The prognostic significance of uPA, uPAR an d the cytokine IL-1-alpha in urinary bladder cancer

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 scientific 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
https://pubmed.ncbi.nlm.nih.gov/10919709

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
https://pubmed.ncbi.nlm.nih.gov/11161396

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)