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. 2023 May 12;92:104601. doi: 10.1016/j.ebiom.2023.104601

Towards an optimal model for gastric cancer peritoneal metastasis: current challenges and future directions

Zehui Li a,c, Jin Wang b,c, Zhenning Wang a,∗∗, Yan Xu a,∗
PMCID: PMC10200840  PMID: 37182268

Summary

Peritoneal metastasis is a challenging aspect of clinical practice for gastric cancer. Animal models are crucial in understanding molecular mechanisms, assessing drug efficacy, and conducting clinical intervention studies, including those related to gastric cancer peritoneal metastasis. Unlike other xenograft models, peritoneal metastasis models should not only present tumor growth at the transplant site, but also recapitulate tumor cell metastasis in the abdominal cavity. Developing a reliable model of gastric cancer peritoneal metastasis involves several technical aspects, such as the selection of model animals, source of xenograft tumors, technology of transplantation, and dynamic monitoring of the tumor progression. To date, challenges remain in developing a reliable model that can completely recapitulate peritoneal metastasis. Thus, this review aims to summarize the techniques and strategies used to establish animal models of gastric cancer peritoneal metastasis, providing a reference for future model establishment.

Keywords: Gastric cancer, Peritoneal metastasis, Animal model, Immunodeficient mouse, Patient-derived xenograft (PDX), Cell line-derived xenograft (CDX)

Introduction

Peritoneal metastasis is present in over 50% of patients with gastric cancer at the time of death.1, 2, 3 Despite recent advances in therapy, such as cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), peritoneal metastasis remains the leading cause of gastric cancer-related deaths.4, 5, 6

Peritoneal metastasis is a multistep process wherein cancer cells penetrate the gastric serosa, reach the peritoneal cavity, survive and proliferate in the peritoneal microenvironment, attach to the peritoneal mesothelial, invade the basement membrane, and eventually metastasize.7,8 Animal models are important in understanding the biological behavior and molecular mechanism of carcinogenesis and assessing drug efficacy.9 Compared with normal tumor xenograft models, peritoneal metastasis models involve more technical aspects and thus are more difficult to establish. Peritoneal metastasis models must present tumor growth at the transplant site and tumor metastasis in the abdominal cavity. And that information is hardly available from a normal tumor xenograft model. The first reason is that the incidence of metastasis in subcutaneous transplanted tumor model is relatively low, and the second is that the site of metastasis is random. Therefore, it is necessary to design and build the peritoneal metastasis model directly. Various peritoneal metastasis models of gastric cancer have been established in recent years,10,11 but these models remain to have several limitations.12 In the opinion of the authors, an ideal model of gastric cancer peritoneal metastasis should have the following characteristics: Supreme comparability in features, such as microenvironment, histology, and molecular genetics, with the tumor mass from patients; high potential for tumorigenesis and peritoneal metastasis; capacity to represent the metastatic cascade; capacity to detect tumor progression in real-time, allowing timely sampling or intervention; and reproducible and simple establishment process. However, an animal model of gastric cancer peritoneal metastasis that meets all of the above criteria is unavailable.

Spontaneous gastric cancer models established using either chemical carcinogens, Helicobacter pylori infection, or transgenic technology also have limitations, including the long tumor formation time (approximately 10–12 months) and the absence of peritoneal metastasis.13 Han et al. treated 144 C57BL/6 mice with N-methyl-N-nitrosourea (MNU) and H. pylori infection. The combination of MNU and H. pylori infection resulted in a significantly higher incidence of gastric adenoma and adenocarcinoma. However, distant metastasis was not observed in any cases.14 Consequently, researchers usually employ implantation to build models of gastric cancer peritoneal metastasis. In this review, we will focus on the current state of technology and challenges in establishing models of gastric cancer peritoneal metastasis, including the selection of model animals, source of xenograft tumors, techniques and strategies of transplantation, and dynamic monitoring of tumor progression.

Selection of model animals

Similar to other tumor models, immunodeficient mice are commonly used to develop animal models of gastric cancer peritoneal metastasis. In 1976, Ueyama et al. established the first animal model of gastric cancer peritoneal metastasis. Malignant ascitic cells from a 64-year-old male patient with gastric cancer were injected subcutaneously into nude mice (BSLB/c), and inoculants were obtained from the subcutaneous tumor after the cells proliferated. Tumors were minced into fragments and then intraperitoneally injected into nude mice. Ascitic fluid began to accumulate 45 days after inoculation, and the morphologies of these cells were similar to those of the original cells of that patient.15 Since then, nude mice with deficient T-cell function have become the most widely used animal models for gastric cancer peritoneal metastasis.

Recently, severe combined immune deficiency (SCID) mice and nonobese diabetic severe combined immune deficiency (NOD/SCID) mice have been gradually applied to patient-derived xenograft (PDX) models of gastric cancer.16,17 SCID mice are immunocompromised mice that lack T and B cells,18 whereas NOD/SCID mice have a lower immune recovery risk than SCID mice because of their lower natural killer (NK) cell activity.19 Given their higher engraftment efficiency and less immunological rejection than nude mice, SCID and NOD/SCID mice are more suitable recipients of peritoneal metastasis models.12

However, NOD/SCID mice have several shortcomings, including short survival periods, and residual NK activities.20 To engraft human cells and tissues successfully and prolong the observation time, previous studies established immunodeficient interleukin (IL) 2rgnull mice (e.g., NOG, NSG) by crossbreeding NOD/SCID mice with IL-2 receptor R-deficient mice.21,22 Those mice are the best immunodeficient animals for the efficient engraftment of primary human tumors because they exhibit composite immunodeficiency (T, B, and NK cell defects and dendrocyte/macrophage malfunction) and lack innate and adaptive immune function.20 Although immunodeficient IL 2rgnull mice are the cornerstone of the PDX models, they have yet to be used to establish a model of peritoneal metastasis. A comparison of the different immunocompromised mouse models is shown in Table 1.

Table 1.

Comparison of different immunocompromised mice.

Mice Features Immune system Limitation References
Nude Furless, applied in observation of subcutaneous xenografts Athymic, T cell deficiency B cell and NK cell function, Leakage of T cells 20,22
SCID With a mutation of Prkdc gene T cell and B cell deficiencies NK cell function, Radiosensitive, Lymphocyte leakage 20,22
NOD/SCID Established by crossing NOD mice and SCID mice T cell, B cell, and NK cell deficiencies Thymus lymphomas, Short survival time 20,22
IL2rgnull (NOG/NSG/BRG) With a mutant IL-2 receptor gene which instructs the production of a common γ-chain protein, applied in humanized mouse models T cell, B cell, and NK cell deficiencies, Other immune deficiencies 21
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Mouse models of peritoneal metastasis have been widely used to study molecular mechanisms and drug resistance11,23, 24, 25 because of their several advantages, such as easy handling, short growth cycle, high fecundity, mature gene editing technology, and low cost.26,27 Mice have a small abdominal cavity space and thin stomach wall (approximately 1 mm), thus requiring delicate operations. In addition, they have low circulating blood volumes, resulting in fluctuating serum concentration. Thus, the drug dose and dosing interval must be calculated precisely.

Large animal models, such as rats and rabbits, offer more advantages than small ones in the studies of clinical interventions including surgical treatment and efficacy evaluation.28, 29, 30 Mei et al. established rabbit models of peritoneal metastasis by injecting VX2 cancer cells into the stomach lining of New Zealand rabbits.31 Using this model, they further investigated the safety and efficacy of CRS plus HIPEC for treating gastric cancer peritoneal metastasis.32 Compared with the control group, in this rabbit model of gastric cancer with peritoneal metastasis, CRS plus HIPEC significantly prolonged survival with acceptable safety in this rabbit model of gastric cancer peritoneal metastasis.

Sources of xenograft tumors

As shown in Fig. 1, animal models are divided into cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models based on the source of xenograft tumors.33, 34, 35 Immortalized cancer cell lines have been widely used to establish multiple types of tumor models because of their easy access, simple cultivation, and low cost. Gastric cancer cell lines commonly used in peritoneal metastasis models include N87, KATOⅢ, NUGC4, and OCUM-1.36,37 Different cell lines possess different biological features with varying tumorigenicities and peritoneal metastasis potentials.38 To establish animal models with high metastasis potentials, Yanagihara et al. assessed several gastric cancer cell lines with highly invasive features and metastasis potentials from clinical specimens.39 They orthotopically inoculated gastric cancer cell lines HSC-44PE and HSC-58 into the stomach wall of nude mice and then collected the second-generation cells in metastasis sites. They orthotopically implanted the second-generation cells that proliferated in vitro and then collected the third-generation metastatic cells. These steps were repeated for at least 12 cycles, and then gastric cancer cell lines (44As3, 58As1, and 58As9) with strong capabilities to induce peritoneal metastasis were finally selected. Compared with the parental HSC-44PE and HSC-58 cell lines, the selected gastric cancer cell lines with high peritoneal metastasis potentials had a 100% engraftment rate and generated malignant ascites in 90% of the nude mice. However, given the long-term culture in vitro, the immortalized cell lines show defects in cytological characteristics and gene expression profiles; these defects include amplified large chromosome segments, varying growth and invasive capacity, and shifting into monoclonal.40,41 Consequently, CDX models are unlikely to retain the heterogeneous histological and genetic features of the original tumor. To elucidate the role of cancer-associated fibroblasts (CAFs) in tumor microenvironment of peritoneal metastasis, Nakamura et al. established a fibrous peritoneal tumor model by co-inoculating the mouse gastric cancer cell line YTN16 and the mouse myofibroblast cell line LmcMF into immune-competent mice.11 To our knowledge, no patient-derived cancer cells and CAFs co-inoculating in animal model have been reported so far.

Fig. 1.

Fig. 1

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Schematic diagram of establishing CDX and PDX models. CDX mouse models are established by inoculating gastric cancer cell lines into immunodeficient mice. CDX models are unlikely to retain the heterogeneous histological and genetic features of the original tumor. While PDX mouse models are established by tumor tissues or cell suspension derived from patients with gastric cancer into immunodeficient mice after pre-experiment procedure. Created with BioRender.com, accessed on 27 February 2023.

PDX models are established by inoculating tumor cells or tissue blots from patients into immunodeficient mice directly or after several passages.42 These models retain the genetic, histological, and phenotypic characteristics and mimic the microenvironment of the original tumor and overcome the shortcomings of CDX models.43 Given their good predictability in preclinical research, PDX models are gradually becoming crucial platforms for investigating the mechanism of tumor growth and drug resistance.44,45 Furukawa et al. were the first to establish patient-derived orthotopic nude mouse models of gastric cancer.46 Neoplastic tissue blots from 36 patients with gastric cancer were transplanted into the serosal surface of the stomach of nude mice. After 2–6 months, tumor growth was observed in 20 cases of the 36 mice, including 5 with hepatic metastasis and 5 with peritoneal metastasis. It's a remarkable fact that PDX models cannot suffer from too many passages, because in that case the stroma is replaced by the components of the mouse.47,48 Cells are dissociated from tumor tissues or PDX to prepare a cell suspension, which is then transplanted. This procedure avoids the above problems and increases the tumorigenesis rate. Giraud et al. prepared a cell suspension from gastric cancer PDX tissues and injected it into the stomach wall of nude mice orthotopically. They obtained a stomach tumor frequency close to 100%. Meanwhile, organ metastasis was observed in the lung and liver with the formation of peritoneal metastasis.49 It seems that the aggressiveness of primary tumor is important to the success rates of PDX. However, several studies have shown that no significant association between PDX growth and the tumor characteristics.50 On the other hand, tumor samples from peritoneal metastasis or ascites are often used to establish models and relatively good results have been obtained.

To increase the frequency of peritoneal metastasis, Song et al. established three new peritoneal carcinomatosis cell lines (GA0518, GA0804, and GA0825) from malignant ascites of patients with gastric cancer. These cells were inoculated into NOD/SCID mice subcutaneously or orthotopically to build PDX models. High tumorigenicity and metastasis rates were obtained in the PDX models, of which the phenotype, molecular, and pharmacological features were similar to those of donor cells from patients.51 In a subsequent study, to investigate the role of YAP1 in peritoneal metastasis, they knocked out YAP1 in GA051816 cells by using LentiCRISPR/Cas9 and successfully established a peritoneal metastasis model again by utilizing these cells as xenografts.52 In vivo and in vitro experiments showed that the tumorigenicity and metastasis of the mice with YAP1-knockout cells were significantly lower than those of the mice with parental cells. Furthermore, this model has been used to verify the therapeutic effect of YAP1 inhibitors on gastric cancer peritoneal metastasis.

Techniques of transplantation

Microsurgical techniques are critical in successful modeling. Reasonable implantation sites and optimized surgical procedures increase modeling efficiency by saving time, cost, and labor. Regarding implantation sites, the induced spontaneous gastric cancer model and the subcutaneous graft tumor model, generally lack peritoneal metastasis.53 Therefore, two strategies are commonly applied in peritoneal metastasis models. One is injecting the neoplasm cell suspension into the abdominal cavity of animals directly to form peritoneal carcinomatosis. This method is preferred by many researchers because of its simple procedures and slight trauma.54, 55, 56 In theory, it can mimic the process by which cancer cells reach the abdominal cavity and metastasize. However, this strategy skips the first stages of peritoneal metastasis [e.g., the neoplasm penetrates the serosa, and the free cells proliferate in the abdominal cavity]. Therefore, it cannot represent the entire process of peritoneal metastasis. The other strategy is orthotopic implantation, transferring the tumor tissue blot or cell suspension into the stomach wall or subserosa.57,58 Compared with the first strategy, this strategy can better recapitulate the natural course of peritoneal metastasis in gastric cancer and ensure higher metastasis rates in the lymph nodes, liver, and lungs.59 Several methods such as incision-embedding,46 injection,59 and OB glue paste60 have been developed to implant tumors into the stomach wall (Fig. 2). Incision-embedding technique is the most common technique and closely matches the concept of orthotopic implantation. Briefly, this technique involves exposing the stomach by making an incision on the abdominal wall, and then embedding the tumor pieces or injecting the cell suspension into the stomach wall.

Fig. 2.

Fig. 2

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Techniques of transplantation. Orthotopic implantation (upper): cell suspension or tissue blots are surgically transplanted into the stomach wall of the mouse. (a) Incision-embedding technique: The serosa of gastric wall is injured by scissors or an injection needle, and tissue pieces are transplanted and fixed with suture or OB glue. (b) Injection method: The cell suspension is injected under the serosal layer in the greater curvature of stomach with a syringe. (c) Posterior wall approach: The needle was pierced through the posterior wall to penetrate into the gastric cavity. Under direct vision, the needle continues to insert into the anterior wall without breaking the serosa. The cell suspension is then slowly injected into the subserosa of the anterior wall. Subcutaneous transplantation (middle): almost no peritoneal metastasis. Intraperitoneal injection (lower): injecting cell suspension into the abdominal cavity of mice directly. Created with BioRender.com, accessed on 27 February 2023.

The main risk of orthotopic implantation techniques is that tumor cells leak into the abdominal cavity resulting in iatrogenic metastases, which produces false-positive outcomes. Owing to the thin stomach wall of the mouse, orthotopic implantation is difficult to perform; tissue embedding is either too deep (tissue detachment into the stomach cavity and modeling failure) or too shallow (tissue detachment into the abdominal cavity, leading to an iatrogenic spread). Poor healing of incisions in the stomach wall and premature exposure of cancer cells may also produce false-positive outcomes. Several efforts have been exerted to overcome this challenge. Kang et al. developed a novel technique for building orthotopic mouse models of gastric cancer.61 After creating a subserosa space by injecting saline or Matrigel solution, the tumor fragment or minced tissue is transplanted into that space. The advantage of this method is that xenografts especially tumor fragments can be completely embedded in the stomach wall. However, this method punctures the surface of the stomach wall; thus, cell leakage could still occur.

We have recently developed a posterior wall approach for orthotopic implantation.51 The most significant improvement of this method is that the needle is pierced through the posterior wall to penetrate the gastric cavity. Under direct vision, the needle is inserted into the anterior wall without breaking the serosa. The cell suspension is then slowly injected into the subserous of the anterior wall (Fig. 2c). Thus, the destruction of the serosa of the anterior wall is completely avoided. Even if cells leak, they can only leak into the stomach. This method is easy to be performed and can be completed within 10 min. The whole procedure consists of only the following steps: exposing the stomach, lifting the stomach, puncture and injection, and finally closing the abdomen. However, this method is only suitable for cell suspensions and not for fragments.

Subcutaneous implantation is generally applied in conventional tumor xenograft animal models because of its simple procedures and visually measurable tumor size.62 However, it's unsuitable for building peritoneal metastasis models because it induces an expansive growth tumor without visible cell invasions and rarely results in distant metastasis (including in the abdomen and other organs). Kuwata et al. subcutaneously implanted 232 gastric cancer specimens into immunodeficient mice and obtained 40 primary xenograft tumors. After five passages, 35 PDX models were established, but none of them showed metastasis.63 Nakano et al. found that compared with the subcutaneous xenograft tumor, although the orthotopic xenograft tumor requires a longer cultivation time, the orthotopic xenograft tumor has no visible capsule and forms abundant stroma, where micro-vessels penetrate the tumor parenchyma.64 These results suggest that the microenvironment of orthotopically transplanted tumors is more similar to that of the original tumor in terms of histology, vascular system, and biological behavior.

Dynamic monitoring of peritoneal metastasis

Peritoneal metastasis in mouse models cannot be directly observed and measured, unless ascites or cachexia are present. Traditionally, intra-abdominal tumor progression can be assessed only after the animal has been sacrificed. However, the timing of sacrifice can merely depend on a predetermined time point, whether the animal shows weakness or changes in body weight.

Imaging techniques commonly used in clinics, such as ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET), have been used in preclinical studies.65 These techniques can accurately assess the primary and metastatic lesions in animal models. However, these imaging techniques require large equipment and are complex and time-consuming. In-vivo optical imaging is suitable for small animal models (e.g., mice) with a large number of entries. Two optical imaging methods are generally used to observe peritoneal metastasis in mouse models: fluorescence and bioluminescence imaging. Compared with CT and MRI, optical imaging is a non-invasive, affordable, and simple imaging modality used to detect peritoneal metastasis in small animal models. Luciferase or fluorescent protein plus in vivo imaging has gradually become the standard configuration for peritoneal metastasis models.66,67

The mechanism of bioluminescence imaging (BLI) is based on light-generating enzymes, such as firefly luciferase, which catalyzes the substrate luciferin into the light-emitting product oxyluciferin.68 As a bioluminescent marker of reporter genes in vivo, luciferase has the following advantages: high sensitivity, as the signal is detected without background noise. Furthermore, bioluminescence reports the number of viable cells because the luciferase enzymatic reaction is ATP-dependent.69,70

However, BLI may be affected by tissue depth, which leads to the refraction of light and absorption of light by other tissues. Bioluminescence also requires a substrate and takes minutes to visualize, whereas fluorescence acquisition can take seconds.71

Compared with bioluminescence, fluorescence is dependent on excitation to re-emit light instead of an enzymatic reaction, but has lower sensitivity because of background autofluorescence.72 Gene-editing enables the encoding of fluorescent protein (e.g., GFP) genes into the genome of tumor cells. In a fluorescence microscope, excitation light is used to illuminate labeled cells, which gives off fluorescence.

Fluorescence and bioluminescence imaging is an optical imaging method that allows noninvasive in vivo studies of molecular events and biological processes, including disease progressions, protein–protein interactions, and treatment efficacy.73,74

Outstanding questions

Animal models, as irreplaceable tools, offer a predictive model platform for preclinical studies, such as the studies of molecular mechanism, drug efficiency, preclinical intervention, etc, which are related to the peritoneal metastasis of gastric cancer.75 Unfortunately, a single animal model that can meet all the basic and translational research needs is currently unavailable. Under the current conditions, a reasonable strategy is to select an appropriate model for each scientific issue. A deep understanding of the principles of building different models, related pathophysiological processes, and combinations of different technologies is required to build models.

Several questions need to be addressed to expand the application of xenograft models in the research of peritoneal metastasis in gastric cancer. First, we should shed light on the application of xenograft models, especially in precision medicine as the different effects are shown between animal models and patient treatments. Although PDX models provide a platform for high efficacy in drug testing, further improvement is still needed because building PDX models and testing drugs are time-consuming and may hinder the timely treatment of patients with aggressive cancer. Furthermore, the study of immune therapy in humanized mice has some limitations, such as the occurrence of graft-versus-host disease and spontaneous thymoma. In addition, tumor burden, tumor stage, cancer type, surgical approach, size and freshness of tumor tissue, hormone supplementation, and risk of tumor cell leakage should all be considered in improving PDX models.76

In the future, combined with interdisciplinary involvement, ideal animal models with several improvements, including accurate implantation, and dynamic monitoring of tumor cells in multidimensions, are expected to be developed to overcome the limitations of existing models.

Contributors

YX contributed to the conception and design of the review. The first draft was written by ZL and JW. YX and ZL designed and produced the figures and tables. ZW and YX critically revised the final manuscript. All authors have read and approved the final version of the manuscript.

Search strategy and selection criteria.

Data for this Review were identified by searches of PubMed, Web of Science, and references from relevant articles using the search terms “gastric cancer”, “peritoneal metastasis”, “animal models”, “patient-derived xenograft models”, “Humanized mouse models”, and “optical imaging”. Abstracts and reports from meetings were included. Only articles published in English between 1970 and 2022 were included, but the vast majority of cited works were from the past 10 years.

Declaration of interests

The authors have no competing interests to declare.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (82072733).

Contributor Information

Zhenning Wang, Email: josieon826@sina.cn.

Yan Xu, Email: yanxu@cmu.edu.cn.

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