ROLE OF NITRIC-OXIDE IN TUMOR PROGRESSION - LESSONS FROM EXPERIMENTAL-TUMORS

Nitric oxide (NO), a potent biological mediator, plays a key role in p hysiological as well as pathological processes, including inflammation and cancer. The role of NO in tumor biology remains incompletely unde rstood. While a few reports indicate that the presence of NO in tumor cells or their microenvironment is detrimental to tumor cell survival and consequently their metastatic ability, a large body of clinical an d experimental data suggest a promoting role of NO in tumor progressio n and metastasis. We suggest that tumor cells capable of very high lev els of NO production die in vivo, and those producing or exposed to lo wer levels of NO, or capable of resisting NO-mediated injury undergo a clonal selection because of their survival advantage; they also utili ze certain NO-mediated mechanisms for promotion of growth, invasion an d metastasis. The possible mechanism(s) are: (a) a stimulatory effect on tumor cell invasiveness, (b) a promotion of tumor angiogenesis and blood flow in the tumor neovasculature, and (c) a suppression of host anti-tumor defense. In this review, we discuss these mechanisms on the basis of data derived from experimental models, in particular, a mous e mammary tumor model in which the expression of eNOS by tumor cells i s positively correlated with invasive and metastatic abilities. Tumor- derived NO was shown to promote tumor cell invasiveness and angiogenes is. The invasion-stimulating effects of NO were due to an upregulation of matrix metalloproteases and a downregulation of their natural inhi bitors. Treatment of tumor-bearing mice with NO-blocking agents reduce d the growth and vascularity of primary tumors and their spontaneous m etastases. We propose that selected NO-blocking drugs may be useful in treating certain human cancers either as single agents or as a part o f combination therapies.