I. Seddighzadeh M, Zhou JN, Kronenwett U, Shoshan MC, Auer G, Sten-Linder M, Wiman B, Linder S (1999). "ERK signalling in metastatic human MDA-MB-231 breast carcinoma cells is adapted to obtain high urokinase expression and rapid cell proliferation. " Clin Exp Metastasis 17(8): 649-54
Pubmed
II. Seddighzadeh M, Steineck G, Jansson O, Larsson P, Wijkstrom H, Norming U, Onelov E, Linder S (2002). "Expression of uPA and uPAR is associated wiyh the clinical course of urinary bladder neoplasms." Journal of Cancer (Accepted)
III. Seddighzadeh M, Steineck G, Jansson O, Larsson P, Wijkstrom H, Adolfsson J, Portwood N, Hansson J, Linder S (2001). "Low interleukin-1alpha messenger RNA levels predict decreased overall survival time of patients with urinary bladder carcinoma. " Br J Cancer 84(3): 329-34
Pubmed
IV. Seddighzadeh M, Larsson P, Ulfgren AC, Onelov E, Berggren P, Tribukait B, Thorstensson A, Wijkstrom H, Linder S, Steineck G (2002). "Low IL-1-alpha expression and death in urinary bladder cancer." (Manuscript)
I. Seddighzadeh M, Zhou JN, Kronenwett U, Shoshan MC, Auer G, Sten-Linder M, Wiman B, Linder S (1999). "ERK signalling in metastatic human MDA-MB-231 breast carcinoma cells is adapted to obtain high urokinase expression and rapid cell proliferation. " Clin Exp Metastasis 17(8): 649-54
Pubmed
II. Seddighzadeh M, Steineck G, Jansson O, Larsson P, Wijkstrom H, Norming U, Onelov E, Linder S (2002). "Expression of uPA and uPAR is associated wiyh the clinical course of urinary bladder neoplasms." Journal of Cancer (Accepted)
III. Seddighzadeh M, Steineck G, Jansson O, Larsson P, Wijkstrom H, Adolfsson J, Portwood N, Hansson J, Linder S (2001). "Low interleukin-1alpha messenger RNA levels predict decreased overall survival time of patients with urinary bladder carcinoma. " Br J Cancer 84(3): 329-34
Pubmed
IV. Seddighzadeh M, Larsson P, Ulfgren AC, Onelov E, Berggren P, Tribukait B, Thorstensson A, Wijkstrom H, Linder S, Steineck G (2002). "Low IL-1-alpha expression and death in urinary bladder cancer." (Manuscript)
Issue date: 2002-03-22
Rights:
Publication year: 2002
ISBN: 91-7349-146-2
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