Limits...
Germline met mutations in mice reveal mutation- and background-associated differences in tumor profiles.

Graveel CR, DeGroot JD, Sigler RE, Vande Woude GF - PLoS ONE (2010)

Bottom Line: Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met.Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America. carrie.graveel@vai.org

ABSTRACT

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.

Show MeSH

Related in: MedlinePlus

Met activation and expression is increased in FVB-MetM1248T/L1193V mammary tumors.Western blot analysis of immunoprecipiated lysates showed increased Met activation (phospho-Met) and expression in mammary tumors isolated from FVB-MetM1248T/L1193V mice compared to normal FVB-MetM1248T/L1193V mammary pads. Met activation and expression was increased in all of the pathologic types observed in the FVB-MetM1248T/L1193V mammary tumors.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2963642&req=5

pone-0013586-g004: Met activation and expression is increased in FVB-MetM1248T/L1193V mammary tumors.Western blot analysis of immunoprecipiated lysates showed increased Met activation (phospho-Met) and expression in mammary tumors isolated from FVB-MetM1248T/L1193V mice compared to normal FVB-MetM1248T/L1193V mammary pads. Met activation and expression was increased in all of the pathologic types observed in the FVB-MetM1248T/L1193V mammary tumors.

Mentions: Because we observed distinct tumor profiles among the Met mutant lines on the B6 background, the mutation-specific differences we observed on the FVB background were not unexpected. The occurrence of diverse tumor patterns on two backgrounds confirmed that the germline Met mutations induce tumorigenesis in multiple cell types. However, there appeared to be mutation-specific variation among the mammary tumor histopathology. As previously mentioned, the FVB-MetM1248T/L1193V mice had the most penetrant mammary tumorigenic phenotype (Table 2). In addition, the mammary tumors that developed in FVB-MetM1248T/L1193V females had a wide range of pathological diversity [24], including squamous metaplasia, solid and tubular patterns, and myoepitheliomas (Figure 3A–B). In contrast, FVB-MetM1248T mammary tumors displayed only tubular and acinar patterns without any observed squamous metaplasia (Figure 3C–D). The histological appearance of FVB-MetY1228C mammary tumors was more consistent with that of the FVB-MetM1248T/L1193V phenotype, where 60% of FVB-MetY1228C mammary tumors contained significant squamous metaplasia and 40% displayed solid and tubular patterns (Figure 3E–F). We also observed mammary hyperplasia in 2 of 21 FVB-MetY1228C mice. Increased Met activation and expression was present in each of the FVB-MetM1248T/L1193V mammary tumor types (Figure 4). All tumors found in the FVB-MetM1248T, FVB-MetY1228C, and FVB-MetD1226N mice were unifocal (62 total animals) whereas multifocal tumors were identified in 6 FVB-MetM1248T/L1193V females (of 56 total) characterized. Although multifocal mammary tumors are not unique in mouse models, the fact that the multifocal FVB-MetM1248T/L1193V tumors had distinct morphologic patterns is uncommon. The most remarkable case was a FVB-MetM1248T/L1193V mouse that developed two contiguous tumors with distinctive morphologic characteristics in the mammary pad (Figure 5A). These tumors had distinct, closely opposed borders consistent with expansile growth of both tumors. These contiguous tumors included an adenocarcinoma with squamous metaplasia and fibromatous changes (Figure 5B) and an adenocarcinoma with solid patterns (Figure 5C). These distinctive tumors, along with the other FVB-MetM1248T/L1193V mice that developed multiple distinctive mammary tumors, suggests that mutationally activated Met is being expressed in a progenitor population leading to diverse mammary pathology.


Germline met mutations in mice reveal mutation- and background-associated differences in tumor profiles.

Graveel CR, DeGroot JD, Sigler RE, Vande Woude GF - PLoS ONE (2010)

Met activation and expression is increased in FVB-MetM1248T/L1193V mammary tumors.Western blot analysis of immunoprecipiated lysates showed increased Met activation (phospho-Met) and expression in mammary tumors isolated from FVB-MetM1248T/L1193V mice compared to normal FVB-MetM1248T/L1193V mammary pads. Met activation and expression was increased in all of the pathologic types observed in the FVB-MetM1248T/L1193V mammary tumors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963642&req=5

pone-0013586-g004: Met activation and expression is increased in FVB-MetM1248T/L1193V mammary tumors.Western blot analysis of immunoprecipiated lysates showed increased Met activation (phospho-Met) and expression in mammary tumors isolated from FVB-MetM1248T/L1193V mice compared to normal FVB-MetM1248T/L1193V mammary pads. Met activation and expression was increased in all of the pathologic types observed in the FVB-MetM1248T/L1193V mammary tumors.
Mentions: Because we observed distinct tumor profiles among the Met mutant lines on the B6 background, the mutation-specific differences we observed on the FVB background were not unexpected. The occurrence of diverse tumor patterns on two backgrounds confirmed that the germline Met mutations induce tumorigenesis in multiple cell types. However, there appeared to be mutation-specific variation among the mammary tumor histopathology. As previously mentioned, the FVB-MetM1248T/L1193V mice had the most penetrant mammary tumorigenic phenotype (Table 2). In addition, the mammary tumors that developed in FVB-MetM1248T/L1193V females had a wide range of pathological diversity [24], including squamous metaplasia, solid and tubular patterns, and myoepitheliomas (Figure 3A–B). In contrast, FVB-MetM1248T mammary tumors displayed only tubular and acinar patterns without any observed squamous metaplasia (Figure 3C–D). The histological appearance of FVB-MetY1228C mammary tumors was more consistent with that of the FVB-MetM1248T/L1193V phenotype, where 60% of FVB-MetY1228C mammary tumors contained significant squamous metaplasia and 40% displayed solid and tubular patterns (Figure 3E–F). We also observed mammary hyperplasia in 2 of 21 FVB-MetY1228C mice. Increased Met activation and expression was present in each of the FVB-MetM1248T/L1193V mammary tumor types (Figure 4). All tumors found in the FVB-MetM1248T, FVB-MetY1228C, and FVB-MetD1226N mice were unifocal (62 total animals) whereas multifocal tumors were identified in 6 FVB-MetM1248T/L1193V females (of 56 total) characterized. Although multifocal mammary tumors are not unique in mouse models, the fact that the multifocal FVB-MetM1248T/L1193V tumors had distinct morphologic patterns is uncommon. The most remarkable case was a FVB-MetM1248T/L1193V mouse that developed two contiguous tumors with distinctive morphologic characteristics in the mammary pad (Figure 5A). These tumors had distinct, closely opposed borders consistent with expansile growth of both tumors. These contiguous tumors included an adenocarcinoma with squamous metaplasia and fibromatous changes (Figure 5B) and an adenocarcinoma with solid patterns (Figure 5C). These distinctive tumors, along with the other FVB-MetM1248T/L1193V mice that developed multiple distinctive mammary tumors, suggests that mutationally activated Met is being expressed in a progenitor population leading to diverse mammary pathology.

Bottom Line: Here, we assessed the effect of genetic background on the tumorigenic potential of mutationally activated Met.Consistent with the mutation-specific tumor spectra, several of the mutations were associated with the same tumor types as observed on C57BL/6 background.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan, United States of America. carrie.graveel@vai.org

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus