Each year some 29,000 American men die of prostate cancer. With about 221,000 more diagnoses expected in the United States
in 2003, the disease trails only skin cancer as the most common male cancer. As a complex disease, multiple genetic and environmental factors contribute to risk and, like most cancers, its onset and
progression depends on the combination of a series of genetic disruptions rather than on a single event. But as Pier Paolo Pandolfi and colleagues report, protein dosethat is, the level of remaining activityalso influences cancer progression.
Focusing on the tumor suppressor gene PTEN, the
researchers used the mouse as a model system to study tumor progression in prostate cancer. PTEN is among the most commonly mutated tumor suppressor genes in human cancer. And like many other tumor suppressors, PTEN targets proteins in signaling pathways that regulate cell growth and apoptosis in healthy tissue and contributes to cancer when dysfunctional. Humans, as diploid organisms, generally have two versions of most genes, including PTEN. In the event that one copy is damaged or lost, gene function is usually maintained by the other copy. In the classic definition of a tumor suppressor, both copies must be lost for a tumor to occur. Yet in many cases of advanced cancer, including prostate cancer, only one copy is lost at the time a patient shows symptoms. It is then not unreasonable to hypothesize that the degree of remaining PTEN activity controls the course of the disease: loss of one copy could influence tumor initiation, while further slight reductions might be sufficient to facilitate the invasion and metastatic behavior of late-stage cancers.
Pandolfi and colleagues chose two strategies to investigate this hypothesis. In the first approach, they genetically engineered one series of mice with minimal levels of murine Pten protein (complete loss results in embryo death). This novel hypomorphic strain of mice exhibits only 2535 active Pten, which appears to be the minimum level of Pten needed to survive embryonic development. This hypomorphic model adds to existing strains of fully functional and 50 active Pten mice. In order to model the full loss of Pten protein, the researchers generated another series of mice in which Pten genes were selectively disabled in the prostate only. The researchers found that subtle reductions in Pten dose did indeed produce progressive changes in the biology of the tumor, while mice having no functional Pten genes showed the most invasive and aggressive cancers. These results, the researchers say, show that Pten plays a crucial dose-dependent role in prostate cancer tumor suppression and that progressive reduction of gene function induces progressive changes in the quantity and quality of molecular and pathological effects on the pathway to full-blown cancer.
By coupling the molecular genetics and dose of Pten protein with the physiological progression of cancer in the prostate, these new mouse models may not only shed light on cancer progression in humans, but also help bolster diagnostic, prognostic, and therapeutic techniques. While evaluation of tumor status has traditionally been determined by pathological analysis of tissue samples, these new models allow scientists to pair anatomical stages with underlying molecular eventssuch as the expression level of a single gene or proteinto allow more accurate assessments. These molecular profiles can also help researchers design targeted, more efficient prostate cancer treatments. For example, if prostate tissue is hypersensitive to reduction of PTEN in humanswhich the results suggest may be the case, since male mice with only 30 of normal Pten levels show massive and selective enlargement of the prostate, and even invasive tumorsthen ongoing monitoring of PTEN levels could help tailor therapies based on promoting PTEN expression. For patients with complete loss of PTEN function, where this would not be an option