Jaime F. Modiano
Integrated Department
of Immunology; AMC Cancer Research Center of the University of Colorado Cancer Center; University of Colorado Health Sciences
Center, Denver, CO
The
last three decades have produced significant advances in our understanding of why cancer arises. The initial discoveries of viral genes that could transform cells and cause tumors (hence called oncogenes)
were followed by the recognition that these genes had cellular counterparts that regulated growth and proliferation (called
proto-oncogenes). Shortly thereafter, it became clear that to the “yin”
of oncogenes there was a “yang”, that is, there were genes that prevented growth and proliferation of normal cells,
and that their dysfunction could also lead to tumors. These were called “tumor
suppressor genes”, and much work has been devoted to understand their roles in sporadic (non-heritable) cancers as well
as in heritable cancer syndromes.
Several dozen-tumor suppressor genes have been identified
in humans and laboratory animals, and results from the AMC Cancer Research Center lab and others show that the function of
every tumor suppressor analyzed to date is evolutionarily conserved in dogs. However,
various important and intriguing questions remain regarding the role of tumor suppressor genes in cancer, such as why does
a deficiency in a given gene that is a global regulator of cell proliferation lead to very specific kinds of tumors, and also
how can individuals who share the same risk exhibit much different disease incidence and outcomes? The answers to these questions are likely to be multifactorial. An
obvious component is the interaction with environment. But, just as the similarities
between humans and dogs allow us to use data from the disease in one species to understand the disease in the other, some
of the differences among these species, for example, the relative prevalence of carcinomas versus sarcomas, indicate that
environmental factors are unlikely to account for the observed tumor specificity or the differences in relative risk.
In hindsight, part of the problem we have faced
is that, by focusing on individual genes, we tended to lose the forest for the trees.
The recognition that the products of proto-oncogenes and tumor suppressor genes are members of non-linear, interactive
biochemical cascades or pathways has offered glimpses into the nature of specificity and risk.
Thus, a single protein can interact in different ways in different cells to achieve different functional outcomes,
so loss of a tumor suppressor protein may increase the probability of transformation in one cell type, but not in another. Yet, if we focus on the pathway rather than the gene, we find that most or all tumors
share common functional (if not genetic) lesions. More importantly, identifying
the genes within a pathway that account for specificity may help us outline those genes that underlie the relative risk in
individuals (or in breeds of dogs). This presentation will show various examples
of how different canine tumors achieve inactivation of two central tumor suppressor gene pathways, and offer insights into
future work that will allow us to design better strategies for treatment and prevention.
