Rodent Xenograft Models 

Several murine cancer models have been developed for studying human cancer. Various factors are involved in the transformation, invasion, and metastasis of malignancy and the response to therapeutic interventions in these models. The mice xenograft model is one of the most widely used models. This model involves transplanting human tumor cells into immunocompromised mice or the organs from which the tumor originated.  

Generally, rats are used in oncology and toxicology studies. Oncology studies use mouse models, whereas toxicology studies use rats, so the nude rat provides a unique tool for testing both anti-tumor drug efficacy and toxicology. Due to their large figure size, nude rat models can also be used to image fine structures of xenografts. 

An athymic nude mouse, a severely compromised immunodeficient (SCID) mouse, or an immunocompromised mouse will readily accept the xenograft. The tumor will develop over 1–8 weeks (or, in some instances, 1–4 months) depending on the number of cells injected and the size of the tumor transplanted. The response to appropriate therapeutic regimens can be studied in vivo.  

Researchers have been using mouse xenograft models and athymic nude mice for decades to examine factors affecting tumor growth. To determine whether a patient’s tumor will respond to a particular treatment regimen, one must examine the response of a human tumor, not a mouse tumor. The human tumor xenograft can be useful when applied to athymic nude mice, SCID mice, or non-obese diabetic (NOD)/SCID mice.   

Even though nude or SCID mouse models lack some immune system components, athymic nude mice have intact B cells, dendritic cells, and granulocytes, as well as an increase in natural killer (NK), cells tumoricidal macrophages. Further, one can argue that the tumor has escaped immune surveillance and cell death when these metastatic lesions are surgically removed or biopsied. 

Advantages of using human tumor xenografts  

Following are the advantages of establishing human tumor xenografts in immunodeficient mice and rats: 

• The triple-immunodeficient mouse can host xenografts, tissues, and human immune system components, making it useful for studies on tumor biology, immuno-oncology, infectious disease, graft-versus-host disease (GvHD), hematopoiesis, and tissue transplantation. 
• It is possible to modulate the tumor’s effect on its microenvironment by placing orthotopic xenografts in the mice organ environment where the tumor grows, with certain T-cell populations being an exception. 
• Xenografts can mimic the human tumor microenvironment by including stroma from the tumor. 
• Injection of peripheral blood or bone marrow cells into NOD/SCID mice allows xenografts to reestablish the immune response completely. Human cell line xenografts used to test drug response do not always correlate with clinical activity.  

Disadvantages 

It is clear that subcutaneous xenografts are more effective than nothing, but they are not without drawbacks. There is no functioning immune system in the mouse, something rare in human cancer, and the tumor grows on an artificial site. It is believed that interferons in the skin cause xenograft tumors to metastasize rarely. Furthermore, mice do not naturally develop tumors. 

The transplanted cells are taken from a fully grown human tumor, another divergence from human biology. Subcutaneous xenografts are a poor predictor of success when drugs behave differently in mice than in humans. These mice respond much more readily to drugs than humans to shrink tumors. 

 Monitoring and predicting therapeutic responses in cancer with mouse xenografts also has several disadvantages. Creating orthotopic tumor models takes a lot of time, money, and technical expertise. Further, nude or SCID mice cannot respond to tumors in a lymphocyte-mediated manner, i.e., nude mice lose certain T-cell responses, and SCID mice lose both T- and B-cell responses. Human tumors can, however, be grafted onto ‘humanized’ NOD/SCID mice to overcome these immunological deficits.  

Orthotopic human tumor xenograft models have many drawbacks when studying therapeutic responses. It is impossible to fully restore the immune system of the ‘humanized mouse’ because restoring HLA class I- and class II-selecting elements in T-cell populations remains challenging. Furthermore, human umbilical cord blood stem cells from the umbilical cord are engrafted into newborn mice after they have been irradiated.  

Since cord blood must be obtained, neonates are irradiated, and the NOD/SCID mice must be verified to be humanized after engraftment, this procedure is time-consuming but extremely valuable.