Reference SummaryGraveel C, Proc Natl Acad Sci U S A 2004 Dec 7;101(49):17198-203

Title

Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele.

Authors

Graveel C; Su Y; Koeman J; Wang LM; Tessarollo L; Fiscella M; Birchmeier C; Swiatek P; Bronson R; Vande Woude G

Journal

Proc Natl Acad Sci U S A

Volume

101

Issue

49

Year

2004

Pages

17198-203

Abstract

Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas as well as in other cancers. These mutations have been examined in several in vitro systems, where they cause constitutive Met activation, focus formation, and cell motility, and are tumorigenic in xenografts. To study the influence of these mutations on tumorigenesis in vivo, we generated mice with targeted mutations in the murine met locus. The following five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. We observed that mice harboring D1226N, Y1228C(,) and M1248T/L1193V mutations developed a high frequency of sarcomas and some lymphomas, whereas the M1248T mice developed carcinomas and lymphomas. Of considerable interest, we observed trisomy of chromosome 6 and duplication of the mutant met allele in a majority of the tumors, similar to what has been reported in patients with hereditary renal papillary carcinomas. These results demonstrate that activating Met mutations and met amplification play key roles in promoting tumorigenesis in vivo. Moreover, our findings show that different mutations in the Met kinase domain can influence the types of cancers that develop.

Links

J:94722 – Mouse Genome Informatics
15557554 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129-Mettm2Gvw/+ Blood vessel hemangiosarcoma Blood vessel

5.26

B6;129-Mettm4Gvw/+ Blood vessel hemangiosarcoma Blood vessel

observed

B6;129-Mettm3Gvw Blood vessel hemangiosarcoma Blood vessel

observed

B6;129-Mettm2Gvw/+ Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

5.26

B6;129-Mettm4Gvw/+ Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

observed - 5.56

B6;129-Mettm3Gvw Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

observed

B6;129-Mettm2Gvw/+ Connective tissue myxoma Connective tissue

5.26

B6;129-Mettm1Gvw/+ Intestine - Large Intestine - Anus squamous cell carcinoma Intestine - Large Intestine - Anus

5.88

B6;129-Mettm2Gvw/+ Leukocyte - Lymphoblast lymphoma - lymphoblastic Leukocyte - Lymphoblast

5.26

B6;129-Mettm4Gvw/+ Leukocyte - Lymphoblast lymphoma - lymphoblastic Leukocyte - Lymphoblast

5.56

B6;129-Mettm5Gvw/+ Leukocyte - Lymphoblast lymphoma - lymphoblastic Leukocyte - Lymphoblast

observed

B6;129-Mettm1Gvw/+ Leukocyte - Lymphocyte - B-lymphocyte - Follicular center cell lymphoma - follicular Leukocyte - Lymphocyte - B-lymphocyte - Follicular center cell

5.88

B6;129-Mettm1Gvw/+ Leukocyte - Lymphocyte lymphoma - lymphocytic Leukocyte - Lymphocyte

5.88

B6;129-Mettm1Gvw/+ Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Leukocyte - Monocyte - Macrophage - Histiocyte

observed

B6;129-Mettm2Gvw/+ Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Leukocyte - Monocyte - Macrophage - Histiocyte

observed

B6;129-Mettm4Gvw/+ Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Leukocyte - Monocyte - Macrophage - Histiocyte

5.56

B6;129-Mettm5Gvw/+ Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Leukocyte - Monocyte - Macrophage - Histiocyte

11.11

B6;129-Mettm1Gvw/+ Leukocyte lymphoma Leukocyte

observed

B6;129-Mettm2Gvw/+ Leukocyte lymphoma Leukocyte

observed

B6;129-Mettm3Gvw Leukocyte lymphoma Leukocyte

0

B6;129-Mettm5Gvw/+ Leukocyte lymphoma Leukocyte

observed

B6;129-Mettm1Gvw/+ Liver hepatoma Liver

5.88

B6;129-Mettm4Gvw/+ Liver hepatoma Liver

5.56

B6;129-Mettm1Gvw/+ Lung adenocarcinoma Lung

5.88

B6;129-Mettm5Gvw/+ Lung adenocarcinoma Lung

11.11

B6;129-Mettm1Gvw/+ Lung adenoma Lung

5.88

B6;129-Mettm5Gvw/+ Lung adenoma Lung

11.11

B6;129-Mettm1Gvw/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

0

B6;129-Mettm2Gvw/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed

B6;129-Mettm4Gvw/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed

B6;129-Mettm3Gvw Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

observed

B6;129-Mettm5Gvw/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

0

B6;129-Mettm4Gvw/+ Mesodermal cell/mesoblast sarcoma - spindle cell Mesodermal cell/mesoblast

5.56

B6;129-Mettm4Gvw/+ Muscle - Smooth leiomyosarcoma Muscle - Smooth

5.56

B6;129-Mettm1Gvw/+ Ureter transitional cell carcinoma Ureter

5.88

B6;129-Mettm1Gvw/+ (Unspecified organ) adenocarcinoma - basosquamous (Unspecified organ)

5.88

B6;129-Mettm1Gvw/+ (Unspecified organ) carcinoma (Unspecified organ)

observed

B6;129-Mettm2Gvw/+ (Unspecified organ) carcinoma (Unspecified organ)

0

B6;129-Mettm4Gvw/+ (Unspecified organ) carcinoma (Unspecified organ)

observed

B6;129-Mettm3Gvw (Unspecified organ) carcinoma (Unspecified organ)

0

B6;129-Mettm5Gvw/+ (Unspecified organ) carcinoma (Unspecified organ)

observed

B6;129-Mettm1Gvw/+ (Unspecified organ) tumor (Unspecified organ)

5.88 - 58.82

B6;129-Mettm2Gvw/+ (Unspecified organ) tumor (Unspecified organ)

89.47

B6;129-Mettm4Gvw/+ (Unspecified organ) tumor (Unspecified organ)

observed - 50

B6;129-Mettm3Gvw (Unspecified organ) tumor (Unspecified organ)

observed - 83.33

B6;129-Mettm5Gvw/+ (Unspecified organ) tumor (Unspecified organ)

11.11 - 44.44