No abstract

The tyrosine kinase receptor Ron has been implicated in several types of cancer, including overexpression in human breast cancer. This is the first report describing the effect of Ron signaling on tumorigenesis and metastasis in a mouse model of breast cancer. Mice with a targeted deletion of the Ron tyrosine kinase signaling domain (TKÀ/À) were crossed to mice expressing the polyoma virus middle T antigen (pMT) under the control of the mouse mammary tumor virus promoter. Both pMT-expressing wild-type control (pMT+/À TK+/+) and pMT+/À TKÀ/À mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation and growth was found in the pMT+/À TKÀ/À mice compared with controls. An examination of mammary tumors showed that there was a significant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminal deoxynucleotidyl transferase-mediated nick end labelingpositive staining in mammary tumor cells from the pMT+/À TKÀ/À mice compared with the pMT+/À TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ and TKÀ/À tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TKÀ/À tumors have deficits in mitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to induce mammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and through proliferative and cell survival pathways regulated by mitogen-activated protein kinase and AKT. (Cancer Res 2005; 65(4): 1285-93)

T he Ron receptor tyrosine kinase (TK), also known as stem cell-derived TK, is a heterodimeric single-span transmembrane glycoprotein involved in a wide range of biologic processes, including modulation of inflammatory responses. [1][2][3][4] The intracellular signaling responses of Ron and its only known ligand, the kringle-containing hepatocyte growth factor-like protein, also known as macrophage-stimulating protein, have been studied largely in vitro in resident peritoneal macrophages. To explore the role of the Ron receptor in vivo, our laboratory generated mice with the deletion of the TK domain of the Ron receptor (Ron TK Ϫ/Ϫ mice). 1 Ron TK Ϫ/Ϫ mice have no overt phenotypic abnormalities; however, the responses of Ron TK Ϫ/Ϫ and other Ron receptor mutant mice in several experimental murine models of inflammation, including injection of endotoxin, are markedly exaggerated compared with Ron TK ϩ/ϩ mice. 1,2,5 Very little is known about the biology of the Ron receptor in the liver, either in vitro or in vivo. Ron messenger RNA and protein have been detected in liver tissue, 6,7 and Ron protein has been localized by immunohistochemistry to the hepatocyte and Kupffer cell populations. 8 Given the observations previously noted with Ron TK Ϫ/Ϫ mice, we hypothesized that mice lacking functional Ron receptor would have exaggerated responses in experimental murine models of lipopolysaccharide (LPS)-and Kupffer cell-mediated liver injury.We tested our hypothesis using a well-characterized LPS-induced murine model of acute liver failure (ALF) in galactosamine (GalN)-sensitized mice. 9-11 LPS-induced

Acute lung injury (ALI), a severe respiratory syndrome, develops in response to numerous insults and responds poorly to therapeutic intervention. Recently, cDNA microarray analyses were performed that indicated several pathogenic responses during nickel-induced ALI, including marked macrophage activation. Macrophage activation is mediated, in part, via the receptor tyrosine kinase Ron. To address the role of Ron in ALI, the response of mice deficient in the cytoplasmic domain of Ron (Ron tk-/-) were assessed in response to nickel exposure. Ron tk-/- mice succumb to nickel-induced ALI earlier, express larger, early increases in interleukin-6, monocyte chemoattractant protein-1, and macrophage inflammatory protein-2, display greater serum nitrite levels, and exhibit earlier onset of pulmonary pathology and augmented pulmonary tyrosine nitrosylation. Increases in cytokine expression and cellular nitration can lead to tissue damage and are consistent with the differences between genotypes in the early onset of pathology and mortality in Ron tk-/- mice. These analyses indicate a role for the tyrosine kinase receptor Ron in ALI.