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Developmental
Biology of Cancer, Self-Tolerance and Autoimmunity 
We are genetically manipulating the mouse genome to model two complex
diseases: cancer and autoimmunity. Transgenic mouse models represent perturbations
that are providing insight into mechanism both of disease and of normal
development.
Tumor development is being studied in several cell types, including the
pancreatic islets, and the dermis and epidermis of the skin. In each case
oncogenes have been introduced into transgenic mice to endow the heritable
development of tissue-specific tumors. There are notable similarities
in these tumor development pathways, suggestive of common principles.
Current areas of investigation include: the multiple signals needed to
induce malignant proliferation; the possibility that programmed cell death
attempts to conteract such inappropriate proliferation; the positive and
negative regulators of tumor angiogenesis, the growth of new blood vessels;
and screens for new genes involved in these tumorigenesis pathways.
Immune self-tolerance and its relationship to autoimmunity is being modeled
by expression of a novel antigen, SV40 Tag, in the pancreatic beta cells,
which are destroyed by the immune system in type I diabetes. Families
of transgenic mice show two alternative phenotypes: self tolerance of
Tag, or autoimmunity. The tolerant mice express Tag in beta cells and
thymus during development, in contrast to the autoimmune mice, who first
express Tag as adults. We are characterizing cellular mechanisms and sites
of tolerance induction, and the parameters of autoimmunity. Current appproaches
include or-gan transplants of thymus and pancreas, and the use of transgenic
mice carrying a rearranged T cell receptor reactive to Tag, which allows
Tag-specific T-lymphocytes to be monitored in both tolerant and autoimmune
genetic backgrounds.
Selected Publications:
Parangi, S., Dietrich, W., Christofori, G., Lander, E., & Hanahan, D.
(1995). Tumor suppressor loci on mouse chromosomes 9 and 16 are lost at
distinct stages of tumorigenesis in a transgenic mouse model of islet
cell carcinoma. Cancer Research 55: 6071-6076.
Smith, K.M., Olson, D.C., Hirose, R. and Hanahan, D. Pancreatic gene expression
in rare cells of thymic medulla: evidence for functional contribution
to T cell tolerance. In press.
Arbeit, J., Howley, P., and Hanahan. D. (1996). Chronic estrogen induced
progressive cervical and vaginal squamous carcinogenesis in HPV16 transgenic
mice. PNAS 93: 2930-2935.
Naik, P.N., Karrim, J., and Hanahan, D. (1996). The rise and fall of apoptosis
during multistage tumorigenesis: down-modulation contributes to progression
from angiogenic progenitors. Genes Dev. 10: 2105-2116.
Hanahan, D. and Folkman, J. (1996). Patterns and emerging mechanisms of
the angiogenic switch during tumorigenesis. Cell 86: 353-364.
Contact Information:
Email: dh@biochem.ucsf.edu
Phone: 415/ 476.9209
Address: Box 0534, HSW 1047
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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