Scientists Use Mouse Models to Explore Cause and Origin of Cancer in Humans [Animation]

Souce: Anthony Beal, NCI

June 7, 2010, 12:40PM

By Linda Perrett

Posted in: Biomarkers | Clinical trials | genetics

Tags: ASCO, biomarker, epigenetics, etiology, methylation, mouse models

Mouse models that mimic human disease play a vital role in understanding the etiology (cause and origin) of cancer. Results of mouse model studies lend evidence toward the next step in biomedical research that leads to early detection of cancer, new cancer drugs, new combinations of treatments, or new methods such as gene therapy.

Scientists use mouse models for investigating mutations in humans triggered by environmental agents, drugs, aging, and diet. Mutations cause a random change in a gene, or chromosome, that results in a new trait or characteristic that can be inherited. The genetic similarity of mice to humans accounts for mice being a good experimental model to study cancer. Also, human tumors can be grafted onto the mouse without rejection. This procedure allows for the study of specific human cancers, as well as the testing of various medical applications.

One particular area of interest in examining the impact of the external factors on cancer development is the field of epigenetics, which is the study of inherited changes in either physical appearance or in how genes are expressed, that are caused by mechanisms other than changes in the underlying DNA sequence.

Epigenetic Presentations at American Society of Clinical Oncology (ASCO)

At a Friday, June 4, 2010, educational session at the annual meeting of the American Society of Clinical Oncology in Chicago, three researchers addressed the topic of ‘Application of Epigenetics to Diagnosis and Therapy’.  They pointed out that numerous publications to date have established DNA methylation as a specific marker for cancer, primarily because it has been established that DNA methylation is very stable and thus is preserved in blood and urine samples.

However, while about a dozen methylation-based clinical trials have been conducted, the trials used relatively poorly controlled clinical samples and therefore there is an urgent need to establish standards for sample collection.  To this end, the NCI-sponsored EDRN is working to establish such standards and work on bladder tumors that use highly standardized samples is moving forward.  The speakers also noted that no assay currently exists to detect histone modification, another potential epigenetic event that could potentially serve as an early marker for cancer progression.

Additionally, NCI grantees will present talks on the application of epigenetics to diagnosis and therapy in humans derived from mouse models throughout the five-day ASCO annual meeting. They will explain how cancer genes, coupled with new molecular techniques, may be used in the early diagnosis of cancer, improved accuracy of cancer prognosis, and in the creation of create individualized cancer care treatments.

Presenters on these topics at ASCO include:

Gerd P. Pfeifer, Ph.D., professor and chair of the Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, Calif., will focus on cancer epigenetics and basic biology.Paul Cairns, Ph.D., associate professor in the Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pa., will discuss epigenetics in early detection of cancer.Jean-Pierre Issa, M.D., principal investigator, University of Texas, MD Anderson Cancer Center, Houston, Texas, will present on the use of epigenetic information for individualized cancer care.

For more information on the ASCO meeting, visit: http://chicago2010.asco.org/.

While the ASCO presentations deal almost exclusively with clinical trials related to diagnosis and treatment of humans with cancer, most medical investigations begin with understanding how cancer develops in basic animal systems, such as mouse models.

Mouse Models at Work

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Mouse Model Used to Investigate Agents that Cause Human Melanoma and Lung Cancer

Pfeifer is using a Hupki mouse model, also known as the human p53 knock-in, for investigating mutations triggered by environmental agents that may cause cancer in humans, such as melanoma and lung cancers. The Hupki mouse model was constructed using gene-targeting technology to create a mouse strain that harbors human TP53 DNA sequences in place of the mouse TP53 gene. The vast majority of TP53 mutations arise from a solitary mutation in the way DNA codes for the protein known as TP53. These inactivating mutations render the mutant TP53 protein unable to carry out its normal functions.

Inactivating mutations in the TP53 gene occur frequently in a variety of human cancers. The pattern and frequency distribution of mutations in the TP53 gene are tumor-specific and reflect past mutagen exposure. Thus, investigating human TP53 mutagenesis in relation to exposure to these mutagenic agents provides valuable information on the underlying etiology of human cancers. For more information on the study, Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing, visit: http://www.ncbi.nlm.nih.gov/sites/entrez.

Mouse Model Used to Identify Genes that May Cause Aging Humans

Issa and his colleagues studied DNA methylation in normal colon tissues in young and old mice and found evidence of changes affecting over 20 percent of genes in the process of aging. DNA methylation is an epigenetic event that affects cell function by altering gene expression. This age-related methylation instability is tissue-specific and highly conserved between mouse and human aging.

The similarities between human and mouse aging extends to recent studies comparing human and mouse leukemia. Thus, mouse models could be useful to study the causes and evolution of epigenetic abnormalities in aging and formation of tumors. For more on the study, Widespread and tissue specific age-related DNA methylation changes in mice, visit:  http://www.ncbi.nlm.nih.gov/sites/entrez.

New Ways to Improve Mouse Models

Cairns discussed ways in which mouse models of human cancer might be improved at a scientific workshop on cancer biomarkers. It was suggested that in genetically modified mice, prone to develop specific cancer types such as ovarian cancer, evaluation of imaging strategies could be undertaken at various stages during the course of cancer progression. This would allow the sensitivity of the imaging methodology to be evaluated. Similarly, body fluids could be collected at early to late time points during the course of cancer progression. Novel analytical technologies could be applied to such samples to inform the sensitivity, specificity, and reliability of the technique.

Cairns also noted that there is a lack of genetic diversity in individual mouse models since the mice are often derived from an inbred strain. He suggests the possibility of cross-breading mice to create a complex mix of genetic backgrounds in a mouse model that would still retain a cancer type that is modeled, to some degree of diversity, on the human population. This could provide for a large number of genetically diverse control samples that are often lacking in human studies.

To learn more about this work, taken from the publication, ‘Cancer Biomarkers, NCI Early Detection Research Network: 5th Scientific Workshop’, visit: http://iospress.metapress.com/content/4806g13r56726741/.

NCI’s Mouse Models of Human Cancers Consortium (MMHCC)

Acknowledging the importance of mice in the study of cancer, over a decade ago NCI established the Mouse Models of Human Cancers Consortium (MMHCC), to provide information on mouse models used for specific areas of cancer research including: gastrointestinal cancer models; hematopoietic cancer models; lung cancer models; mammary gland cancer models; nervous system cancer models; ovarian cancer models; prostate cancer models; and skin cancer and melanoma models. For more information on MMHCC, visit: http://emice.nci.nih.gov/mouse_models. The establishment of the MMHCC resource and the many years of data collection and model development have given the study of epigenetics in mice an inestimable boost.