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Mouse
Models for the Study of Hum an
Cancer Susceptibility and Cancer Progression
Our laboratory is focussed on two major project areas:
1. Genetic dissection of the mechanisms of invasion and metastasis. Tumours
develop in both mice and humans as a consequence of sequential genetic
alterations at critical genomic loci. These changes involve mutations
in oncogenes such as ras, and in tumour suppressor loci, including the
p53and p16 genes. Our strategy has been to investigate the genetic alterations
which take place during mouse skin tumour development, and subsequently
to use both transgenic and knock-out mice to test the functions of candidate
genes in vivo. Genes implicated in multistage carcinogenesis include H-ras,
p53 and Transforming Growth Factor Beta (TGFb). Mice expressing TGFb develop
fewer papillomas than non-transgenic littermates, but have elevated rates
of tumour progression. This indicates that TGFb can act either positively
or negatively at different stages of carcinogenesis. We have proposed
that TGFb can act as a negative regulator of cell cycle progression during
the early phase of tumorigenesis, but positively induces invasion and
angiogenesis during progression to malignancy. This possibility is supported
by studies involving transfection of dominant negative TGFb type II receptor
constructs into invasive carcinoma cells. This results in suppression
of the invasive phenotype and the restoration of expression of some adhesion
proteins such as E-cadherin. We have shown that TGFb signalling can also
be upregulated by genetic alterations in highly malignant spindle carcinoma
cells. Many of the features characteristic of the invasive, metastatic
phenotype of these cells can be reversed by the introduction of dominant
negative interfering mutants that disrupt Smad signalling. Thresholds
of Smad activity are important at distinct stages of tumor progression,
cooperating with activated ras to induce invasion or dissemination to
distant sites (refs 1-4).
2. Identification of Genetic Modifiers of Cancer Susceptibility Another
class of genes that are important in tumor development are those that
control genetic predisposition. Studies of mouse models of human cancer
have demonstrated the existence of multiple tumor modifiers that influence
important parameters of cancer susceptibility such as tumour multiplicity,
size, or the probability of malignant progression. It is highly likely
that such tumor modifiers also segregate in humans, and play a major role
in determining cancer predisposition or the outcome of therapeutic intervention.
In previous work on skin carcinogenesis, we have mapped at least ten independent
tumor resistance loci in the spretus genome. Some of these affect the
early development of tumors, while others influence primarily tumor progression.
A specific subset of three of these modifier loci dramatically prolongs
the survival of tumor-bearing mice, suggesting that they modify either
tumor growth rate or the ability to invade and metastasize. Candidate
genes have been identified for several of these loci and further studies
on their identification are in progress (refs 5-8). Additional experiments
are in progress to map modifiers of susceptibility to mouse tumors of
the lung, prostate and lymphoid system, as well as to investigate candidate
human tumor modifiers using DNA samples from human cancer patients and
control populations.
Selected Publications:
Cui, W.; Fowlis, D.J.; Cousins, F.M.; Duffie, E.; Bryson, S.; Balmain,
A.; Akhurst, R.J., (1995) Concerted action of TGF-beta 1 and its type
II receptor in control of epidermal homeostatis in transgenic mice, Genes
Dev;9(8);945-55.
Nagase, H; Bryson, S.; Cordell, H.; Kemp, C.J.; Fee, F. and Balmain, A.,
(1995) Distinct genetic loci control development of benign and malignant
tumours in mice, Nat Genet (4):424-9.
Cui, W.; DFowlis, D.J.; Bryson, S.; Duffie, E.; Ireland, H.; Balmain,
A.; Akhurst, R.J., (1996) TGFbeta1 inhibits the formation of benign skin
tumors, but enhances the progression to invasive spindle carcinomas in
transgenic mice, Cell;86(4):531-42.
Portella, G.; Cumming, S.A.; Liddell, J.; Cui, W.; Ireland, H.; Akhurst,
R. and Balmain, A, (1998) TGF-b is essential for spindle cell conversion
of mouse skin carcinoma in vivo: Implications for tumour invasion, Cell
Growth Differ 9:393-404.
Balmain, A. and Nagase, H., (1998) Cancer resistance genes in mice: models
for the study of tumour modifiers, Trends in Genetics, 14, 139-44.
A subset of skin tumor modifier loci determines survival time of tumor-bearing
mice. (1999) Nagase H, J-H.Mao and A.Balmain.: Proc Natl Acad Sci U S
A. Dec 21;96(26):15032-7.
Petritsch,C, Beug,H., Balmain, A., and Oft, M.(2000) TGF-b inhibits p70S6
Kinase via Protein Phosphatase 2A to induced G1 arrest, Genes Dev., in
press.
Frame,S. and Balmain, A. (2000) Integration of positive and negative growth
signals during ras pathway activation in vivo Curr Op.Genet Dev., in press.
Contact Information:
Email: abalmain@cc.ucsf.edu
Phone: 415/502-4192
Address: Box 0128
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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