Germline Met Mutations in Mice Reveal Mutation- and Background-Associated Differences in Tumor Profiles

BACKGROUND: The receptor tyrosine kinase Met is involved in the progression and metastasis of numerous human cancers. Although overexpression and autocrine activation of the Met signaling pathway are commonly found in human cancers, mutational activation of Met has been observed in small cell and non-small cell lung cancers, lung adenocarcinomas, renal carcinomas, and mesotheliomas. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the influence of mutationally activated Met in tumorigenesis, we utilized a novel mouse model. Previously, we observed that various Met mutations developed unique mutation-specific tumor spectra on a C57BL/6 background. Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met. For this purpose, we created congenic knock-in lines of the Met mutations D1226N, M1248T, and Y1228C on the FVB/N background. Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background. However, on the FVB/N background most developed a high incidence of mammary carcinomas with diverse histopathologies. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that on two distinct mouse backgrounds, Met is able to initiate tumorigenesis in multiple cell types, including epithelial, hematopoietic, and endothelial. Furthermore, these observations emphasize that even a modest increase in Met activation can initiate tumorigenesis with both the Met mutational spectra and host background having profound influence on the type of tumor generated. Greater insight into the interaction of genetic modifiers and Met signaling will significantly enhance our ability to tailor combination therapies for Met-driven cancers

Fibrosis of diaphragm muscle from 1-year-old <i>mdx</i> and wild type control mice after 22 weeks of treatment with saline or P-188 NF.

<p>Sections of diaphragms from the same groups of mice described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134832#pone.0134832.g001" target="_blank">Fig 1</a> were stained with Picosirius Red to visualize collagen deposition. All staining was done on diaphragm muscle from 12-month old mice with the exception of Panel B. Shown in the figure are cross sections of diaphragm muscle from: Panel A, wild type control saline-treated mouse; Panel B, a 7 month old <i>mdx</i> mouse; Panel C, an <i>mdx</i> saline-treated mouse; Panel D, an <i>mdx</i> mouse treated with 3 mg/Kg P-188 NF; Panel E, an <i>mdx</i> mouse treated with 1 mg/Kg prednisone.</p

Effect of P-188 NF on collagen composition in diaphragm muscle.

<p>Measurements of picosirius red staining were determined from in <i>mdx</i> (panel A) and dko mice (panel B) at the end of the respective treatment periods. All surviving mice were use in the analysis. Staining was quantified using Nikon Elements software to determine the percentage of area stained in each section. A minimum of 6 sections/diaphragm was assessed. The wild type saline group was significantly different from all other groups, ^#P < 0.0001. Panel A, ^** P <0.01 vs. <i>mdx</i> saline; Panel B ** P < 0.01 vs. dko saline.</p

Echocardiography results from wild type and <i>mdx</i> mice treated with saline or P-188 NF for 22 weeks from 7 months to 1 year of age.

<p>* P < 0.05 vs. mdx saline.</p><p>** All mice were 1 year old with 22 weeks treatment.</p><p>Echocardiography results from wild type and <i>mdx</i> mice treated with saline or P-188 NF for 22 weeks from 7 months to 1 year of age.</p

The main treatment effect on respiratory function in <i>mdx</i> mice over 22 weeks of treatment with saline or P-188 NF.

<p>¹ Two-way ANOVA using a multiple comparisons (main treatment effect) post-hoc test.</p><p>² All comparisons to <i>mdx</i> saline group; nd, not different; ns not significant.</p><p>**** P < 0.0001.</p><p>*** P = 0.001 to 0.0001.</p><p>** P = 0.01 to 0.001.</p><p>* P < 0.05.</p><p>The main treatment effect on respiratory function in <i>mdx</i> mice over 22 weeks of treatment with saline or P-188 NF.</p