Macrophage Priming and Activation During Fibrosarcoma Growth: Expression of c-myb, c-myc, c-fos, and c-fms

Abstract

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