Incidence and distribution of experimental metastases in mutant mice with defective organ microenvironments (genotypes Sl/Sld and W/Wv).

Abstract

Mice carrying mutations at the Sl (steel) and W (dominant white spotting) loci develop abnormalities on 3 migratory embryonic stem cell populations: hematopoietic stem cells, neural crest-derived melanocytes, and primordial germ cells. Transplantation experiments have indicated that the Sl locus affects the microenvironment where stem cells migrate, proliferate, and differentiate, while the W locus affects the migratory cells themselves. The Sl locus encodes for a multipotent growth factor known as stem cell factor. The W locus encodes the c-kit protein tyrosine kinase receptor whose ligand is the stem cell factor. We have investigated the incidence and organ distribution of experimental metastases after systemic intra-arterial injection of B16-G3.26 melanoma cells into mutant Sl/Sld and W/Wv mice. Both mutant mouse strains had a markedly lower incidence of ovarian metastases when compared with their congenic +/+ mice. In contrast to the rare colonization of the ovaries, Sl/Sld and W/Wv mice developed metastases in the myocardium, kidney, and stomach--anatomic sites that were infrequently or never affected in their congenic nonmutant mice. The only organs in which the average number of metastatic colonies differed between Sl/Sld and W/Wv mice were the bone marrow and kidneys. The average number of colonized bones per mouse in the Sl/Sld group was 5.0 +/- 3.1 (SD), compared with 12.7 +/- 5.3 in the W/Wv group. The average number of metastatic nodules in the kidneys of Sl/Sld mice was 24.6 +/- 9, while W/Wv mice had 15.5 +/- 2.5. Mutant mice with multiple metastatic nodules in the kidneys, heart, and stomach were also found to have forestomach papillomas, an enlarged duodenum, kidney abnormalities, and small body size. The results of this study provide useful information on potential mechanisms of interaction of metastatic cells with their target organs, and suggest that there are additional organ defects associated with the mutations in the Sl and W loci. They also document the importance of mutant mice in metastasis research.