UCSF Comprehensive Cancer Center researchers have identified genetic regions inmice that confer susceptibility and resistance to a human-like skin cancer,suggesting, they say, that mouse studies may reveal genetic markers ofsusceptibility and resistance to cancer in humans.
The researchers also determined that several of the regions discovered areassociated with survival time once cancer has developed -- the first suchregions ever reported.
The findings will be presented at the American Association for Cancer Researchmeeting on Wednesday (April 5) in San Francisco. Some of the findings werepublished in December in Proceedings of the National Academy of Science.
The mice used in the UCSF study developed cancer the way humans do - the tumorsarose at the normally occurring site of the disease and had genetic alterationssimilar to those seen in human tumors. In contrast, in traditional mouse modelsof cancer, a malignant tumor that has been grown for years in culture isimplanted under the skin of an immunodeficient mouse.
"These new models mimic natural conditions of cancer," says the senior authorof the study, Allan Balmain, PhD, UCSF professor of biochemistry. "They reflectthe growth rate of the tumor, the ability of the tumor to spread andmetastasize - they reflect everything you would see in humans."
Balmain's research program is part of a new consortium for studies of mousemodels of tumors that recently received support from the National CancerInstitute. Three other UCSF research programs, as well as those at 15 otherinstitutions, are also involved.
The identification of similar genetic markers in humans could directly impactthe screening and assessment of cancers in humans. "Accurate prediction oftumor growth rate and survival time would be enormously beneficial indetermining patient-specific treatment modalities, and could spare somepatients surgery and many patients unnecessarily harsh exposure to cytotoxictherapeutic drugs," says Balmain.
Moreover, he says, "If we could predict who has which variants of these genes,we could proactively assess people for the likelihood of susceptibility tocancer and recurrent tumors through blood tests."
The researchers conducted their study in two species of mice - one, known asMus musculus, has been inbred over many generations in the laboratory, so thatall of the animals in any one strain are genetically identical; the secondspecies, known as Mus spretus, is, by nature, highly resistant to tumordevelopment in several organs, such as the lung, skin, liver and colon.
The investigators made hybrids between these two types of mice to track thegenes responsible for making the spretus mice resistant to cancer. They exposedthe two species to cancer-causing agents, and then used genetic mappingtechniques to find regions of the genome that influence the number of benigntumors that formed, whether they progressed to malignancy, and at what rate.
The investigators identified ten genetic regions that significantly influencedtumor development. They also discovered a specific combination of a subset ofthe resistance-associated regions that was significantly associated withincreased survival time once a malignant tumor developed.
"The study shows that some of these variants are very potent at preventingcancer," says Balmain. Most likely, he says, the genes involved controldifferent aspects of the process leading to cancer, such as the growth rate ofcells and the ability of tumors to grow blood vessels that will then providethem with the nutrients they need to grow.
Notably, the UCSF researchers have discovered that some of the genes thatcontrol the susceptibility to skin cancer are in the same positions in themouse genome as those associated with susceptibility to colon and lung cancer.And this suggests, says Balmain, that there may be some "master" genes thatcontrol the development of multiple tumor types in different organs. Mostlikely there are also some genes that are tissue and organ specific.
The next step in the research, he says, is to move from the identification ofthe genetic regions to the genes themselves. From there, researchers couldbegin working to identify the proteins produced by these genes and themolecular chain of events - whether beneficial or harmful - that these proteinshelp to instigate. The final step would be developing drugs that either mimicor thwart this molecular outcome.
Significantly, the process of identifying individual genes in the mouse isbecoming increasingly efficient, thanks to progress on sequencing the overallmouse genome. Comparing gene regions that confer susceptibility or resistanceto cancer with a map that identifies each gene in the mouse genome will allowscientists to move in on the implicated genes more quickly. The sequencing ofthe mouse genome is expected to be completed within the next year.
Co-authors of the UCSF study are Hiroki Nagase, MD, formerly a visitingresearcher in the UCSF Comprehensive Cancer Center, and Jian-Hua Mao, PhD, anassociate specialist in the UCSF Comprehensive Cancer Center.
The study was funded by the Cancer Research Campaign (UK), Onyx Pharmaceuticalsand the UCSF Comprehensive Cancer Center.
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