Loss of function of vascular smooth muscle cells by nitric oxide-dependent and -independent interactions with tumorigenic cells.

Little is known about the interaction of tumor cells with host vascular smooth muscle cells. In reconstitution experiments, tumorigenic cell lines (including the rat hepatocarcinoma Morris 7777 and human melanoma M-21) were cultured for 17 hr in the presence of rat aortic rings, subsequently evaluated in contractility assays (response to phenylephrine and KCl). An agonist-independent loss of contractility was observed in rings pre-incubated with either tumorigenic cell lines or their conditioned medium (CM). The depressing effect of Morris cells depends largely on the expression of inducible nitric oxide synthase (iNOS) in smooth muscle cells and was reversed by an inhibitor of this enzyme; iNOS immunoreactivity was verified in some muscular vessels at the periphery of tumors formed by the Morris cell line in rats. The M-21 melanoma produces cytotoxicity in rat aortic rings (presence of single stranded DNA, cleavage of PARP, in differentiated smooth muscle only), accounting for the irreversible loss of contractility. The cytotoxicity produced by M-21 CM is not dependent on NO. Gel filtration of CM suggests that both the iNOS- and cytotoxicity-inducing substances from Morris hepatoma cells or M-21 cells, respectively, are mainly of low molecular weight (1 kDa or less). Other cell lines derived from rat or human tumors produce minimal effects on the rat aorta smooth muscle (H4-II-E-C3) or an irreversible anergy (RBL, MDA-MB-231, HEP-3B, HEP G2). The results emphasize that inhibition of vascular smooth muscle is relevant to tumor biology both by modulation of tumoral hemodynamics and by influencing the state of vessel maturation. (c) 2004 Wiley-Liss, Inc.