Urokinase (u-PA) is an endogenous activator of the thrombolytic mediator plasminogen, however in a tumor environment its proteolytic activity is directed towards the extracellular matrix. As a result u-PA contributes to the dissemination of tumor cells, facilitation of capillary tip advancement, and consequent tumor progression. Likewise, the u-PA receptor uPAR is central to several pathways implicated in tumor progression and angiogenesis. High u-PA levels are significantly associated with short overall survival in both premenopausal and postmenopausal breast cancer patients, while on the other hand, inhibitors of plasminogen activation/u-PA have been shown to slow tumor progression. Similarly, a very recent publication reports the anticancer activity of selective uPAR receptor antagonists. Tumor hypoxia increases the ability of breast carcinoma cells to invade the extracellular matrix, and is also therefore associated with a poor prognosis for breast cancer patients. Canadian based researchers have now implicated nitric oxide (NO) signaling pathways in the control of uPAR over-expression, hypoxia and metastasis. Hypoxia was reported to increase breast cancer invasiveness and uPAR expression. NO-mimetics inhibited these effects; and in a manner similar to hypoxia, pharmacological inhibition of NO synthesis increased uPAR expression, suggesting that NO is an endogenous and tonically active inhibitor of this phenomenon. Targeting of the NO pathway may therefore have beneficial effects in the treatment of cancer and indeed a number of modulators of the NO pathway are in development for this indication. In general the effects of NO depend on the level of production and often, high concentrations of NO can produce the opposite effect to low concentrations. Consequently NO scavengers and donors are both in development for the treatment of cancer. Mechanistic study into the role of NO in cancer should lead to improved therapies. In the present study, hypoxia lowered cGMP levels, while inhibition of sGC activity increased uPAR expression. Activation of the cGMP-dependant protein kinase G (PKG) prevented hypoxia-induced increases in uPAR expression and enhanced invasiveness. On the other hand a selective PKG inhibitor, increased uPAR expression. These findings reveal that hypoxia-induced increases in tumor cell invasiveness (and possibly metastasis) requires inhibition of the nitric oxide signaling pathway and that this process involves sGC and PKG activation. Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it is estimated that well over 1 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. Some cancers, notably of the breast and prostate, have 5-year survival rates in excess of 80%. However once tumors metastasize disease is not usually curable. The development of therapeutic strategies for the prevention and treatment of metastatic cancers thus represents a key priority for the pharmaceutical industry (see "Cancer Treatment 2002" a full analysis of current and future pharmaceutical approaches to cancer). Selective activators of PKG may offer one such therapeutic strategy.

Entry date October, 2002

Adapted from Postovit et al, J Biol Chem 2002 Sep 20;277(38):35730-7