During the past five years we have been developing transgenic models of oncogenesis and studying their characteristics. In these experiments the transforming oncogenes from simian virus 40 (SV40), activated ras, and c-myc have been expressed in liver or pancreas to create several heritable and predictable tumor phenotypes. In these models at least one additional event, the activation of another oncogenic element or the loss of a tumor suppressor factor, appears to be necessary for final transformation to a complete malignant phenotype. Since the basic pattern of the premalignant condition and eventual tumorigenesis is clearly defined in these unique transgenic lines, other genes can now be introduced into mice and expressed in transformed liver or pancreas to determine their influence on the course of tumor formation and progression. Several classes of genes believed to be intricately involved in tumor development (e.g. growth factors, proteases, and antioncogenes) are ideal candidates to study for their effect on tumor phenotypes resulting from oncogenes. Therefore, new lines of mice will be generated that express these genes, and they will be characterized and then crossed to lines of mice that show an oncogene-induced phenotype. The effect of expression of each gene on tumor growth, invasion, and metastasis will then be assessed. We have three specific aims: 1. We will determine if growth factors (including transforming factor alpha, cholecystokinin, and angiogenin) influence the development and progression of tumors induced by transgenic oncogenes. 2. We will determine if proteases (including collagenase, stromelysin/transin, and urokinase) enhance the invasive or metastatic capability of tumors induced by transgenic oncogenes. 3. We will determine if expression of """"""""tumor suppressor"""""""" genes, (including retinoblastoma and gap junction) interferes with the progression of tumors induced by transgenic oncogenes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038635-07
Application #
3176742
Study Section
Pathology B Study Section (PTHB)
Project Start
1985-01-01
Project End
1994-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Sandgren, E P; Schroeder, J A; Qui, T H et al. (1995) Inhibition of mammary gland involution is associated with transforming growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice. Cancer Res 55:3915-27
Rhim, J A; Sandgren, E P; Palmiter, R D et al. (1995) Complete reconstitution of mouse liver with xenogeneic hepatocytes. Proc Natl Acad Sci U S A 92:4942-6
Quaife, C J; Hoyle, G W; Froelick, G J et al. (1994) Visualization and ablation of phenylethanolamine N-methyltransferase producing cells in transgenic mice. Transgenic Res 3:388-400
Hammang, J P; Behringer, R R; Baetge, E E et al. (1993) Oncogene expression in retinal horizontal cells of transgenic mice results in a cascade of neurodegeneration. Neuron 10:1197-209
Cullen, J M; Sandgren, E P; Brinster, R L et al. (1993) Histologic characterization of hepatic carcinogenesis in transgenic mice expressing SV40 T-antigens. Vet Pathol 30:111-8
Luetteke, N C; Lee, D C; Palmiter, R D et al. (1993) Regulation of fat and muscle development by transforming growth factor alpha in transgenic mice and in cultured cells. Cell Growth Differ 4:203-13
Sandgren, E P; Luetteke, N C; Qiu, T H et al. (1993) Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol 13:320-30
Sandgren, E P; Palmiter, R D; Heckel, J L et al. (1992) DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice. Proc Natl Acad Sci U S A 89:11523-7
Messing, A; Behringer, R R; Hammang, J P et al. (1992) P0 promoter directs expression of reporter and toxin genes to Schwann cells of transgenic mice. Neuron 8:507-20
Gibson, C W; Lally, E; Herold, R C et al. (1992) Odontogenic tumors in mice carrying albumin-myc and albumin-rats transgenes. Calcif Tissue Int 51:162-7

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