UCSF Comprehensive Cancer Center researchers have identified genetic regions in mice that confer susceptibility and resistance to a human-like skin cancer, suggesting, they say, that mouse studies may reveal genetic markers of susceptibility and resistance to cancer in humans.
The researchers also determined that several of the regions discovered are associated with survival time once cancer has developed -- the first such regions ever reported.
The findings will be presented at the American Association for Cancer Research meeting on Wednesday (April 5) in San Francisco. Some of the findings were published in December in Proceedings of the National Academy of Science.
The mice used in the UCSF study developed cancer the way humans do -- the tumors arose at the normally occurring site of the disease and had genetic alterations similar to those seen in human tumors. In contrast, in traditional mouse models of cancer, a malignant tumor that has been grown for years in culture is implanted under the skin of an immunodeficient mouse.
"These new models mimic natural conditions of cancer," says the senior author of the study, Allan Balmain, PhD, UCSF professor of biochemistry. "They reflect the growth rate of the tumor, the ability of the tumor to spread and metastasize -- they reflect everything you would see in humans."
Balmain's research program is part of a new consortium for studies of mouse models of tumors that recently received support from the National Cancer Institute. Three other UCSF research programs, as well as those at 15 other institutions, are also involved.
The identification of similar genetic markers in humans could directly impact the screening and assessment of cancers in humans. "Accurate prediction of tumor growth rate and survival time would be enormously beneficial in determining patient-specific treatment modalities, and could spare some patients surgery and many patients unnecessarily harsh exposure to cytotoxic therapeutic 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 to cancer and recurrent tumors through blood tests."
The researchers conducted their study in two species of mice - one, known as Mus musculus, has been inbred over many generations in the laboratory, so that all of the animals in any one strain are genetically identical; the second species, known as Mus spretus, is, by nature, highly resistant to tumor development in several organs, such as the lung, skin, liver and colon.
The investigators made hybrids between these two types of mice to track the genes responsible for making the spretus mice resistant to cancer. They exposed the two species to cancer-causing agents, and then used genetic mapping techniques to find regions of the genome that influence the number of benign tumors that formed, whether they progressed to malignancy, and at what rate.
The investigators identified ten genetic regions that significantly influenced tumor development. They also discovered a specific combination of a subset of the resistance-associated regions that was significantly associated with increased survival time once a malignant tumor developed.
"The study shows that some of these variants are very potent at preventing cancer," says Balmain. Most likely, he says, the genes involved control different aspects of the process leading to cancer, such as the growth rate of cells and the ability of tumors to grow blood vessels that will then provide them with the nutrients they need to grow.
Notably, the UCSF researchers have discovered that some of the genes that control the susceptibility to skin cancer are in the same positions in the mouse genome as those associated with susceptibility to colon and lung cancer. And this suggests, says Balmain, that there may be some "master" genes that control the development of multiple tumor types in different organs. Most likely 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 of the genetic regions to the genes themselves. From there, researchers could begin working to identify the proteins produced by these genes and the molecular chain of events - whether beneficial or harmful - that these proteins help to instigate. The final step would be developing drugs that either mimic or thwart this molecular outcome.
Significantly, the process of identifying individual genes in the mouse is becoming increasingly efficient, thanks to progress on sequencing the overall mouse genome. Comparing gene regions that confer susceptibility or resistance to cancer with a map that identifies each gene in the mouse genome will allow scientists to move in on the implicated genes more quickly. The sequencing of the mouse genome is expected to be completed within the next year.
Co-authors of the UCSF study are Hiroki Nagase, MD, formerly a visiting researcher in the UCSF Comprehensive Cancer Center, and Jian-Hua Mao, PhD, an associate specialist in the UCSF Comprehensive Cancer Center.
The study was funded by the Cancer Research Campaign (UK), Onyx Pharmaceuticals and the UCSF Comprehensive Cancer Center.