MOUSE XENOGRAFT MODELS

As discussed earlier, mouse models are more attractive than big animal models because of the low cost, ease-of-handling and known genetic information.

Xenograft = a tissue graft or organ transplant from a donor of a different species from the recipient.  Xenotransplantation = Xenotransplantation is the transplantation of living cells, tissues or organs from one species to another.

One of the most widely used models is the human tumor xenograft. In this model, human tumor cells are transplanted, either under the skin or into the organ type in which the tumor originated, into immunocompromised mice that do not reject human cells.  For example, the xenograft will be readily accepted by athymic nude mice, severely compromised immunodeficient (SCID) mice, or other immunocompromised mice.

After establishment of cancer cell lines for anticancer screening in National Cancer Institute (NCI), xenograft models derived from these cell lines were developed. Sixty cell lines derived from eight organs were used for establishment of xenograft models.

HUMANIZED MOUSE: 

·       This refers to a mouse that has a few human cells, a short strand of human DNA, human tissues, a human tumor, or a humanized immune system.  Mice that are humanized can be powerful models of the human being and thus better for research into the problems of human development and disease.

·        Mouse engrafted with human tumor, known as patient-derived xenograft (PDX).  In general immunocompromised mice are engrafted with PDX tumors.  Tumor from a patient is collected and cut into pieces and put these pieces into multiple mice.  Each fragment grows and can then be divided into pieces and put into additional mice.  Through this process, you can end up with dozens of mice, each with tumors nearly identical to each other and to the original human patient’s tumor.  Now we can treat different groups of PDX mice with alternative drugs, drug combinations, and drug sequences allowing us to determine with approach works best to eliminate a very specific tumor type.

·        Interestingly, a mouse with no immune system can be selected and to it specific human stem cells typically derived either from fetal tissue or cord blood can be injected to obtain mouse with humanized immune system.

·        CRISPR CAS/9 technique can be used to break a strand of DNA at a very precise location and either can eliminate a short stretch of genetic code or add code from another organism.  Using this technique, DNA in a mouse embryo is broken in this way and a human genetic sequence is inserted into its genome.  By doing so, we can determine whether a human gene or a specific genetic variation functions or impacts on human health the way they we think it does.  These mice an be treated with alternative therapies to see if a disease causing genomic abnormality can be stopped or mitigated.

Ectopic tumor xenograft model. Generally, human cancer cells are subcutaneously injected into the hind leg or back of mice. In an ectopic tumor xenograft model (ectopic model), the transplanted site is different from the origin of the cultured cells.  Because an ectopic model can be used to monitor tumorigenicity and tumor growth easily, many researchers have utilized this model for evaluation of anticancer efficacy.

Orthotopic tumor xenograft model. Alternative models for assessment of tumor sensitivity have been developed. The orthotopic tumor xenograft model (orthotopic model) is an advanced tool, but is based on a immunosuppressive murine microenvironment. In the orthotopic model, the human cancer cells are transplanted into the same origin site of the tumor. For instance, lung cancer cells were directly injected into the mouse lung for the orthotopic model.

Patient-derived tumor xenograft model. Xenograft models, despite their advantages, are limited in their ability to demonstrate how a cancer patient would respond to a particular treatment. The reliable prediction of drug response in a clinical trial is needed, and the current models are not sufficient. In an effort to address the shortcomings of these models, a patient-derived tumor xenograft (PDTX) was developed and utilized.

Humanized Mouse Xenograft Models.

ü  Xenograft rodent models and cultured cells have long been used in pre-clinical studies of cancers and other human problems.  There are significant limitations to both of these model systems.

ü  Immune system humanized mice have allowed for researchers to examine cancer xenograft growth in the context of a human-like immune system and resulting tumor microenvironment.

ü  Humanized mouse models are “engineering mouse strains expressing human cytokines or HLA proteins and implanting human bone, liver, and thymus tissues to facilitate immune cell maturation and trafficking.”