Tumor Assessment

Transgenic mice have long been an important resource for studying human neoplasms, both benign and malignant. In addition to the numerous genetically engineered mouse models developed over the years, many popular background strains have a genetic predisposition toward certain types of tumors. Knowing the effect of the background strain is important in research involving genetic manipulation with genes involved in tumor pathways. In addition, a detailed understanding of the biochemical cycles intrinsic in cell regulation is vitally important to the researcher dealing with transgenic mice in cancer research. As described in the pathology section, there are many assays in addition to normal necropsy procedures and techniques useful to the researcher experimenting with the cellular regulation details of cancer research. Flow cytometry, immunohistochemistry, Southern blot analysis, and fluorescence in situ hybridization can all be used to assist in evaluating the phenotype of specific cancers induced or discovered in genetically engineered mice.

The first step in phenotypic characterization of genetically engineered mice in cancer research is to develop a tumor tracking study specific to the type of cancer expected in the mouse model. For example, if the research involves hematopoietic tissues and neoplasms derived from them, an integral part of the tumor tracking would be periodic blood exams to evaluate complete blood counts and the status of hematopoiesis in mice involved in the study. In all types of studies, all mice expressing the cancer-related gene should be monitored at least weekly for signs of illness. A phenotypic endpoint should be determined so that no individual animal is left to suffer with a large tumor burden. That endpoint can be determined by reviewing IACUC requirements. In many cases, monitoring attitude, behavior, and simple biological parameters such as weight or body temperature is enough to fully maintain a colony of transgenic mice with potential tumors. In others, a weekly noninvasive evaluation of individual animals, including an assessment of attitude, measurement of weight, and performance of a basic physical exam including abdominal palpation of internal organs and all accessible lymph nodes will allow the researcher to track all developing neoplasms and comply with given tumor endpoint requirements. However, for transgenic mice that do not show a phenotype or tumor development as readily, such as those with intrathoracic, central or peripheral nervous system lesions, or for experiments in which the identification of the initial stages of tumor development is the research goal, there are other more invasive and more sensitive methods of tumor tracking available.

One method of additional phenotypic characterization is to attempt to induce tumorigenesis by the administration of a carcinogenic agent or radiation treatment to mice genetically engineered to be susceptible to carcinogenic insults. A popular chemical agent that is easy to administer and is a well-characterized mouse-specific carcinogen is ENU (A-ethyl-#-nitrosurea). An alkylating agent, ENU will provide a wide range of DNA damage and subsequent systemic tumorigenesis. Exposure to ENU commonly occurs through IP injection (5 umol per gm per mouse) in weanling mice, 3 weeks of age. Control mice followed for 12 months generally develop 5 to 10% tumors, so numbers above this in the transgenic group are indicative of tumor susceptibility. Latency to tumor development statistics of percent tumor-free survival can be performed using Kaplan Meier plots in addition to the use of log rank tests for determination of significant differences.

As gross observation and general physical exam measurements are lacking in sensitivity to the beginning stages of tumorigenesis, more advanced technologies to detect impending tumors are often required. One method of detecting early tumor growth is through the use of ultrasound imaging. Using ultrasound imaging, developing tumors can be seen as an unnatural enlargement of a previously normal size organ or as discrete nodules or extensions of a different grayness within or beside a normally colored tissue of origin. In this method, tumors can be visualized before they can be felt by palpation and long before the tumor develops to the point where illness occurs or the tumor burden becomes too great and euthanasia is required.

An emerging technology in advanced tumor imaging is PET, or positron emission tomography. It is known that tumorigenesis is associated with a high need for glucose for energy and to provide the carbon backbone to meet the high cell replication rates of tumors through activation of the hexose monophosphate shunt. This knowledge led to the development of the tracer 18F deoxyglucose (FDG), so that when injected systemically, high levels of FDG signal delineate neoplasms from surrounding tissues. In fact, whole-body FDG PET scanning is capable of detecting abnormal tumor metabolism before anatomic changes occur and is able to distinguish between malignant and benign anatomic abnormalities.

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