With the multitude of genetic information found in the human genome, how do scientists determine whether a single gene plays an important role in the development and progression of cancer?
"Sometimes you have to start with a simpler model system that you can manipulate," said Dr. Christopher Kemp, an investigator in the Human Biology Division whose laboratory studies tumor formation in mice. The mouse has played a key role as a model in helping scientists understand the development of human cancer.
"The clearest example of the power of laboratory mice is to establish a causal role for a single gene in tumor suppression," he said.
To make the link between a gene and its role in cancer development, scientists analyze mice with defects, or mutations, in individual genes - so-called knockout mice. Knockout mice are generated in the laboratory to lose both copies of the sequence that encodes a particular gene of interest. The knockout mouse is then compared to the normal mouse to understand the role of the particular gene in development and tumor susceptibility of the living organism.
Using the knockout mouse for the gene p27, generated by Drs. James Roberts of the Basic Sciences Division and Matthew Fero of the Clinical Research Division, Kemp showed the p27 gene plays a unique role in inhibiting cancer progression.
The p27 gene is a member of a class of cell cycle inhibitors that act to block cell proliferation. Mice that have lost one or both copies of p27 are predisposed to tumors in multiple tissues when challenged with irradiation or chemical carcinogen. Thus, p27 is classified as a tumor suppressor that normally functions to control cell proliferation and inhibit or suppress the formation of tumors.
The common operational definition of a tumor-suppressor gene requires the demonstration of mutation of both copies of a candidate gene in tumors. However, the p27 gene shows a rare dosage sensitivity called haplo-insufficiency, wherein the loss of just one copy of p27 results in decreased protein expression and increased tumor growth.
In addition, mutations in the p27 gene sequence itself are rare; usually the decreased levels of protein expression of p27 are not enough to suppress tumor growth. This makes p27 an exception to the tumor-suppression rule, and, Kemp said, "Exceptions always are to be highly valued."
Abnormally low levels of the p27 protein are frequently found in human cancers. Dr. Peggy Porter, an investigator in the Human Biology and Public Health Sciences divisions, has shown that decreased p27 levels in human breast-cancer patients is prognostic for survival.
"Virtually every human cancer has shown a population of patients with reduced p27 protein expression correlating to reduced prognosis for survival," Kemp said. Thus, he said, "the findings in the mouse have established causality between decreased p27 and cancer progression, a conclusion not possible from human studies."
Kemp's laboratory is testing for genetic interactions between p27 loss and other activated oncogenes - cancer-causing genes - such as ras and tumor suppressor genes p53 and APC. A strong cooperation between loss of p27 and mutations in other genes indicates p27 functions as a tumor suppressor in multiple tissues and in multiple genetic pathways.
While one aspect of Kemp's laboratory focuses on the genetic and biochemical characteristics of the role of p27 in mouse cancers, "the overall goal of our research is to understand how environmental exposure to carcinogens interacting with the genetic susceptibility of the host leads to cancer," said Kemp.
Entire natural history
Multi-stage carcinogenesis in the mouse is used to model the entire natural history of cancer development. Cancer stages can be studied from the one initiated cell, to promotion of that cell population to form a benign tumor, to progression resulting in an invasive malignant carcinoma. In addition, the effects of different carcinogen treatments on tumor development can be studied.
"The knowledge gained from mouse models can be applied to both mouse and human forms of cancer," said Kemp.
Dr. Denise Galloway, head of the Cancer Biology program, called the use of mouse models to understand tumor-suppressor pathways "an essential approach to unravelling how human tumors develop.
"In vitro studies using cells in culture may miss organ-specific features of regulation, and examining human tumors directly is so complex. Chris has found a way to link the two systems, making his research a great asset to the Cancer Biology Program."
Using a three-pronged approach - basic science, mouse models of cancer, and public-health science studies of human cancer - the study of real tumors in a natural environment or habitat can lead to the understanding of the stages of tumorigenesis and the discovery of new therapies to treat cancer.
[Dr. Karen Spratt works in the Kemp lab.]