Macrophage priming and activation during fibrosarcoma growth: expression of c-myb, c-myc, c-fos, and c-fms

Abstract

Macrophages (M phi)3 function by a two-step process that includes priming (induction of cytokine and enzyme mRNA) and activation (production of effector molecules). The initial steps in M phi priming involve the expression of certain proto-oncogenes that regulate expression of other genes. Because tumor growth primes M phi to produce several suppressor monokines, we determined if cancer induced M phi expression of these proto-oncogenes. Unstimulated peritoneal M phi from tumor-bearing hosts (TBH) constitutively expressed the proto-oncogenes c-fms, c-fos, c-myc, and c-myb, whereas normal host (NH) M phi had little or no expression of these proto-oncogenes. When M phi were given a 24-h adherence priming stimulus, NH M phi expressed c-fms and c-fos at levels equivalent to TBH M phi constitutive expression. Adherence had little or no effect on c-fms and c-fos expression in TBH M phi or on NH and TBH M phi c-myc expression. c-myb expression was not induced in NH M phi during adherence and was strongly decreased in TBH M phi. Activation with a 1-h lipopolysaccharide-treatment increased NH and TBH M phi expression of c-fms, c-fos, and c-myc, with higher expression of these proto-oncogenes in TBH M phi. Activation failed to induce c-myb expression in NH M phi and completely inhibited expression in TBH M phi. Because c-fms, c-fos, and c-myc are normally expressed early during M phi activation, our results suggest that tumor growth primes M phi by inducing expression of these proto-oncogenes. c-myb is expressed in immature M phi and is downregulated during M phi activation. These observations explain why NH M phi expression of c-myb was not induced and are consistent with reports that suggest TBH M phi have not reached full developmental maturity. The induction of M phi proto-oncogene expression during cancer may put M phi in a primed state, which leads to earlier and stronger production of adverse suppressor and cytotoxic molecules.