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Application of Animal Models in Cancer Research: Recent Progress and Future Prospects

Authors Li Z, Zheng W, Wang H, Cheng Y, Fang Y, Wu F, Sun G, Sun G, Lv C, Hui B

Received 20 January 2021

Accepted for publication 25 February 2021

Published 15 March 2021 Volume 2021:13 Pages 2455—2475

DOI https://doi.org/10.2147/CMAR.S302565

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Eileen O'Reilly

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Zhitao Li,1,* Wubin Zheng,1,* Hanjin Wang,1,* Ye Cheng,1 Yijiao Fang,2,3 Fan Wu,1 Guoqiang Sun,1 Guangshun Sun,1 Chengyu Lv,1 Bingqing Hui4

1Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Anesthesiology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 4Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Chengyu Lv; Bingqing Hui Email [email protected]; [email protected]

Abstract: Animal models refers to the animal experimental objects and related materials that can simulate human body established in medical research. As the second-largest disease in terms of morbidity and mortality after cardiovascular disease, cancer has always been the focus of human attention all over the world, which makes it a research hotspot in the medical field. At the same time, more and more animal models have been constructed and used in cancer research. With the deepening of research, the construction methods of cancer animal models are becoming more and more diverse, including chemical induction, xenotransplantation, gene programming, and so on. In recent years, patient-derived xenotransplantation (PDX) model has become a research hotspot because it can retain the microenvironment of the primary tumor and the basic characteristics of cells. Animal models can be used not only to study the biochemical and physiological processes of the occurrence and development of cancer in objects but also for the screening of cancer drugs and the exploration of gene therapy. In this paper, several main tumor animal models and the application progress of animal models in tumor research are systematically reviewed. Finally, combined with the latest progress and development trend in this field, the future research of tumor animal model was prospected.

Keywords: animal model, cancer, patient-derived xenotransplantation model, PDX model, tumor microenvironment

Introduction

With the effective control of severe infectious diseases and the extension of human life expectancy, cancer has become one of the major diseases that seriously endanger human health. According to 2015 estimates by the World Health Organization (WHO), cancer is the first or second leading cause of death among people under the age of 70 in 91 of these countries.1 Under the combined influence of population aging and population growth, the number of new cancer cases each year is expected to rise from 18.1 million in 2018 to 29.4 million in 2040.2 Due to the late diagnosis of most cancers and inadequate prevention measures, cancer is becoming a heavy burden on residents in low-and middle-income countries. The development and research of new diagnostic methods and innovative treatment tools are essential to reduce the global incidence of cancer.The animal experiment is an important bridge between cell experiment and clinical experiment. Under certain conditions, the occurrence and development of animal diseases are similar to that of human beings, and animals have similar anatomy, physiology and heredity to human beings. Therefore, animal models are often used to study human diseases. In cancer research, the use of animal models can help us understand the genetic basis of cancer and the role of specific genes and gene mutations in the occurrence and development of cancer, which also facilitates the development and testing of antineoplastic drugs.3 With the continuous development of precision medicine and personalized medicine, researchers are looking for standardized and personalized tumor models that are more similar to human tumors.4 There are many animal types and construction methods used to construct cancer animal models, and the progress of each animal model in tumor research has its own characteristics, which will be described below (Figure 1).

Figure 1 Two commonly used classification methods of cancer animal models. Dashed red box represents the classification according to different modeling methods. Another classification is carried out according to different species. Blue arrows indicate the species of animals included in this classification.

Abbreviations: PDX, patient-derived tumor xenograft; CDX, cell line-derived xenograft.

Mouse Model

The mouse genome is highly homologous to the human genome, which can simulate a series of biological characteristics such as the occurrence, development and metastasis of human cancer cells in vivo,5 and has the advantages of convenient feeding, low price and easy gene modification. It provides a good tool for cancer research and a valuable platform for drug discovery and verification. At present, there are four commonly used methods to construct mouse cancer model: chemically induced model, cell line-derived xenograft (CDX) model, patient-derived xenograft (PDX) model and genetically engineered mouse model (GEMM).6 The chemical induction model refers to the model of experimental tumor induced by chemical carcinogens, which has the advantage of imitating the occurrence of human cancer from the beginning of the carcinogenic process.7 But the main disadvantage of this method is that it takes 30–50 weeks to form a tumor after using carcinogens.8 The cell line-derived xenograft (CDX) model refers to the xenotransplantation model produced by subcutaneous injection of cancer cell lines into immunodeficient mice.9 The establishment of this model is simple and takes a short time to form a tumor, but after long-term culture in vitro, the biological behavior and tumor heterogeneity of human tumor cell lines are quite different from those of the original tumor tissue.10 The patient-derived xenograft (PDX) model is an animal model established by directly implanting tumor tissue samples from tumor patients into mice, which well maintains the characteristics of tumor histopathology and genetics.11 The genetically engineered mouse model (GEMM) is to induce tumorigenesis by promoting the expression of oncogenes (such as BRAF V600E in melanoma)12 or the deletion of tumor suppressor genes (such as PTEN in prostate cancer)13 by genetic engineering. Compared with the above two transplantation models, GEMM formed an orthotopic tumor in an innate immune maturation microenvironment (natural immune-proficient microenvironment), simulating the process of tumorigenesis.14 However, due to the species differences of the immune system among mammals, these existing models cannot accurately predict the interaction between the human immune system and tumor. Many antineoplastic drugs with a good therapeutic effect in preclinical animal models cannot play a corresponding role in tumor patients. Therefore, it is necessary to establish an animal model that cannot only replicate the tumor microenvironment, but also have a “humanized” immune system at the same time. The humanized mouse model of the human immune system is a mouse model that reconstructs the human immune system by implanting human hematopoietic cells, lymphocytes or tissues into immunodeficient mice.15 On this basis, the implantation of human tumor cells or tumor tissue can be used to study tumor growth in the environment of the human immune system and evaluate anti-tumor therapy, especially the effect of immunotherapy and related mechanism. At present, a variety of human tumor cell lines have been successfully established in humanized mice, such as lymphoma, glioma, breast cancer, colorectal cancer, kidney cancer and prostate cancer cell line.16–19 According to the method of human immune system reconstruction, the humanized mouse models of the immune system are divided into three categories: Hu-BLT (human bone marrow, liver and thymus) model, Hu-HSCs (human hematopoietic stem cell) model and Hu-PBL (human peripheral blood lymphocyte) model (Figure 2).

Figure 2 Construction method of humanized mice of human immune system. The construction of humanized mice needs to use immunodeficient mice as a tool. By transplanting different human immune organs or cells into immunodeficient mice, three different humanized mice can be constructed. Among them, the Hu-HSC model also needs to destroy the hematopoietic function of bone marrow in mice.

Abbreviations: Hu-HSC, human hematopoietic stem cell; Hu-PBL, human peripheral blood lymphocyte; Hu-BLT, human bone marrow, liver and thymus.

Hu-BLT Model

The model is established by co-transplanting human embryonic liver and thymus into the renal capsule of immunodeficient mice and injecting liver hematopoietic stem cells from the same embryo into mice.20 It can reconstruct the human immune system most perfectly, and detect many kinds of human immune cells, such as T cells, B cells, macrophages and so on, in mice, thus producing human adaptive immune response.21,22 Therefore, the hu-BLT model is considered to be an important model for the study of cancer in the human immune system. For example, Vatakis et al23 used hu-BLT mice to build melanoma models and treated them with T-cell-based immunotherapy. Kaur et al implanted pancreatic tumor cells into hu-BLT mice and found that NK cells could block tumor growth through differentiation and cleavage.24 However, due to the complex and elaborate surgical procedures required in the establishment process and the limited sources of fetal liver and thymus, the application of the hu-BLT model is also limited.25

Hu-HSC Model

The construction of this model requires the destruction of bone marrow hematopoiesis in newborn or adult immunodeficient mice, and then the injection of human hematopoietic stem cell (HSC) into the body. Multi-line hu-HSC developed into immune cells, including B cells, T cells, NK cells and myeloid cells.26 These immune cells interact with transplanted tumor cells and can simulate the tumor microenvironment. Meraz et al27 constructed a hu-HSC model using fresh umbilical cord blood CD34+ HSCs to evaluate the immune response of lung cancer. Hu-HSC model can establish human innate immune system and lymphocytes, but it also has some limitations. For example, a small number of low-active human T cells could not be detected in the peripheral blood until 12 weeks after HSC was implanted into mice.28–30

Hu-PBL Model

Hu-PBL model was established by injecting human peripheral blood lymphocytes into immunodeficient mice. It is the simplest and most economical humanized mouse model at present. At present, the hu-PBL model has been used in many types of cancer research, such as lung cancer, thyroid cancer, cervical cancer, breast cancer, nasopharyngeal carcinoma and so on.31–35 Compared with the hu-HSC model, it can reconstruct high levels of T cells and is an ideal model for the study of mature effector T cells. However, due to the rejection of human T cells and mouse immune cells, this model is prone to graft-versus-host disease (GVHD), which shortens the life span of mice, which limits the research time.

Zebrafish Model

The zebrafish cancer model is a vertebrate model rising in recent years, and it is one of the most promising models at present. The genomes of zebrafish are homologous and conservative to humans, which provides a good basis for the study of the development of various cancers.36,37 Compared with the most commonly used mouse models, the zebrafish model has some unique advantages in cancer research:38 (1) small size, low cost and fast reproduction; (2) transparent embryos, it is convenient to observe and track the proliferation, spread and metastasis of cancer cells in real time; (3) transgenic zebrafish39 and immunodeficient zebrafish40 can remain transparent after adulthood. (3) because zebrafish is fertilized in vitro, the gene operation is relatively easy, and the transgenic animal model can be established quickly. At present, a variety of zebrafish cancer models have been established by means of transgenic, genome editing, xenotransplantation, drug-induced toxic damage and so on (Table 1).

Table 1 Zebrafish Model

Zebrafish Melanoma Model

Melanoma is a highly malignant tumor derived from melanocytes, which is the most difficult to cure in skin cancer.41,42 With the deepening of the understanding of the molecular mechanism of melanoma invasion, proliferation and metastasis, remarkable achievements have been made in the treatment of melanin. Melanoma cells achieve the purpose of rapid growth and metastasis by interacting with the microenvironment.43 Therefore, the establishment of the zebrafish melanoma model is very important for the study of melanoma pathogenesis and anti-melanoma drugs.

Dovey et al44 constructed a zebrafish model expressing NRAS Q61K by transgenic technology, which proved that the loss of p53 and the expression of NRAS promote the occurrence of melanoma. After Fornabaio et al45 injected melanoma cells into zebrafish embryos, the interaction between cancer cells and the outer surface of zebrafish blood vessels was monitored, and the first zebrafish model of melanoma angiogenesis and extravascular migration was established. Gomez-Abenza et al46 in order to study the role of Spint1a in melanoma, zebrafish models were constructed by transgenic technology. The results show that the absence of Spint1a promotes the development of melanoma, which also provides a new direction for the treatment of melanoma. Gabellini et al47 demonstrated that the high expression of bcl-xL and pro-inflammatory chemokine interleukin-8 (CXCL8) in patients with melanoma led to a poor prognosis using a zebrafish model.

Zebrafish Leukemia Model

The similarity between zebrafish and human hematopoietic systems has led to the increasing use of zebrafish to simulate leukemia.48 The establishment of the zebrafish leukemia model plays an important role in understanding the occurrence, development and drug research of human leukemia. Langenau et al49 injected rag2, encoding a lymphocyte-specific promoter into zebrafish to drive the expression of the mouse-derived c-Myc gene. It was found that the fluorescence-labeled leukemia cells in zebrafish were implanted into the immunodeficient thymus, suggesting that the proto-oncogene c-Myc is involved in the formation of zebrafish tumors. Gutierrez et al50 found that 4-hydroxytamoxifen (4HT) can activate Myc, to induce acute T-lymphoblastic leukemia in zebrafish by constructing MYC-ER transgenic zebrafish. Corkery et al51 successfully established a leukemia zebrafish casper model by implanting K562 and NB-4 human leukemia cell lines into zebrafish casper embryos, and conducted targeted inhibitor intervention experiments on this model, which laid a good foundation for tumor research in this whole animal. Since the construction of the first leukemic zebrafish model in 2003, zebrafish has made a great contribution to the study of leukemia. Through these studies, we not only have a deeper understanding of the pathogenesis of leukemia, but also proved a variety of anti-leukemia drugs, including Nimesulide, Lenaldekar and Perphenazine.52–54

Zebrafish Digestive Tract Tumor Model

Due to the concealment of the disease, the difficulty of early diagnosis and the lack of effective treatment, the incidence and mortality of digestive tract tumors are at a high level. Understanding the molecular mechanism of digestive tract tumorigenesis and looking for new drug therapy targets is the focus of the current research. Zebrafish do not have stomach and genes that express specific gastric function, but the gastric cancer cells in the gastric cancer xenotransplantation model have high similarity with humans.55 Tsering et al56 induced zebrafish to establish a gastric cancer xenotransplantation model and found that Triphala could inhibit the growth and metastasis of transplanted gastric cancer cells. Zebrafish liver cancer gene is highly conservative with humans,57 which makes the zebrafish model widely used in liver cancer research. Yan et al58 found an increase in the level of fibrinogen in the zebrafish hepatocellular carcinoma model induced by krasV12. They also found that fibrinogen may bind to Integrin α v β 5 on HSC to activate hepatic stellate cells. Jung et al59 introduced the hIL6 gene into zebrafish to study the relationship between hIL6 expression and liver cancer. The results showed that the transgenic zebrafish liver developed into typical liver cancer, which indicated that the high level of hIL6 caused the occurrence of hepatocellular carcinoma. At present, zebrafish intestinal tumor models are mostly xenotransplantation models. With the development of genetic engineering technology, the application of transgenic models is increasing. Topi et al60 studied the effect of estrogen receptor activator ERB-041 on colon cancer cells in a zebrafish xenotransplantation model. Compared with the control group, it was found that distant metastasis of cancer cells decreased after ERB-041 treatment. Lu et al61 established a krasV12 transgenic zebrafish model induced by mifepristone, which provides a good in vivo model for the study of krasV12-induced colorectal cancer. Although zebrafish do not have a discrete pancreas, it has exocrine acinar cells and intestines similar to the functional and histological characteristics of mammalian pancreas.62 Guo et al63 established a model of pancreatic cancer xenotransplantation by injecting human pancreatic cancer cells into zebrafish and found that a small molecule U0126 can inhibit the proliferation and metastasis of human pancreatic cancer cells in zebrafish by inhibiting Ras/Raf/MEK/ERK pathway. This also shows the feasibility of the zebrafish model for screening and identifying new therapeutic drugs for pancreatic cancer.

Other Zebrafish Cancer Models

Breast cancer is the most common cancer among women,64 and the incidence is increasing and getting younger worldwide. The mouse is a traditional tool to study breast cancer. It has many disadvantages, such as long cycle, high cost, complex operation and so on.65,66 With the development of the zebrafish model, more and more breast cancer studies take zebrafish as the experimental object. Ren et al67 constructed xenograft zebrafish breast cancer (co-) injection models to study the role of BMP antagonists GREMLIN-1 (GREM1) in the infiltration and exudation of breast cancer cells. In this model, they found that GREM1 promotes fibrosis in breast cancer-associated fibroblast (CAF) and promotes intravasation and extravasation in breast cancer. Zhu et al68 established a breast cancer xenotransplantation model in zebrafish and used Furanodiene and 5-FU (5-Fluorouracil) to treat zebrafish. Compared with the results of furadiene alone, the results showed that the two drugs had an obvious synergistic anticancer effect. Lung cancer is a kind of cancer with the highest morbidity and mortality in the world. In order to improve the diagnosis and treatment of lung cancer, it is necessary to further understand the pathogenesis and related molecular mechanism of lung cancer. Shen et al69 established a xenotransplantation model after LINC00152 knockout lung cancer cells were implanted into zebrafish. The comparison between the control group and stereoscopic microscope showed that the silencing of LINC00152 could inhibit the proliferation and metastasis of lung cancer cells. The zebrafish model can also be used to evaluate the efficacy and safety of anti-lung cancer drugs to find a more suitable treatment. In order to evaluate the effect of DFIQ (a Novel Quinoline Derivative) on non-small-cell lung cancer (NSCLC) in vivo, Huang et al70 used the zebrafish lung cancer model to receive DFIQ treatment. By monitoring cell growth, migration and apoptosis, it was found that DFIQ could inhibit cancer cells to a certain extent. From the current research, with the in-depth study of the zebrafish tumor model, it will open a new way for the molecular research mechanism of various cancers.

Patient-Derived Tumor Xenograft (PDX) Model

The traditional xenotransplantation model is to establish a stable cell line by screening human tumor cells in vitro, subculturing them, and then injecting them into immunodeficient mice to establish model.71 This model is called the cell line-derived xenograft (CDX) model, which has the advantages of easy to obtain tumor cell lines and easy to repeat experiments. However, with the continuous passage of tumor cells in order to adapt to the external petri dish environment, the tumor microenvironment has changed, resulting in the formation of tumors in mice cannot accurately reflect the characteristics of the original tumor. PDX model is a tumor model established by transplanting fresh tumor tissue from patients into animals by surgery.72,73 At present, the animals used are mainly immunodeficient mice. With the exploration of researchers, zebrafish and other animals provide a new tool for the establishment of PDX models. Compared with the CDX model, the most important advantage of the PDX model is that it completely retains the tumor microenvironment, avoids the effect of repeated passage on tumor heterogeneity, and can better simulate the tumor growth process in patients.74 The researchers carried out various biological tests on the transplanted tumors in liver cancer, colorectal cancer, melanoma, esophageal cancer and borderline cancer. It was confirmed that the PDX model maintained the biological characteristics of primary tumors and provided an accurate animal model for the study of oncology.75–77 Because the tumor tissue comes from different patients and uses one model to correspond to the pattern of one patient, the PDX model can reflect the genetic diversity of patients.72 These advantages make the PDX model widely used in all kinds of cancer research (Table 2). With the development of tumor research, the shortcomings of the traditional PDX model are also exposed. The traditional PDX model generally uses immunodeficient mice, but the immune system of mice is different from that of humans, so it can reflect the interaction between immunity and tumor.78 At the same time, the life span of immunodeficient mice is short, At the same time, the life span of immunodeficient mice is short, and there is the possibility of spontaneous tumor.79 The success rate of PDX modeling was also different among different tumor types, and the success rate of colorectal cancer and lung cancer was significantly higher than that of prostate cancer.80 These shortcomings promote the emergence of some improved PDX models.

Table 2 PDX Model

Humanized Patient-Derived Xenograft (Hu-PDX) Model

Firstly, the immune system of severe immunodeficiency mice (NOG or NSG, etc.) was rebuilt into a state consistent with that of normal people or clinical patients, and then human tumor tissue blocks were orthotopically transplanted into immune system humanized mice. This model is called the hu-PDX model. This model can provide a growth environment more similar to that of the human body for tumors, and has important application value in tumor treatment and the study of tumor occurrence, development and metastasis, especially in tumor immunotherapy.81–83 Hu-PDX model has been applied to many types of tumor research. Lin et al28 established human immunodeficient mice by implanting peripheral blood lymphocytes and proved that this PBMCs-derived PDX model is an effective tool for studying PD-L1/PD-1 targeted cancer immunotherapy. Rosato et al84 demonstrated the availability of anti-programmed cell death-1 (PD-1) immunotherapy in the TNBC study after constructing a PDX model derived from triple-negative breast cancer patients. Sanmamed et al16 injected lymphocytes from gastric cancer patients into immunodeficient mice, then transplanted gastric cancer tissue from the same patient into mice and finally injected mice with nivolumab (a PD-1 inhibitor) and urelumab (an anti-CD137 agonist). The results show that the use of the above drugs can induce the attack of self-T cells and slow down the growth of tumors. However, there are some problems in the current Hu-PDX model, such as low success rate of modeling, short existence time of humanized immune system, incomplete immune function and so on. Future research should focus on improving the modeling technology of humanized mice and improving the efficiency and duration of immune system implantation.85

Patient-Derived Orthotropic Xenograft (PDOX) Model

Most of the transplantation sites of the PDX model are subcutaneous or renal capsule, lack of in situ environment for tumor growth. It has been found that orthotopic transplantation of tumor tissue into animal organs corresponding to the primary site can provide an in vivo environment suitable for tumor growth.86 Therefore, the PDOX model is established on the basis of the PDX model. Compared with the traditional PDX model, this model can simulate the evolution of human tumors in vivo more objectively and accurately. Hiroshima et al87 established 10 cases of subcutaneous injection of PDX model and 8 cases of PDOX model using cervical cancer tissue. The results showed that tumor metastasis was found in half of the PDOX model, but not in the PDX model. The results show that the PDOX model is more likely to show the biological characteristics of malignant tumor invasion and metastasis than the PDX model. And a number of studies have shown that swelling. The organ microenvironment in which the tumor grows can directly affect the biological characteristics of the tumor. PDOX model can also accurately predict the prognosis of cancer patients and select the most suitable individual treatment for patients. Hiroshima once again established the PDOX model and subcutaneous PDX model of human cervical cancer again and treated the two models with entinostat (a benzamide histone deacetylase inhibitor).88 Finally, it was found that only the tumor growth was inhibited in the PDOX model. Because most of the tumors in the PDOX model are located in vivo, it is difficult to observe the growth of tumors by traditional detection methods, and it is more difficult to find the location of metastatic focus.89 Making a PDOX model that is easy to measure has become a problem that needs to be solved in the future.

Mini Patient Derived Xenograft (Mini-PDX) Model

Mini-PDX model is a drug sensitivity test model established after human tumor tissue was transplanted into immunodeficient mice by a special method.90 This special method is to first inject the digested cell suspension of the patient’s tumor tissue into the microcapsule and then transplant the capsule into the mouse.91 Zhan et al92 established a Mini-PDX model using tumor tissues of patients with gallbladder cancer to detect the sensitivity of the five most commonly used chemotherapeutic drugs, (gemcitabine, oxaliplatin, 5-fluorouracil and nanoparticle albumin-bound (nab)-paclitaxel, and irinotecan). The results showed that the proliferation rate of gallbladder cancer cells in the model was relatively low after treatment with irinotecan and gemcitabine. The advantages of this model for drug sensitivity testing are short time, low cost, and high consistency with the results of the traditional PDX model. Zhang et al90 constructed Mini-PDX models of lung cancer, gastric cancer and pancreatic cancer, and used the PDX model as a reference to test the drug sensitivity of the Mini-PDX model. The results show that the consistency of the results of drug sensitivity testing using the Mini-PDX model and the traditional PDX model is 92%, but the time required to use Mini-PDX model is significantly shorter than that of the PDX model. This shows that this model can be used as a good substitute for the PDX model in evaluating cancer treatment. Because of these advantages, the Mini-PDX model is expected to become a tool to help cancer patients with personalized treatment.

Other Animal Models

With the deepening of cancer research, more and more animals are used to build animal models. At present, most of the animal models commonly used in cancer research are small animal models, such as mice, rats, zebrafish, fruit flies and so on. Among them, mice and zebrafish are the most widely used. Small animal models have many advantages, such as strong reproductive ability, low cost, easy maintenance and so on. However, because of its small size and limited blood supply, it is difficult to carry out interventions such as surgery and radiography on small animals.93 The emergence of some large animal cancer models has provided new directions for researchers, including dogs, non-human primates, tree shrews and pigs.

Compared with rodents, canine genomes are more similar to human genomes.94 Canines can spontaneously form some cancers, which are similar to human cancers in clinical, molecular and histological features.95 Uva et al96 analyzed gene expression in human and dog breast cancer and normal breast samples and found that uncontrolled genes in human breast cancer could also be observed in canine breast cancer samples. Ressel et al97 found that there is also a loss of expression of the PTEN gene in canine breast cancer, and the same phenomenon can be observed in human breast cancer. These findings support the possibility of canine cancer models as a study of human cancer. Non-human primates are closely related to human beings and highly similar to human beings in physiology, metabolism, immunity, heredity and many other aspects, so it is an excellent cancer research model. Puente et al98 found that almost all human cancer genes are highly conserved between chimpanzees and humans. However, due to the high cost of breeding and feeding, complex experimental techniques and ethical problems, the use of non-human primates has been limited.99 The tree shrew is a new experimental animal in recent years, its whole genome is very similar to primates, and its physiology and biochemistry, tissue anatomy and immunology are similar to humans.100 Tu et al101 constructed the pancreatic cancer model of tree shrew using lentivirus and analyzed the gene expression profile by RNA sequencing. The results showed that the molecular mechanism of the tree shrew pancreatic cancer model was more similar to that of the human pancreatic cancer model than that of the mouse pancreatic cancer model. Compared with non-human primates, it also has the advantages of small size, short reproductive cycle, easy feeding and so on. It also allows tree shrews to replace primates for cancer research. Ge et al102 successfully constructed a tree shrew breast cancer model with lentivirus expressing PyMT gene and found that chemotherapy drugs commonly used in human breast cancer (cisplatin and Ebramycin) can significantly inhibit tree shrew breast tumor. The pig genome has highly conserved epigenetic regulation and has high homology with the human genome.103,104 The anatomical, physiological and genetic characteristics of pigs are very similar to those of humans, and they are ideal animal models for cancer research. Mitchell et al105 induced hepatocellular carcinoma in pigs using diethylnitrosamine (DEN) and found that partial hepatic embolism could promote the construction of the model. And the emergence of gene editing pigs provides a new tool for the study of cancer-related genes. Wang et al106 established gene editing pigs expressing Cas9 under the induction of Cre enzyme, and established a pig model of lung cancer after activating one oncogene (KRAS) and five tumor suppressor genes (TP53, PTEN, APC, BRCA1 and BRCA2) at the same time. Importantly, studies have shown that young pigs can predict pharmacokinetics in children,107 which provides a basis for the use of piglet models to develop anticancer drugs.

Summary and Prospect

As an excellent tool to study the pathogenesis of human diseases and explore the principles of disease prevention and treatment, animal models are constantly providing new ideas for cancer research. However, there are some differences in physiology, heredity and immunity between animal models and human beings. Therefore, it is an urgent need for the current biomedical development to develop animal models that can better reflect human biological characteristics and replace human beings to carry out preclinical research. Because of the strong heterogeneity of cancer, the tumor tissue constructed by cell line-derived xenograft (CDX) model and traditional in vitro culture is different from humans, which cannot accurately reflect the biological process of human tumor tissue and reduce the efficiency of cancer research.108 The use of the patient-derived xenograft (PDX) model can better simulate the tumor growth process in patients, and the consistent rate of drug response is high.74 On this basis, in order to further simulate the physiological or pathological state of human beings, the humanized animal model came into being. In recent years, with the continuous development and improvement of gene-editing technology, it is possible to make a variety of cancer animal models, which has greatly promoted the related research of cancer. Researchers are working on a model that is more similar to the human genome.109 In the future, we can combine various construction methods with the help of gene-editing technology to construct a model that is more suitable for cancer research.

Acknowledgment

The following authors contributed equally to this work and are all first authors: Zhitao Li, Wubin Zheng, and Hanjin Wang.

Funding

This work was supported by a grant from the Medical Science and Technology Development Foundation (ZKX18027) to Hanjin Wang.

Disclosure

The authors report no conflicts of interest for this work.

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