Mouse Genome Informatics

involves: FVB/N * NMRI
phenotype observed in females
phenotype observed in males
N normal phenotype
• mice from 2 lines (1 and 2) of double transgenic founders die within 2 months postpartum; early mortality can be prevented by repression of MET expression with doxycycline administration to mating parents, and then to pups until 4 weeks of age
• with this doxycycline treatment, animals appear normal until 10 months of age, then mice start dying
• mice from 2 other lines (3 and 4) of double transgenic parents are healthy at birth, then begin to die at 4 months of age

• animals dying without evidence of tumors are usually cachexic

liver/biliary system
• hepatocytes in foci of hyperplasia develop foamy cytoplasm containing fat deposits
• with progression of hyperplastic foci toward malignancy, cytologic changes are observed such as cellular and nuclear enlargement with disorganization of cell plate and lobular structures; malignant foci enlarge and develop trabeculae lined with endothelial cells, often separated from each other by blood-filled spaces
• pups are born with enlarged and fatty livers
• fully developed tumors often display areas of necrosis
• pups are born with enlarged and fatty livers
• animals dying without evidence of tumors display jaundice

• 85% of animals dying after 10 months after receiving DOX till 4 weeks of age show hepatocellular carcinoma (HCC); incidence by 1 year is >60% in lines 1 and 2
• for lines 3 and 4, 85% of deaths are accompanied by HCC, which appears as an abdominal mass at 6 months of age or later; incidence by 1 year is 60%
• by 60 weeks of age, many small foci of hyperplasia are detected, often around central hepatic lobule and become more numerous, larger, and uniformly distributed by 4 months of age
• zones of progression to malignancy are observed within hyperplasias by 6 months, with cells in the zones showing poor organization and less differentiation than normal livers
• majority of moribund mice treated with doxycycline regain health tumors nearly regress completely, with liver morphology becoming almost normal by 4 months of treatment
• fully developed tumors often display areas of necrosis

Mouse Models of Human Disease
Hepatocellular Carcinoma 114550 J:69731