Research ArticleExperimental Studies
Open Access

Suppression of Sleeping Beauty-induced Gliomagenicity in Ts1Cje Mice, a Model of Down Syndrome

KEIICHI ISHIHARA, RYUTO SAKODA, MASAKO MIZOGUCHI, MITSUGU FUJITA, CHIAMI MOYAMA, YURI OKUTANI, KAZUYUKI TAKATA, MIWA TANAKA, TAKASHI MINAMI, HARUHIKO SAGO, KAZUHIRO YAMAKAWA, TAKURO NAKAMURA, ERI KAWASHITA, SATOSHI AKIBA and SUSUMU NAKATA
Anticancer Research February 2024, 44 (2) 489-495; DOI: https://doi.org/10.21873/anticanres.16836

Abstract

Background/Aim: Individuals with Down syndrome (DS), attributed to triplication of human chromosome 21 (Hsa21), exhibit a reduced incidence of solid tumors. However, the prevalence of glioblastoma among individuals with DS remains a contentious issue in epidemiological studies. Therefore, this study examined the gliomagenicity in Ts1Cje mice, a murine model of DS. Materials and Methods: We employed the Sleeping Beauty transposon system for the integration of human oncogenes into cells of the subventricular zone of neonatal mice. Results: Notably, Sleeping Beauty-mediated de novo murine gliomagenesis was significantly suppressed in Ts1Cje mice compared to wild-type mice. In glioblastomas of Ts1je mice, we observed an augmented presence of M1-polarized tumor-associated macrophages and microglia, known for their anti-tumor efficacy in the early stage of tumor development. Conclusion: Our findings in a mouse model of DS offer novel perspectives on the diminished gliomagenicity observed in individuals with DS.

Key Words:

Down syndrome (DS), resulting from triplication of human chromosome 21 (Hsa21), is the most prevalent form of aneuploidy, occurring in approximately 1 in 700 live births. Infants with DS, characterized by trisomy of Hsa21, have a unique predisposition to transient myeloproliferative disorders and acute megakaryocytic leukemia (DS-AML) (1). Mutations of genes, GATA1 and tribbles pseudokinase 1, which are detected in individuals with DS-AML (2, 3), are suggested to promote the development of AML in human induced pluripotent stem cells with trisomy 21 and a mouse model of DS, respectively (4, 5). Conversely, an increasing body of evidence suggests a reduced incidence of solid tumors in individuals with DS, although this trend varies among tumor types (6-10). Solid brain tumors, including cerebral gliomas and medulloblastoma, are infrequently reported in children and adults with DS (11, 12). The incidence of brain tumors in adults with DS is controversial (13). Consequently, epidemiological studies have presented divergent findings concerning the relative risk of tumor development in the DS population.

The gene-dosage hypothesis (14) postulates that over-expression of Hsa21, which harbors over 300 genes, can disturb oncogenic and tumor suppressive pathways. To this end, several murine models have been developed, each harboring trisomic segments encoding genes orthologous to those in Hsa21 (15). Studies using tumor-prone murine models and the Ts65Dn mouse model – a typical genetic model carrying an additional copy of a portion of mouse chromosome 16 (Mmu16), which contains approximately 100 genes orthologous to those on Hsa21 – have demonstrated the tumor-suppressive effects of triplicated Hsa21 genes on ileal tumor carcinogenesis and tumor development in a xenograft model (16, 17). Notably, a significant reduction in ileal tumors was observed in Ts65Dn-ApcMin mice compared with their ApcMin counterparts, with the Ets2 gene implicated as a key factor in this tumor-suppressive effect, as elucidated through the “in vivo gene subtraction method” using Ts65Dn-Ets2+/+/− mice (16).

Furthermore, studies have shown that suppression of tumor growth in xenografts on a Ts65Dn background is attributable to inhibited angiogenesis in tumor vessels (17). The Rcan1 gene in the trisomic region of Ts65Dn mice was found to be responsible for this suppressive effect, as demonstrated using the “in vivo gene subtraction method” in Ts65Dn-Rcan1+/+/− mice (17). Thus, over-expression of some Hsa21 genes appears to inhibit tumorigenesis and tumor progression. However, as previously mentioned, the frequency of gliomagenesis in individuals with DS remains debatable.

Glioblastoma multiforme, known as the most malignant primary brain tumor in adults, is extremely invasive, characterized by intense and aberrant vascularization (18). We therefore assessed the effect of DS-relevant gene alteration on gliomagenesis. Glioblastoma induction was achieved via gene transfer of mutated tumor suppressor genes in the DS mouse model Ts(12;16)1Cje, referred to as Ts1Cje mice, which carry a shorter trisomic region than Ts65Dn, encompassing the annotated genes Ets2 and Rcan1 (19).

Materials and Methods

Mice. Ts1Cje male mice with a genetic background of C57BL/6J (spanning over 30 generations) were backcrossed to BALB/cCrSlc females for a minimum of six generations. Mice were housed under specific-pathogen-free conditions. In each cage, no more than five mice were accommodated and subjected to a 12-h light-dark cycle. Food and water were provided ad libitum. Genotypic identification of these mice was carried out by polymerase chain reaction (PCR) amplification, as described in previous studies (20). All experimental procedures were conducted in accordance with the guidelines of the Animal Experiments Committee (permission number: 18-17-067).

Intraventricular DNA transfection for gliomagenesis. This procedure was conducted as previously described (21). In brief, to initiate Sleeping Beauty-mediated de novo murine glioblastoma, newborn mice subjected to hypothermia anesthesia were positioned in a stereotaxic apparatus (51730D; Stoelting Co., Wood Dale, IL, USA). Intracranial injections were performed using a 10 μl Hamilton syringe equipped with a 30-gauge needle attached to an infusion system (Legato130; KD Scientific, Holliston, MA, USA). The injection comprised 2 μl of a DNA/polyethylenimine (PEI) complex administered into the right lateral ventricle at a rate of 1 μl/min. The coordinates for the injection were established as 1.5 mm anterior-posterior, 0.7 mm medial-lateral, and −1.5 mm dorsoventral relative to the lambda reference point. The cocktail of plasmid DNAs used for the transfection included pT2/C-Luc//PGK-SB13 (0.2 μg), pT/CAGGS-NRASV12 (0.4 μg), pT3.5/CMV-EGFRvIII (0.4 μg), and pT2/shP53 (0.4 μg), using an in vivo-compatible DNA transfection reagent (In vivo-JetPEI; Polyplus Transfection, New York, NY, USA). To monitor tumor growth, in vivo bioluminescence intensity measurements were conducted weekly starting seven weeks post-transfection. This was achieved using the IVIS Lumina XR imaging system (Summit Pharmaceuticals International, Tokyo, Japan), following intraperitoneal injection of D-luciferin (Wako Pure Chemical Industries, Osaka, Japan) at a dose of 150 mg/kg.

Histological analyses. After experimentation, the mice underwent transcardial perfusion with saline followed by 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS) under anesthesia. Subsequently, the brains harboring glioblastomas were post-fixed in 4% PFA for 72 h at 4°C. For cryoprotection, the brains were cryoprotected in 30% sucrose and then frozen in medium containing 50% Tissue-Tek O.C.T. (Sakura Fine Technical, Tokyo, Japan) and 15% sucrose. Serial brain sections were prepared at a thickness of 40 μm and stored at −20°C in a cryoprotectant solution containing 30% (w/v) sucrose, 30% ethylene glycol, and 1% (w/v) Polyvinylpyrrolidone (PVP-40) in 50 mM phosphate buffer (pH 7.4). The brain sections were subsequently rinsed with PBS and 100 mM phosphate buffer (pH 7.4). The sections were mounted onto glass slides, thoroughly dried, rehydrated with PBS, and stained with hematoxylin and eosin (H&E). Photomicrographs of stained sections were captured using an IX71 microscope (Olympus, Tokyo, Japan) equipped with a digital camera.

Immunofluorescence labeling of brain tissue. Brain sections, previously stored at −20°C in cryoprotectant solution, were initially washed with PBS and then blocked for 1 h in a solution containing 0.3% Triton X-100 and 5% (w/v) BSA in PBS. These sections were subsequently incubated overnight at 4°C in the same blocking solution supplemented with primary antibodies directed against various targets: Collagen IV (cat. #2150-1470, 1:400; Bio-Rad Laboratories, Hercules, CA, USA), Iba1 (1:2,000, cat. #019-19741, FUJIFILM Wako Pure Chemical), CD68 (cat. #ab53444, 1:200; Abcam, Cambridge, MA, USA), S100A9 (cat. #AF2065, 1:400; R&D Systems, Minneapolis, MN, USA), F4/80 (Cat. #ab6640, 1:200; Abcam) and iNOS (cat. #ab15323, 1:800, Abcam). Following primary antibody incubation, the sections were rinsed with PBS and incubated for 1 h at room temperature with the appropriate secondary antibodies (Invitrogen cat. #A31619, #A11007, #A21206 and #A11058, 1:400; Invitrogen, Carlsbad, CA, USA). Photomicrographs of the treated sections were captured using an advanced imaging system involving a confocal laser microscope (NIKON A1R; Nikon, Tokyo, Japan) and a fluorescent microscope BZ-X710 (Keyence, Osaka, Japan).

Statistical analyses. Gliomagenesis was quantitatively defined as a threshold of 1×105 photons/s. The Kaplan–Meier method was used to evaluate the differences in tumor formation between wild-type (WT) and Ts1Cje mice. The statistical significance of these differences was determined using the Mantel-Haenszel log-rank test, and p-values were calculated accordingly. All data presented in the graphs are expressed as the mean±standard error of the mean (SEM).

Results

Suppression of gliomagenicity in Ts1Cje mice. To ascertain the influence of DS genes on gliomagenicity, we used the Sleeping Beauty transposon system to induce glioblastoma in newborn Ts1Cje mice with the BALB/cCrSlc genetic background. Suppression of gliomagenicity in Ts1Cje mice was detected in comparison with that in WT littermates (Figure 1). These findings suggest that the over-expression of trisomic genes in Ts1Cje mice may contribute to the suppression of gliomagenesis.

Figure 1.
Figure 1.

Suppression of gliomagenicity induced by the Sleeping Beauty transposon in Ts1Cje mice. (A) Kaplan–Meier survival curves show significant suppression of gliomagenicity in Ts1Cje mice. Tumor formation was assessed for 17 weeks after transfection by IVIS imaging. Mice with tumor were defined as over 105 photon/sec in IVIS analysis. The statistical significances examined by the log-rank (Cochran-Mantel-Haenszel) test are indicated. WT: Wild-type mice. (B) Representative brain tissue sections from mice that developed tumors as assessed by IVIS imaging were stained with hematoxylin and eosin. Tumor tissues are surrounded by a dotted yellow line. Scale bar=1 mm.

Blood vessels in the glioblastoma of Ts1Cje mice. Previous research has proposed that the Rcan1 gene mediates suppression of angiogenesis in xenograft experiments using another mouse model of DS, Ts65Dn mice (17). Therefore, we sought to characterize morphological abnormalities in glioblastomas formed in Ts1Cje mice. Tumor vessels were identified using a collagen IV antibody. However, our analysis revealed no significant phenotypic differences in the tumor vasculature between Ts1Cje and wild-type controls (Figure 2). This finding suggests that the observed suppression of gliomagenicity in DS is not attributable to decreased angiogenesis.

Figure 2.
Figure 2.

Comparable angiogenesis rates and more S100A9-positive cells in the glioblastoma formed in Ts1Cje mice than in those of wild-type mice. (A) Immunofluorescence micrographs show the expression of collagen IV (green) and S100A9 (red) in the glioblastoma of wild-type (WT) and Ts1Cje mice. Glioblastoma tumors show a high density of nuclei stained with DAPI (blue). (B) The area of tumor vessels expressing Collagen IV was quantified by the Image J software program. (C) The number of infiltrated monocytes and neutrophils expressing S100A9 was manually counted. Data are shown as the mean±standard error (SE) (WT, n=6; Ts1Cje, n=4), *p<0.05, Student’s t-test. Scale bars=250 μm.

Increased numbers of S100A9-positive cells in glioblastoma of Ts1Cje mice. Glioma cells are known to secrete numerous factors, including chemokines, cytokines, and growth factors. These secretions facilitate the infiltration of various cells, particularly immune cells of myeloid origin, such as macrophages and neutrophils, into the tumor milieu (22). Given that S100A8 and S100A9 are highly expressed in myeloid-derived immune cells, including macrophages and neutrophils (23, 24), their presence in gliomas was also investigated. To this end, an immunohistochemical analysis was conducted using an anti-S100A9 antibody. The results revealed a significant increase in the number of peripheral immune cells expressing S100A9 in glioblastomas of Ts1Cje mice (Figure 2A and C).

Since S100A9-positive cells are relatively scarce in the adult murine brain (25), it is plausible that the permeability of tumor vessels may be increased in the glioblastomas found in Ts1Cje mice compared with WT mice. To explore this hypothesis, we quantified the presence of monocytes and macrophages. This was achieved by identifying a distinct population of Iba1−/CD68+ cells located near blood vessels, indicative of infiltrated/perivascular monocytes/macrophages (26, 27). The analysis revealed a higher number of Iba1−/CD68+ cells in the glioblastomas of Ts1Cje mice than in WT mice (Figure 3), suggesting an increase in tumor vessel permeability and/or augmented inflammation in glioblastomas of Ts1Cje mice. Furthermore, the numbers of Iba1/CD68-double-positive cells, indicative of activated microglia, were also increased in the glioblastomas of Ts1Cje mice (Figure 3B; middle graph). In contrast, the number of inactivated microglia (Iba1+/CD68−) remained similar across both genotypes (Figure 3B, right panel). These findings suggest the presence of an inflammation-enhanced environment in glioblastomas of Ts1Cje mice.

Figure 3.
Figure 3.

More infiltration of peripheral monocytes in the glioblastoma on Ts1Cje mice. (A) Immunofluorescence micrographs show the expression of Iba1 (green) and CD68 (red) in the glioblastoma on wild-type (WT) and Ts1Cje mice. (B) Cell densities of Iba1−CD68+ (left graphs), Iba1+CD68+ (center graphs), and Iba1+CD68− cells (right graphs) in the glioblastoma induced by transposon were measured in WT (n=6) and Ts1Cje mice (n=4). Data are shown as the mean±standard error (SE), *p<0.05, Student’s t-test. Scale bars=250 μm.

Increased number of tumor-associated microglia and macrophages (TAMs) and ratio of M1-polarized TAMs in the glioblastoma of Ts1Cje mice. TAMs are recognized for their role in the progression of glioblastoma, with M1-polarized TAMs particularly implicated in inhibiting glioblastoma development (28). Therefore, we assessed the presence of M1 TAMs within the glioblastomas of Ts1Cje mice. To achieve this, TAMs and M1 TAMs were identified by immunohistochemical staining using anti-F4/80 and anti-iNOS antibodies, respectively. This experiment revealed a significant increase in the number of F4/80-positive TAMs within the glioblastomas of Ts1Cje mice compared with their WT counterparts (Figure 4).

Figure 4.
Figure 4.

Accelerated M1-polarization of tumor-associated microglia and macrophages (TAMs) in Ts1Cje mice. (A) Immunofluorescence micrographs show the expression of iNOS (green) and F4/80 (red) in the transposon-induced glioblastoma on wild-type (WT) and Ts1Cje mice. (B) The numbers of F4/80+ cells were significantly increased in Ts1Cje mice (left graph). The ratio of the number of F4/80+iNOS+ M1-TAMs among all F4/80+ TAMs was significantly increased in the glioblastomas of Ts1Cje mice (n=4) compared to those of WT mice (n=6). Data are shown as the mean±standard error (SE), *p<0.05, **p<0.01, Student’s t-test. Scale bars=100 μm.

Discussion

In this study, we demonstrated the suppression of gliomagenesis in a DS model using Ts1Cje mice for the first time. Although previous investigations using a xenograft model in Ts65Dn mice, another DS model, indicated a suppressive effect on tumorigenicity due to Rcan1-mediated impairment of tumor angiogenesis (17), our analysis did not show any abnormal morphologies in tumor vessels in a murine de novo glioblastoma model. This model was established through the transduction of oncogenic genes using the Sleeping-Beauty transposon system. In addition, our findings indicate predominant polarization towards M1 macrophages in the glioblastomas of Ts1Cje mice. This observation suggests the potential for both enhanced inflammation and increased permeability of tumor vessels in these mice. These insights add a new dimension to our understanding of the mechanisms by which DS genes influence tumor development and progression.

TAMs are broadly categorized into two distinct phenotypes: pro-inflammatory M1 and anti-inflammatory M2 (29). M1-polarized TAMs are known to induce a Th1-type immune response, characterized by their capacity to promote inflammation and antitumor immune activity (30). Conversely, M2-polarized TAMs, which secrete interleukin-10 (IL-10), IL-1 receptor antagonists (IL-1RA), and various chemokines, exhibit reduced antigen-presenting capabilities. They primarily induce Th2-type immune responses and are involved in cell growth and angiogenesis, thus contributing to tumor growth (31). In our study, we observed a dominance of M1-polarized TAMs in glioblastomas from Ts1Cje mice, consistent with the hypothesis of enhanced inflammation in these tumors. M1-polarized macrophages are known for their ability to directly kill tumor cells through the secretion of agents, such as nitric oxide or tumor necrosis factor (32). Therefore, the presence of M1-TAMs in Ts1Cje mice may be a key factor in suppressing gliomagenesis, potentially through direct cytotoxic effects on tumor cells. This predominant M1 polarization might play a crucial role in mitigating gliomagenicity in Ts1Cje mice, further underscoring the potential antitumor activity of M1-TAMs.

Although the specific genes on Hsa21 responsible for suppression of gliomagenesis in Ts1Cje mice have yet to be identified, Ets2 is a plausible candidate for this suppressive effect. Ets2 is proposed to be involved in the increased expression of miR-155, a microRNA encoded by Hsa21 but not in the trisomic region of Ts1Cje mice, particularly in response to lipopolysaccharide exposure (31). Furthermore, studies have shown that silencing miR-155 leads to an increase in M2-macrophages and a decrease in M1 macrophages (33). Thus, triplication of the Ets2 gene might foster M1 polarization of TAMs in DS. Interestingly, a deficiency of Ets2 in TAMs has been shown to promote tumor angiogenesis and suppress tumor proliferation (34). This finding contrasts with that of our study, in which no abnormalities in tumor angiogenesis were detected. This discrepancy highlights the complexity of genetic interactions in DS and their impact on tumor biology, warranting further investigation into the role of Ets2 and other Hsa21 genes in modulating the tumor microenvironment and angiogenesis in DS.

In this study, we presented evidence suggesting that the predominant M1 polarization of TAMs may play a role in the suppression of gliomagenesis in DS. This mechanism may explain the reduced incidence of solid tumors in individuals with DS, as reported in various epidemiological studies. However, whether or not a similar alteration in the polarization of M1-TAMs occurs in other types of tumors remains to be determined. To fully understand the scope and impact of this phenomenon, further research, including studies involving human cases, is necessary. Such investigations would not only deepen our understanding of the tumor microenvironment in DS but also potentially unveil new therapeutic targets for cancer treatment in the broader population.

Acknowledgements

This work was supported in part by the Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (20H05521 to KI and 23K06642 to SN) and a grant from the Vehicle Racing Commemorative Foundation (KI, MT, and TM). This work was enhanced by the use of ChatGPT, DeepL, and Trinka for the manuscript preparation. The Authors also thank Japan Medical Communication (https://www.japan-mc.co.jp/?utm_source=google&utm_medium=cpc&utm_campaign=10&gclid=CjwKCAiA1fqrBhA1EiwAMU5m_1kQDW28Z5BITwi5L4CuE-qfltS_JOh4GwOgVreEas0zyz-utzfvjhoC0lsQAvD_BwE) for editing a draft of this manuscript.

Footnotes

  • Authors’ Contributions

    K.I., R.S., M.M., Y.O. K.T., and S.N. performed experiments; K.I., C.M. and S.N. performed data analyses; H.S. and K.Y. supplied experimental materials and resources; K.I. and S.N. designed this research; K.I., M.F., M.T., T.M., T.N., E.K., S.A., and S.N. drafted the manuscript; all the Authors contributed to the discussion and review of the final manuscript; and all the Authors approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received December 20, 2023.
  • Revision received January 9, 2024.
  • Accepted January 10, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Suppression of Sleeping Beauty-induced Gliomagenicity in Ts1Cje Mice, a Model of Down Syndrome
KEIICHI ISHIHARA, RYUTO SAKODA, MASAKO MIZOGUCHI, MITSUGU FUJITA, CHIAMI MOYAMA, YURI OKUTANI, KAZUYUKI TAKATA, MIWA TANAKA, TAKASHI MINAMI, HARUHIKO SAGO, KAZUHIRO YAMAKAWA, TAKURO NAKAMURA, ERI KAWASHITA, SATOSHI AKIBA, SUSUMU NAKATA
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