Xenografting and Xenotransplantation
The xenotransplant, also known as xenograft, is a tissue or an organ transplanted between members of different species
The limited availability of allografts motivates the extensive research occuring on xenotransplantation techniques. The preferred donor species for humans are pigs, due to the low risk of introducing new infections in the human population and for physiological compatibility; the widely used models for humans are baboons. Non-human primates are not used as donors because they are closely related to humans and their infectious agents could potentially be transmitted to human populations.
Xenotransplantation is a very important technique, due to the low availability of human organs. Research on xenograft and non-human primate models provides imperative information regarding the rejection process and preventative measures. Xenografts are a useful tool in tissue and organ failure and would save the lives of the patience that do not have the chance to find a compatible allograft donor. While the need for human organs is continuously increasing, researchers study the “humanization” of other species, mainly pigs, to try to solve the rejection problems with another useful tool (i.e. genetic engineering).
The key problem with xenografts is rejection caused by the recipient’s immune system. Hyperacute rejection occurs within minutes or hours from the transplant and is mediated by xenoreactive natural antibodies (XNAs). Acute vascular rejection occurs within two or three days, as an immune response of macrophages and Natural Killer (NK) cells . Cellular rejection is slower than the previous two types, and it is caused by the cellular immunity barrier, represented mainly by T cells and NK cells. Chronic rejection occurs very slowly and its cause may be arteriosclerosis.
Xenograft studies are an important part of the development of novel therapeutics and remains the gold standard for oncology research. Xenograft studies are provided as a professional service by companies offering preclinical oncology research services (Altogen Labs). Xenograft studies provide unique data that are relevant to human care. When xenograft data is compared to cell-based in vitro studies, the in vivo xenograft studies provide a more accurate schema of both the development of a particular tumor as well as the efficacy of the drug.
In the preclinical phase development of new anti-cancer drugs and therapeutics, mouse models have been crucial to determining in vivo results for decades. Profiling a therapeutic agent can be accomplished through selecting the appropriate model, carrying out studies in different tumor types and evaluating efficacy with hematology analysis, histopathology, biomarker screening and pharmacokinetic/pharmacodynamic (PK/PD) analysis.
Xenograft services rely on the use of immunocompromised small animals (laboratory mice and rats). Severe combined immune deficient (SCID) mice and nude mice (nu) are effective as proxies for human subjects.
The biologic scaffolds containing connective tissues and other proteins are used in surgical procedures, as well as in cancer research. According to their source, the biological scaffolds can be allografts, originated from a donor that belongs to the same species as the host, or xenografts, when the donor and the host do not belong to the same species. Although allografts are broadly used due to their biocompatibility with the host, the limited availability triggers extensive research for reducing the risk of rejection and for evaluating the risk of transferring viruses to the human population.
The research on xenografts is extremely important due to availability. The scientific community is very optimistic regarding the success of genetic engineering “humanization” of other species.
Xenograft animal models
Human cancer causes are not fully understood, and an effective treatment for each of the 200 known cancer types needs extensive research. As the experimental therapeutics cannot be performed on humans, scientists utilize xenograft animal models in their studies. The tumor cells are transferred to immunocompromised or athymic nude mice, which allow the tumor development in several weeks, without a rejection caused by the immune system. The human tumors obtained this way can be used for testing new anticancer drugs and qualify them for human clinical trials, along with offering a better understanding of carcinogenesis.
Xenograft models are used in studies related to tumor development, signaling, inhibitors, novel therapeutics and drug interactions. These studies provided valuable knowledge to scientists and allowed the identification of some elements of carcinogenesis mechanism and the development of various drugs which can interfere with this process.
Cancer drugs were tested on mouse tumors starting in the 1950s, and in several decades it became evident that the studies were limited by the different response of human tumors and mouse tumors to similar treatments. By the mid-1980s, the xenotransplant of human tumor cells in immunodeficient mice was possible.
The most widely used are the xenografts derived from the patient explant for predicting the response to a certain treatment, or the resistance to a certain drug. The xenograft cells are similar to the original tumor cells, and the tests proved a high reliability for some types of cancer. In such a research protocol, the subject of the study is a particular tumor similar to the tumor of a particular patient, and the developed treatment will be personalized.
The orthotropic human tumor xenografts are obtained by injecting the human tumor cells inside the similar organ in the immunodeficient mice. This technique provides more reliable results on human tumor response to a certain treatment. The researchers can qualify the treatment for human clinical trials if they obtain a 50% inhibition in the orthotropic human tumor as a response to that particular treatment and if regrowth of the tumor is not significant as compared to pre-treatment growth. The tumoral cells in these studies are not cultivated in Petri plates, and tumor stroma can be injected together with the tumor cells in order to obtain a reliable response as close as possible to the original tumor response.
The xenograft models used in oncology research are not perfect, but they provide useful information regarding tumor development and new treatments. They are used for crucial studies on tumor growth mechanism, carcinogenesis, tumor growth inhibitors, new treatments and for studying the interactions between various factors and drugs.
The human tumor xenograft models are used for new drug discovery and development and are extremely useful tools in oncology. They can be used for general treatment research and for identifying the details of tumor growth and development. The xenograft models are also widely used for personalized cancer treatment set up and tests, as their cancerous cells are similar to those of the original tumor. The xenograft model techniques allow in vivo tests on human tumors, not on mouse tumors, which do not have the same response to a particular therapeutic or drug concentration.
Xenotransplantation is a very important technique. Due to low availability of human organs, research on xenografts and non-human primate models provides useful information regarding the rejection process and preventative measures. Xenografts would be a useful tool in tissue and organ failure, and would save the lives of patients that do not have the chance to find a compatible allograft donor. While the need for human organs is continuously increasing, researchers study the “humanization” of other species, mainly pigs, to try to solve rejection problems by incorporating another useful tool, i.e. genetic engineering.
History of xenograft cancer models
It was in 1894 that mice were first used for cancer research. At that time, mice were mostly employed for tumor transplantations within the same species as well as drug treatment studies. Later, the decision to test drug therapies on mice and rats was validated as research found that they possess a startling genetic similarity to humans. This, and the fact that they reproduce quite easily and quickly, have made mice the mammal of choice for genetic manipulation. Since then, scientists have bred many different types of mice, all with different features. All the inbreeding between the different types of genetically altered mice led to mice that were predisposed to getting cancerous tumors. The year was 1921, the inbred strains were disseminated among cancer researchers and a new era was ushered in.
A mutant mouse was discovered in 1962 as having very little immunity. A human tumor was transplanted into the mutant mouse and an important step forward for cancer research was taken. Another breakthrough in the early 1990’s led to the creation of transgenic mice. The genes in these mice could be altered to produce a distinctive feature or quality. This led the way to more detailed studies of oncogenes, i.e. genes that cause cancer.
Xenografts are an important part of creating personalized treatments. Today, scientists and doctors are only beginning to understand how to modify healthcare to a person’s exclusive genetic makeup. Altogen Labs xenograft services are an essential means helping basic science research to revolutionize personalized medicine.
How xenografts help find a cure for cancer
Our xenograft services use immunocompromised rodents as a model for human cancer. We have developed over 60 xenograft tumor models in immune-deficient mice, transgenic mice and conditional engineered mice to pinpoint the known tumor supporting pathways. A careful characterization of xenograft tissue and the mice lets us effectively determine the drug-target interaction. It also gives us the ability to test the forecasts regarding the pathway-targeted anti-tumor effectiveness of test compound. Tumor xenograft models have become an important tool in the fight against cancer.
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