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Current Opinion in Urology Jul 2024Bladder cancer (BC) is a highly heterogenous disease comprising tumours of various molecular subtypes and histologic variants. This heterogeneity represents a major... (Review)
Review
PURPOSE OF REVIEW
Bladder cancer (BC) is a highly heterogenous disease comprising tumours of various molecular subtypes and histologic variants. This heterogeneity represents a major challenge for the development of novel therapeutics. Preclinical models that closely mimic in vivo tumours and reflect their diverse biology are indispensable for the identification of therapies with specific activity in various BC subtypes. In this review, we summarize efforts and progress made in this context during the last 24 months.
RECENT FINDINGS
In recent years, one main focus was laid on the development of patient-derived BC models. Patient-derived organoids (PDOs) and patient-derived xenografts (PDXs) were demonstrated to widely recapitulate the molecular and histopathological characteristics, as well as the drug response profiles of the corresponding tumours of origin. These models, thus, represent promising tools for drug development and personalized medicine. Besides PDXs, syngenic in vivo models are of growing importance. Since these models are generated using immunocompetent hosts, they can, amongst others, be used to develop novel immunotherapeutics and to evaluate the impact of the immune system on drug response and resistance.
SUMMARY
In the past two years, various in vivo and in vitro models closely recapitulating the biology and heterogeneity of human bladder tumours were developed.
Topics: Urinary Bladder Neoplasms; Humans; Animals; Disease Models, Animal; Organoids; Precision Medicine; Xenograft Model Antitumor Assays; Antineoplastic Agents
PubMed: 38630912
DOI: 10.1097/MOU.0000000000001182 -
Journal of Innate Immunity 2021To investigate immunological differences and the role of CD38+/F4/80 + M1 macrophages in C57BL/6J- and BALB/c-recipient mouse corneal transplantation models. (Comparative Study)
Comparative Study
PURPOSE
To investigate immunological differences and the role of CD38+/F4/80 + M1 macrophages in C57BL/6J- and BALB/c-recipient mouse corneal transplantation models.
METHODS
Allogeneic transplantation was performed crosswise in BALB/c mice and C57BL/6J mice; syngeneic transplantation was performed in both strains. Anterior chamber depth (ACD) was measured before and central corneal thickness (CCT) was measured both before and after transplantation. In vivo graft rejection was monitored using anterior eye segment optical coherence tomography (ASOCT) evaluating the CCT and grading of corneal oedema using a well-established clinical score (CS). Histology of corneal grafts was performed 18 or 21 days after surgery. Immunohistochemistry with anti-F4/80 antibody and anti-CD38 antibody was used for detecting M1 macrophages within the grafts.
RESULTS
High CS and CCT values after allogeneic transplantation persisted in both BALB/c (n = 18) and C57BL/6J recipients (n = 20). After syngeneic transplantation, CS and CCT values increased in both models in the early phase after surgery due to the surgical trauma. Surprisingly, in the syngeneic C57BL/6J model, high CCT values persisted. Furthermore, anterior synechiae developed in C57BL/6 recipients after both syngeneic and allogeneic transplantation, whereas BALB/c recipients showed almost no synechiae - even though C57/BL6J animals tended to have a deeper anterior chamber (281 ± 11 pixels [mean ± SD]) compared with BALB/c animals of the same age (270 ± 9 pixels [mean ± SD]). Immunohistochemistry revealed numerous CD38+/F4/80 + M1 macrophages in grafts of C57BL/6J recipients following both syngeneic and allogeneic transplantation. However, in BALB/c-recipient mice only sparse M1 macrophages were detectable (CD38 + M1 macrophages relative to all F4/80 + cells: 75 vs. 17% [after allogeneic transplantation] and 66 vs. 17% [after syngeneic transplantation]; p < 0.05).
CONCLUSIONS
Allogeneic corneal transplants are rejected in BALB/c as well as C57BL/6J mice, but tissue alterations with anterior synechiae are more pronounced in C57BL/6J recipients. Following syngeneic transplantation, C57BL/6J-recipient animals show a persistent graft swelling with increased numbers of CD38+/F4/80 + M1 macrophages in grafted tissue, in contrast to the common model using BALB/c-recipient mice. Our data strongly suggest that strain-dependent differences convey different innate immune responses in BALB/c and C57BL/6J strains. Accordingly, in murine keratoplasty experiments, the mouse line of both donor and recipient animals must be carefully considered. C57BL/6J-recipient mice might be particularly suited to study corneal graft rejection in a clinical setting considered "high risk."
Topics: ADP-ribosyl Cyclase 1; Animals; Anterior Eye Segment; Antigens, Differentiation; Cell Movement; Corneal Transplantation; Genetic Background; Genetic Predisposition to Disease; Graft Rejection; Immunity, Innate; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Tomography, Optical Coherence; Transplantation, Homologous; Transplantation, Isogeneic
PubMed: 32906119
DOI: 10.1159/000509716 -
Journal of Mammary Gland Biology and... Jun 2019In order to develop a practical model of breast cancer, with in vitro and syngeneic, immune-intact, in vivo growth capacity, we established a primary cell line derived...
In order to develop a practical model of breast cancer, with in vitro and syngeneic, immune-intact, in vivo growth capacity, we established a primary cell line derived from a mammary carcinoma in the transgenic FVB/N-Tg(MMTV-ErbB2*)NDL2-5Mul mouse, referred to as "NDL". The cell line is adapted to standard cell culture and can be transplanted into syngeneic FVB/N mice. The line maintains a stable phenotype over multiple in vitro passages and rounds of in vivo transplantation. NDL tumors in FVB/N mice exhibit high expression of ErbB2 and ErbB3 and signaling molecules downstream of ErbB2. The syngeneic transplant tumors elicit an immune reaction in the adjacent stroma, detected and characterized using histology, immunophenotyping, and gene expression. NDL cells also express PD-L1 in vivo and in vitro, and in vivo transplants are reactive to anti-immune checkpoint therapy with responses conducive to immunotherapy studies. This new NDL cell line model is a practical alternative to the more commonly used 4T1 cells, and our previously described FVB/N-Tg(MMTV-PyVT)634Mul derived Met-1 and FVB/NTg(MMTV-PyVT) derived DB-7 cell lines. The NDL cells have, so far, remained genetically and phenotypically stable over many generations, with consistent and reproducible results in immune intact preclinical cohorts.
Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Drug Screening Assays, Antitumor; Feasibility Studies; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Primary Cell Culture; Receptor, ErbB-2; Reproducibility of Results
PubMed: 30810966
DOI: 10.1007/s10911-019-09425-3 -
Cold Spring Harbor Perspectives in... May 2024The recent rise in effective immuno-oncology therapies has increased demand for experimental approaches to model anticancer immunity. A variety of mouse models have been...
The recent rise in effective immuno-oncology therapies has increased demand for experimental approaches to model anticancer immunity. A variety of mouse models have been developed and used to study cancer immunology. These include mutagen-induced, genetically engineered, syngeneic, and other models of cancer immunology. These models each have the potential to define mechanistic aspects of anticancer immune responses, identify potential therapeutic targets, and serve as preclinical models for further therapeutic development. Specific benefits and liabilities are characteristic of particular cancer immunology modeling approaches. The optimal choice and utilization of models depends on the cancer immunology scientific question being addressed and can serve to increase mechanistic understanding and development of human immuno-oncology therapies.
PubMed: 38772704
DOI: 10.1101/cshperspect.a041682 -
Frontiers in Immunology 2018Adaptive immune system, principally governed by the T cells-dendritic cells (DCs) nexus, is an essential mediator of gestational fetal tolerance and protection against...
Adaptive immune system, principally governed by the T cells-dendritic cells (DCs) nexus, is an essential mediator of gestational fetal tolerance and protection against infection. However, the exact composition and dynamics of DCs and T cell subsets in gestational tissues are not well understood. These are controlled in human physiology by a complex interplay of alloantigen distribution and presentation, cellular/humoral active and passive tolerance, hormones/chemokines/angiogenic factors and their gradients, systemic and local microbial communities. Reductive discrimination of these factors in physiology and pathology of model systems and humans requires simplification of the model and increased resolution of interrogative technologies. As a baseline, we have studied the gestational tissue dynamics in the syngeneic C57BL/6 mice, as the simplest immunological environment, and focused on validating the approach to increased data density and computational analysis pipeline afforded by highly polychromatic flow cytometry and machine learning interpretation. We mapped DC and T cell subsets, and comprehensively examined their maternal (decidual)-fetal (placental) interface dynamics. Both frequency and composition of decidual DCs changed across gestation, with a dramatic increase in myeloid DCs in early pregnancy, and exclusion of plasmacytoid DCs. CD4+ T cells, in contrast, were lower at all gestational ages and an unusual CD4CD8TCRαβgroup was prominent at mid-pregnancy. Dimensionality reduction with machine learning-aided clustering revealed that CD4CD8 T cells were phenotypically different from CD4+ and CD8+ T cells. Additionally, divergence between maternal decidual and fetal placental compartment was prominent, with absence of DCs from the placenta, but not decidua or embryo. These results provide a novel framework and a syngeneic baseline on which the specific role of alloantigen/tolerance, polymicrobial environment, and models of pregnancy pathology can be precisely modeled and analyzed.
Topics: Adaptive Immunity; Animals; Cells, Cultured; Decidua; Dendritic Cells; Female; Fetus; Gestational Age; Humans; Immune Tolerance; Male; Mice, Inbred C57BL; Placenta; Pregnancy; T-Lymphocyte Subsets; Uterus
PubMed: 30283441
DOI: 10.3389/fimmu.2018.02087 -
Transplant Immunology Aug 2021Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are attractive immune cells to induce immune tolerance. To explore a strategy for improving the...
BACKGROUND
Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are attractive immune cells to induce immune tolerance. To explore a strategy for improving the efficacy of MDSC therapies, we examined the impact of adoptive transfer of several types of MDSCs on graft rejection in a murine heart transplantation model.
METHODS
We analyzed the effects of induced syngeneic and allogeneic bone marrow-derived MDSCs (BM-MDSCs) on graft survival and suppressive capacity. We also compared the ability of syngeneic monocytic MDSCs (Mo-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) to inhibit graft rejection and investigated the suppression mechanisms.
RESULTS
Both syngeneic and allogeneic donor- or allogeneic third-party-derived BM-MDSCs prolonged graft survival, although syngeneic BM-MDSCs inhibited anti-donor immune responses most effectively in vitro. Syngeneic Mo-MDSCs, rather than PMN-MDSCs, were responsible for immune suppression through downregulating inducible nitric oxide synthase (iNOS) and expanded naturally occurring thymic originated Treg (nTreg) in vitro. Adoptive transfer of Mo-MDSCs, but not PMN-MDSCs, prolonged graft survival and increased Treg infiltration into the graft heart.
CONCLUSION
Recipient-derived Mo-MDSCs are most effective in prolonging graft survival via inhibiting T cell response and nTreg infiltration.
Topics: Adoptive Transfer; Animals; Cells, Cultured; Disease Models, Animal; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppression Therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; Myeloid-Derived Suppressor Cells; Nitric Oxide Synthase Type II; T-Lymphocytes, Regulatory; Transplantation, Homologous
PubMed: 33975012
DOI: 10.1016/j.trim.2021.101405 -
Frontiers in Oncology 2020Preclinical animal models of oral squamous cell carcinoma (OSCC) have been extensively studied in recent years. Investigating the pathogenesis and potential therapeutic... (Review)
Review
Preclinical animal models of oral squamous cell carcinoma (OSCC) have been extensively studied in recent years. Investigating the pathogenesis and potential therapeutic strategies of OSCC is required to further progress in this field, and a suitable research animal model that reflects the intricacies of cancer biology is crucial. Of the animal models established for the study of cancers, mouse tumor-bearing models are among the most popular and widely deployed for their high fertility, low cost, and molecular and physiological similarity to humans, as well as the ease of rearing experimental mice. Currently, the different methods of establishing OSCC mouse models can be divided into three categories: chemical carcinogen-induced, transplanted and genetically engineered mouse models. Each of these methods has unique advantages and limitations, and the appropriate application of these techniques in OSCC research deserves our attention. Therefore, this review comprehensively investigates and summarizes the tumorigenesis mechanisms, characteristics, establishment methods, and current applications of OSCC mouse models in published papers. The objective of this review is to provide foundations and considerations for choosing suitable model establishment methods to study the relevant pathogenesis, early diagnosis, and clinical treatment of OSCC.
PubMed: 32158692
DOI: 10.3389/fonc.2020.00212 -
Transplantation Proceedings Nov 2018The hippocampus is a brain structure that plays a fundamental role in memory and learning. Many animal studies have demonstrated that the structure of the hippocampus...
The hippocampus is a brain structure that plays a fundamental role in memory and learning. Many animal studies have demonstrated that the structure of the hippocampus has evolved through exercise and play. However, little is known on the relationship between the brain and immunological reaction. In this study, we investigated the correlation between the weight of the hippocampus and transplant immunology in a murine heart transplant model. Fully vascularized heterotopic hearts from CBA (H2, allogeneic group) or C57BL/6 (H2, syngeneic group) donors were transplanted into C57BL/6 recipients by using microsurgical techniques. The weights of the whole brain and hippocampus from syngeneic and allogeneic groups were recorded 1, 2, and 4 weeks after grafting, and histologic assessments were performed. The syngeneic group maintained beating cardiac grafts for over 30 days, but the allogeneic group rejected CBA cardiac allografts acutely within 8 days. The average weight of whole brain from syngeneic and allogeneic group 1, 2, and 4 weeks had no significant differences. However, the average weight of hippocampus at 2 and 4 weeks was considerably increased in the allogeneic group compared with the syngeneic group. Histologic assessments with hematoxylin-eosin and Kluver-Barrera staining of hippocampus from allogeneic group 1 week after grafting demonstrated a greater number of granule and pyramidal cells in the hippocampus. Alloimmune responses in our model increase the weight of hippocampus.
Topics: Animals; Graft Survival; Heart Transplantation; Hippocampus; Histocompatibility; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Organ Size; Postoperative Period; Transplantation, Homologous; Transplantation, Isogeneic
PubMed: 30401400
DOI: 10.1016/j.transproceed.2018.03.107 -
FASEB Journal : Official Publication of... Jan 2020Endometriosis is a chronic inflammatory, gynecological disease characterized by the presence of endometrial-like tissue lesions outside of the uterus. Neutrophils are...
Endometriosis is a chronic inflammatory, gynecological disease characterized by the presence of endometrial-like tissue lesions outside of the uterus. Neutrophils are elevated in the systemic circulation and peritoneal fluid of endometriosis patients; however, whether and how neutrophils contribute to endometriosis pathophysiology remain poorly understood. With emerging roles for neutrophils in chronic and sterile inflammatory conditions, we sought to provide in-depth characterization of neutrophil involvement in endometriosis. We demonstrate that neutrophils reside within patient endometriotic lesions and that patient lesions possess a microenvironment that may influence neutrophil recruitment and function. We also provide the first evidence that systemic circulating neutrophils from endometriosis patients display distinct transcriptomic differences compared neutrophils from healthy control subjects. Time course characterization of our syngeneic, immunocompetent mouse model of endometriosis revealed that neutrophils are rapidly recruited to the peritoneal environment early after endometriotic lesion establishment and remain present in murine lesions long term. In vivo neutrophil depletion altered the systemic and peritoneal immune microenvironment of mice with endometriosis as demonstrated by changes in pro-inflammatory and angiogenic mediators. Taken together, these findings highlight a novel role for neutrophils in early events such as angiogenesis and modulation of the local inflammatory environment associated with endometriosis pathogenesis.
Topics: Animals; Disease Models, Animal; Endometriosis; Endometrium; Female; Humans; Inflammation; Mice; Neovascularization, Pathologic; Neutrophil Infiltration; Neutrophils; Peritoneum
PubMed: 31914688
DOI: 10.1096/fj.201902272R -
Cancer Science Mar 2023Chemotherapy drugs, such as gemcitabine and cisplatin (GC), are frequently administered to patients with advanced urothelial carcinoma, however the influence of the gut...
Chemotherapy drugs, such as gemcitabine and cisplatin (GC), are frequently administered to patients with advanced urothelial carcinoma, however the influence of the gut microbiota on their action is unclear. Thus, we investigated the effects of GC on the gut microbiome and determined whether oral supplementation with a probiotics mixture of Lactobacillus casei Shirota and Bifidobacterium breve enhanced the anti-tumor immune response. After subcutaneous inoculation with MBT2 murine bladder cancer cells, syngenic C3H mice were randomly allocated into eight groups. The gut microbiome cluster pattern was altered in both the GC and oral probiotics groups (p = 0.025). Both tumor-bearing conditions (no treatment) and GC chemotherapy influenced Pseudoclostridium, Robinsoniella, Merdimonas, and Phocea in the gut. Furthermore, comparison of the GC-treated and GC + probiotics groups revealed an association of four methyltransferase family enzymes and two short-change fatty acid-related enzymes with oral probiotics use. A significant difference in tumor volume was observed between the GC and GC + probiotics groups at week 2 of treatment. Additionally, decreased recruitment of cancer-associated fibroblasts and regulatory T cells, and activation of CD8 T cells and dendritic cells were observed in the tumor microenvironment. Our findings reveal the positive effects of a probiotics mixture of Lactobacillus and Bifidobacterium in enhancing anti-tumor effects through the gut-tumor immune response axis. Future clinical trials are needed to evaluate the full benefits of this novel supplement with oral probiotics in patients with advanced urothelial carcinoma.
Topics: Animals; Mice; Cisplatin; Gemcitabine; Carcinoma, Transitional Cell; CD8-Positive T-Lymphocytes; Urinary Bladder Neoplasms; Mice, Inbred C3H; Probiotics; Immunity; Tumor Microenvironment
PubMed: 36398663
DOI: 10.1111/cas.15666