Overview of common mouse tumor model features
[Dry goods] mouse tumor model, those things
Hey, my friends are good evenings! First of all, Xiaobian wants to ask everyone a question. How do we build a mouse tumor model that we hang every day? What are the characteristics of each model? Which is the best model? ..... In fact, to say that the model is better , of course, the more it reflects the occurrence and development of human diseases, the better, after all, "persisting people-oriented" is our ultimate goal!
But then, each model has its own advantages and disadvantages. No model can answer all the questions for us . Therefore, it is especially important to understand the characteristics of each model. Below, Xiaobian makes a brief overview of several commonly used mouse tumor models.
Carcinogen-induced tumor model
In 1915, Japanese pathologist Katssaburo Yamagiwa and his assistant Koichi Ichikawa applied coal tar to the rabbit's ears (150 days). Finally, they found that the rabbit had a tumor. Yamagiwa's rabbit model is also considered to be the first animal model for cancer research [2] .
Melissa Reeves, a cancer biologist at the University of California, San Francisco, used this method to apply a known carcinogen called DMBA and TPA to the skin of mice to induce skin cancer in mice. Further study how the tumor is transferred from the primary site to the secondary site. Her findings suggest that skin cancer does not migrate from one location to another in order—for example, from skin to lymph nodes to the lungs, but “through parallel transmission, while entering lymph nodes and lungs†[2] .
Chemical carcinogens can disrupt DNA at hundreds of sites, and this model mimics the natural evolution of tumors caused by extensive genetic damage , which mimics human tumors that are repeatedly exposed to specific environments, such as persistent UV radiation. Very important reference, but this type of model takes a long time, the continuous monitoring of tumors is difficult, high heterogeneity may cause the difficulty of data processing, lack of clear genetic manipulation, etc. [2] .
Figure 1 on the importance of sun protection [1]
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Genetically Engineered Mouse Model (GEMM)
As the name implies, GEMM (Genetically engineered mouse model) is a tumor model constructed by engineering mouse genes. The transformation methods include transposon technology, embryonic stem cells based on homologous recombination (or non-homologous end joining) and CRISPR-Cas9. Technology, etc.
For example, if the mouse tumor suppressor gene p53 is knocked out , the probability of developing tumors will increase, and these spontaneous tumors completely retain their heterogeneity, which can better simulate the characteristics of human cancer, but on the other hand, such genes Knockout usually induces multi-system tumors, and the spontaneous tumor-forming cycle is also difficult to maintain synchronization due to individual mouse differences, and GEM usually contains only one or two genetic changes, while human tumors generally have multiple gene mutations ....
Speaking of this, the problem is coming. Since the mouse model mentioned above is not satisfactory, what are the tumor models commonly used by researchers now? The main ones are as follows:
Homologous transplantation mouse model
Figure2 |... Transplantable mouse cancers Strategies for developing immune checkpoint blockers (ICBs) (part a) In the standard transplantable model, histocompatible cancer cell lines are injected into immunocompetent inbred mice (usually subcutaneously into the flank) After a few days, developing Tumours are palpable and experimental immunotherapy with ICBs can commence (for example, every 3 days for 15 days) with regular monitoring of tumour growth. Tumour-infiltrating lymphocyte (TIL) populations may be studied from harvested tumours at the end of the observation period ( For example, to investigate treatment-related immune effects). [3]
A syngeneic model of a syngeneic model is to inoculate a histocompatibility tumor cell line , a tumor cell line of the same background, into an immunologically inbred mouse (usually C57BL/6 or BALB/c strains). In vivo, the inoculation site is often subcutaneous (convenient to directly observe the growth of the tumor), in situ (simulating the source environment of tumor growth), systemic injection (peritoneal or intravenous injection, monitoring the spread of the tumor), as shown in Figure 2.
The model is simple to operate, low cost, repeatable, tumor growth is rapid and tends to be synchronized, but the inoculated tumors are usually derived from homogenous cancer cells cultured in vitro and lack the microenvironment of human tumor growth.
CDX
Human-derived tumor cell line xenograft (CDX), which is to inoculate tumor cells subcultured in vitro to immunodeficient mice . The inoculation site is usually subcutaneous, intravenous or in situ, as shown in Fig. 3.
The cell line model was established by inoculation of in vitro cultured passaged tumor cells in immunodeficient mice. Due to long-term passage in vitro, the cells showed high homology. The model was easy to establish and reproducible, and there was still a great demand in the development of tumor drugs. However, during the in vitro culture and passage process, the tumor heterogeneity is significantly different from the original tumor tissue, which is not ideal for predicting clinical efficacy.
PDX
A human tumor xenograft (PDX) model, a tumor model established by directly transplanting a patient's fresh tumor tissue into an immunodeficient mouse . The common site of inoculation is subcutaneous, vein, in situ, as shown in the figure. 3.
Figure 3 CDX and PDX
Compared with CDX, the specimens used for PDX transplantation are directly derived from human tumor tissues. They have not been cultured in vitro and stably retain the genetic characteristics, histology and phenotypic characteristics of the tumor, ie tumor heterogeneity, and the tumor growth microenvironment is closer. The actual situation of the human body and the results of the screening test also have good clinical predictability. (For details, see previous tweets: PDX and CDX)
But the problem is again. Most of the tumors that the human body suffer are not caused by immunodeficiency. In order to prevent the immune rejection of human tumors inoculated in mice, the mouse model constructed by CDX and PDX must be required. Immunodeficiency.
Is there a mouse model that contains both the human immune system and human tumors?
The answer is: of course!
At present, the pre-clinical immune system reconstruction techniques are mainly divided into two categories: one is to implant mature human peripheral blood mononuclear cells (hPBMC) into the immunodeficiency mice through the abdominal cavity or tail vein to reconstruct the human immune system, ie hPBMC type. The other is the injection of human bone marrow-derived CD34 + hematopoietic stem cells (HSC) into the immunodeficient mice via the abdominal or tail vein, ie HSC (CD34 + ) type [4] . (For details, see previous tweet: Human immune system) Reconstruction - assisted medical research )
Today, Xiaobian will tell you about this first. I want to know more about the more detailed mouse tumor model partners, remember to continue to pay attention to us~
Reference material
[1] https://
[2] Mike May. (2018) Cancer research with a human touch. Nature, 556: 259-261.
[3] Zitvogel L, Pitt JM, et al. Mouse models in oncoimmunology. Nat Rev Cancer. 2016 Dec;16(12):759-773.
[4] Walsh NC, Kenney LL, et al. Humanized Mouse Models of Clinical Disease. Annu Rev Pathol. 2017 Jan 24;12:187-215.
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