Research ArticleExperimental Studies
Open Access

Long-term Intravital Investigation of an Orthotopic Glioma Mouse Model via Optical Coherence Tomography Angiography

KAILI ZHENG, GUANGXING WANG, KANGWEI ZHOU, XIAOFEI WEN, YUYING ZHOU, SHUTING LING, QIONG YANG, HUILING WU, JIWEI XING, LISONG LIN and QINGLIANG ZHAO
In Vivo May 2024, 38 (3) 1192-1198; DOI: https://doi.org/10.21873/invivo.13554

Abstract

Background/Aim: Probing brain tumor microvasculature holds significant importance in both basic cancer research and medical practice for tracking tumor development and assessing treatment outcomes. However, few imaging methods commonly used in clinics can noninvasively monitor the brain microvascular network at high precision and without exogenous contrast agents in vivo. The present study aimed to investigate the characteristics of microvasculature during brain tumor development in an orthotopic glioma mouse model. Materials and Methods: An orthotopic glioma mouse model was established by surgical orthotopic implantation of U87-MG-luc cells into the mouse brain. Then, optical coherence tomography angiography (OCTA) was utilized to characterize the microvasculature progression within 14 days. Results: The orthotopic glioma mouse model evaluated by bioluminescence imaging and MRI was successfully generated. As the tumor grew, the microvessels within the tumor area slowly decreased, progressing from the center to the periphery for 14 days. Conclusion: This study highlights the potential of OCTA as a useful tool to noninvasively visualize the brain microvascular network at high precision and without any exogenous contrast agents in vivo.

Key Words:

Glioma is the most common primary cancer in the brain with a poor prognosis, and is characterized by microvascular proliferation (1, 2). Specifically, sufficient nutrients and metabolic substrates delivered by blood vessels are indispensable to satisfy the rapidly growing tumors (3). On the other hand, cancer cell metastasis, immune cell transportation, and anti-cancer drug delivery heavily rely on the tumor’s vascular network (4). Thus, probing tumor microvascular progress in living subjects holds great significance in both basic cancer research and clinical practice, enabling us to monitor tumor development, offer prognostic assessments, and provide feedback on the therapeutic responses. Currently, magnetic resonance imaging (MRI) and computer tomography (CT) are commonly used to investigate the vasculature of tumors in the clinic (5, 6). Nevertheless, they are limited to observing a single microvessel (7, 8). Recently, advances in fluorescence imaging technology have allowed single- or multi-photon fluorescent microscopy to visualize tumor vessels at subcellular-scale resolution (9). Unfortunately, potentially toxic exogenous contrast agents are always required to facilitate microvascular imaging (10). Therefore, an intravital imaging strategy that can achieve high-resolution tumor microvascular visualization without any exogenous contrast agent needs to be developed.

In recent years, based on a particular imaging mechanism (dual-beam interferometry), optical coherence tomography (OCT) imaging technology has become a high-resolution and non-contact tool in biomedical research (11-15). In particular, according to the principle of dynamic scattering detection of red blood cells in the vasculature, OCT angiography (OCTA), as a powerful and supplementary technology of the OCT, has the capability of visualizing microcirculation without an exogenous contrast agent (16, 17). Until now, the OCTA imaging technology has mainly focused on ophthalmic research, such as choroidal neovascularization (18), glaucoma (19), and diabetic retinopathy (20), which have achieved successful clinical application. However, to the best of our knowledge, no research on long-term monitoring of microvascular network progression in orthotopic glioma mouse models via OCTA has been reported. Hence, in this report, we successfully constructed the orthotopic glioma mouse model confirmed by bioluminescence imaging and MRI. OCTA was then employed to monitor the microvasculature alteration in the orthotopic glioma mouse model, for up to 14 days. It is suggested that OCTA used in this study is capable of realizing long-term in vivo high-resolution tumor microvascular visualization without any exogenous contrast agent and would be beneficial to understanding tumor pathological state, predicting prognosis, and assessing treatment outcomes.

Materials and Methods

Cell culture. U87-MG-luc cells (Chinese Academy of Sciences Cell Bank, Shanghai, PR China) were cultured in DMEM medium (Thermo Fisher Scientific Inc., Waltham, MA, USA) containing 10% fetal bovine serum (Thermo Fisher Scientific Inc.) and 1% antibiotic solution (Shanghai Shenggong Bioengineering Co., Ltd, Shanghai, PR China). All cells were grown at 37°C in a humidified atmosphere comprising 5% CO2. All cell culture operations were performed in the biosafety cabinet and aseptic practice procedures were strictly followed.

Orthotopic glioma model construction. Female Balb/c nude mice (Shanghai Slack Laboratory Animal Company, Shanghai, PR China) aged 3 to 5 weeks and weighing between 18 g and 22 g were selected. The animal experiments were conducted following the protocol (XMULAC20160040) approved by the Animal Experiment Ethics Review Committee of the Laboratory Animal Center of Xiamen University, and all experiments and procedures were conducted under full anesthesia. The mice were anesthetized with isoflurane (RWD Life Science Co., Ltd, Shenzhen, PR China) (4.0% isoflurane to induce anesthesia and 2.0% isoflurane to maintain it) and fixed in a stereotactic apparatus (Beijing Zhongshi Technology Co., Ltd, Beijing, PR China) for U87-MG-luc cell implantation, as shown in Figure 1. Then, the skull was exposed and cleaned by using sterile surgical instruments (RWD Life Science Co., Ltd). With the assistance of a stereotaxic instrument, a hole for cell implantation was drilled at the position of 1.2 mm before the coronal suture and 1.2 mm to the right of the sagittal suture. After that, a microsyringe (Hamilton Laboratory Equipment Co., Ltd, Shanghai, PR China) containing 105 U87-MG-luc cells suspended in 5 μl of PBS (Biosharp Life Science, Hefei, PR China) was slowly advanced to a depth of 2.5mm in the brain. Subsequently, the cells were injected at a rate of 0.5 μl/min for 10 min. After the injection was completed, the needle of the microsyringe was left for 5 min, and then slowly removed. Later, the bone hole was filled with bone wax (Beijing Cinontech Co., Ltd, Beijing, PR China) to prevent reflux of the cell suspension. The scalp was sutured and disinfected with iodophor (Biosharp Life Science, Hefei, PR China). Finally, the mice were placed on a small animal thermostatic heating pad (Beijing Cinontech Co., Ltd.) and returned to the cage after they were awake.

Figure 1.
Figure 1.

Orthotopic glioma mouse model generation. (A) Photograph of the stereotaxic apparatus used in this study. (B) Schematic diagram of orthotopic glioma mouse model generation. (C-D) With the assistance of stereotaxic apparatus, U87-MG-luc cells were stereotactically injected into the brain of Balb/c nude mice.

Bioluminescence imaging. Bioluminescence imaging was performed at 7 and 14 days after U87-MG-luc cell injection to trace the location and activity of brain tumor cells. Mice were anesthetized and intraperitoneally injected with 200 μl of fluorescein potassium salt (Shanghai yuanye Bio-Technology Co., Ltd, Shanghai, PR China) working solution (150 mg/kg body weight) prepared at a concentration of 15 mg/ml. 5 min after injection, the mice were placed in the Caliper IVIS Lumina II chamber (PerkinElmer, Shelton, CT, USA) for bioluminescence imaging of the orthotopic U87-MG-luc tumor. The bioluminescence signal was collected continuously using a full reception filter and setting the exposure time to 30 s.

Magnetic resonance imaging. The Bruker 9.4 T Micro MRI equipment (Bruker, Billerica, MA, USA) was utilized to perform MRI on the orthotopic glioma mouse model at 14 days after U87-MG-luc cell injection. The mice were anesthetized using inhalation anesthesia, and their heads were placed inside the radiofrequency coil. A Rapid Acquisition with Relaxation Enhancement (RARE) T2-weighted imaging (T2WI) sequence was selected to acquire coronal and axial plane images. The parameters were set as follows: FOV of 2.5 cm×2.5 cm, TR/TE=3,000/100 ms, 25 layers, layer thickness 0.5 mm, spacing-free cross-sectional scan.

OCTA imaging and quantitative analysis. To achieve long-term, high-precision, and non-invasive orthotopic glioma microvasculature monitoring, a self-built swept-source OCT system was employed, which comprised a swept-source laser (central wavelength of 1060 nm, Axsun 105, AXSUN Technologies Inc., Billerica, MA, USA) operating at a 200kHz sweep rate. This imaging system enables an axial resolution of approximately 5 μm in air and a lateral resolution of 29 μm. More details of the system have been described in our previous work (21). Based on above mentioned OCT system, the high-resolution microvascular maps were obtained through endogenous contrast originating from the varying time-related light scattering characteristics between the blood inside the vessels and the adjacent “solid” tissues, which refers to the OCTA technology (Figure 2). During OCTA imaging, the mice were anesthetized with isoflurane, and placed on the small animal adapter, while their heads were fixed to ensure flatness and no tilt. Then, the orthotopic glioma microvascular images were obtained at different time points (7, 10 and 14 days). Furthermore, the alteration of orthotopic tumor vasculature was quantified using the OCTAVA algorithm on the MATLAB (MathWorks Inc., Natick, MA, USA) platform (22).

Figure 2.
Figure 2.

Schematic of label-free high-resolution brain microvasculature imaging via optical coherence tomography angiography (OCTA) in vivo. (A) White light image of OCTA imaging ROI area (the white dotted line represents the cerebral cortex of the mouse). (B) A representative B-scan image of the corresponding ROI in (A). (C) Repeated B-scans at the same location for the subsequent OCTA process. (D) En-face maximum intensity projection (MIP) OCTA image after OCTA algorithm processing.

Results

In order to verify whether the orthotopic glioma mouse model was successfully constructed, we performed bioluminescence imaging and MRI tests in vivo. As shown in Figure 3A and B, bioluminescence signal intensity generated from the injection site gradually increased over time (~14 days), which means that the tumor formed and grew. In addition, the quantified results of the bioluminescence signal are shown in Figure 3C to manifest the time-dependent growth of the tumor.

Figure 3.
Figure 3.

In vivo bioluminescence imaging of the orthotopic glioma tumor growth. (A) Representative bioluminescence images of control (I) and orthotopic glioma mouse model (II). (B) 7 and 14 days after U87-MG-luc cell injection, the mice (n=7) were imaged to observe the growth of the tumors. (C) Quantitative analysis of the bioluminescence signal indicated the time-dependent growth of the tumor.

Furthermore, MRI, an indispensable method for determining the tumorigenicity of the orthotopic glioma model in animals, was used to characterize the anatomic structure of the orthotopic glioma mouse model. At 14 days after glioma cell injection, significant differences between normal and tumor tissues (highlighted in Figure 4 with a yellow dotted line) in the MRI image could be observed. These showed that the tumor foci were located in the right cerebral cortex, with a relatively uniform signal and significant differences from the surrounding tissues, and the midline of the brain was mildly displaced and squeezed the lateral ventricles. In other words, the orthotopic glioma mouse model was successfully established.

Figure 4.
Figure 4.

Representative T2-weighted magnetic resonance imaging (MRI) of orthotopic glioma tumor mouse model (14 days after U87-MG-luc cell injection) at the axial (A) and coronal plane (B). Tumor location is shown by the yellow dotted line.

After the successful establishment of the model, OCTA imaging of the control group and orthotopic glioma group at different time points (7, 10 and 14 days) was performed to monitor tumor microvasculature advancement. Figure 5A and D shows representative orthotopic glioma microvascular maps obtained by OCTA imaging from the control and the orthotopic glioma group at different time points. Besides, in Figure 5A and D, as the tumor grew, the microvessels within the tumor area slowly decreased, progressing from the center to the periphery for 14 days. Furthermore, this phenomenon was quantified by the OCTAVA algorithm through segmentation (Figure 5E-H), skeletonization (Figure 5I-L), microvascular network identification (Figure 5M-P), and measurement (Figure 6).

Figure 5.
Figure 5.

Long-term orthotopic glioma microvasculature OCTA monitoring in vivo and quantification analysis. En-face OCTA images of the control group (A) and orthotopic glioma group at different time points [(B): 7 days; (C): 10 days; (D): 14 days]. The binarized OCTA images of the control group (E) and orthotopic glioma group at different time points [(F): 7 days; (G): 10 days; (H): 14 days]. Based on the binarized images, these images were further skeletonized [(I): control; (J): 7 days; (K): 10 days; (L): 14 days]. Overlay images of extracted microvasculature and OCTA images [(M): control; (N): 7 days; (O): 10 days; (P): 14 days]. Various architectural components, such as segments, branches, mesh regions, isolated elements, and nodes of the extracted microvascular network in (M-P) are represented by yellow lines, green lines, light blue lines, dark blue lines, red and blue circles, respectively. Scale bar: 600 μm.

Figure 6.
Figure 6.

Vessel area density of the control group (n=5) and orthotopic glioma group (n=5) at different time points, quantified by the OCTAVA algorithm.

Discussion

Angiogenesis is a pivotal factor in the advancement of glioma tumors, as it stimulates the development of new blood vessels, which are essential for the growth and sustenance of the tumor (23). Consequently, tumor vasculature has emerged as a diagnostic and prognostic biomarker, as well as a therapeutic target in relation to glioma (24). Thus, visualization and monitoring the changes of tumor vasculature during glioma progression facilitate the understanding of vascular pathology about glioma and development effective therapeutic approach. Venugopal et al. utilized magnetic resonance vascular fingerprinting (MRVF) method to visualize and estimate the glioma vascular parameters (vessel radius and relative cerebral blood volume) (25). With a relative quick acquisition time, MRVF allows for the characterization of vasculature in glioma, and there is potential to advance our understanding of glioma physiology. Nevertheless, the resolution of the MRVF approach is relatively low (at the millimeter level), making it challenging to achieve microvascular visualization at the micrometer level. And, the gadolinium-based contrast agent was required before MRVF vascular imaging, which may cause damage to the patient's kidneys induce allergic reactions. In addition, Wang et al. employed multiphoton imaging technique to investigate the architectural feature of blood vessels in glioma without any exogenous contrast agent (26). Second harmonic generation and two-photon excited fluorescence multiphoton imaging modal were applied to qualitatively and quantitatively visualize the morphology pattern of glioma microvasculature (at the micrometer level), which may serve as a diagnosis biomarker to assist clinicians in decision making. However, the approach proposed in this study depends on ex vivo excised human tissues, which is limited to in investigatinge microvasculature changes during glioma progression in vivo. Therefore, we utilized OCTA, a powerful label-free, high resolution microcirculation imaging technique, to visualize and monitor the changes of microvasculature during brain tumor development in an orthotopic glioma mouse model. Representative orthotopic glioma microvascular maps were obtained by OCTA imaging from the control and the orthotopic glioma group at different time points in this work. These indicate that OCTA has the ability of longitudinally visualizing tumor microvasculature at high resolution in vivo, particularly, without using any exogenous contrast agent. Additionally, contrary to previous opinions on tumor angiogenesis (27), the vessel area density in the orthotopic glioma area gradually decreased (Figure 6), which could be attributed to the fast proliferation of cancer cells in a relatively confined space (28). On the other hand, in future research, OCTA imaging with longer wavelength, such as 1,700 nm (29), should be conducted to further investigate the microvascular alteration in the subcortical structures.

Conclusion

In summary, we demonstrated one useful application of OCTA to investigate glioma microvascular alteration in the orthotopic glioma mouse model. The orthotopic glioma model was successfully constructed, verified by bioluminescence imaging and MRI. Long-term in vivo monitoring of brain microvascular alteration of the orthotopic glioma model was implemented with a duration of 14 days via OCTA technology, which suggests that OCTA is able to visualize brain microvasculature at high resolution without any exogenous contrast agent. This technology could be beneficial to understanding tumor pathological state, predicting prognosis, and assessing treatment outcomes.

Acknowledgements

This work was supported by grants from the Guangdong Basic and Applied Basic Research Foundation (2021A1515011654), Fundamental Research Funds for the Central Universities of China (20720210117), Fujian Province Science and Technology Plan Guiding Project (2022Y0002), Science and Technology Projects Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM) (RD2022050901), Fundamental Research Funds for the Central Universities (20720232020), XMU Undergraduate Innovation and Entrepreneurship Training Programs (2020Y0799, S202010384334, 2021X1119, 2021Y111, S202110384391, S202210384404, and 202210384051), National Natural Science Foundation of China (81971665), Natural Science Foundation of Fujian Province (2021J011366), Medical and Health Guidance Project of Xiamen (3502Z20214ZD1016), Xiamen Health High-Level Talent Training Program, and Joint Funds for the Innovation of Science and Technology of Fujian province(2019Y9128).

Footnotes

  • Authors’ Contributions

    Q.L.Z. and L.S.L. designed this experiment. K.L.Z., K.W.Z., and X.F.W. conducted experiments. G.X.W. analyzed the data and wrote the manuscript. Y.Y.Z., S.T.L., and Q.Y. explained the experimental results. H.L.W. and J.W.X. prepared the figures. All Authors participated in reading and discussing the manuscript. K.L.Z., G.X.W., K.W.Z., and X.F.W. contributed equally to this work.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in this study.

  • Received October 16, 2023.
  • Revision received November 26, 2023.
  • Accepted November 28, 2023.

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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Long-term Intravital Investigation of an Orthotopic Glioma Mouse Model via Optical Coherence Tomography Angiography
KAILI ZHENG, GUANGXING WANG, KANGWEI ZHOU, XIAOFEI WEN, YUYING ZHOU, SHUTING LING, QIONG YANG, HUILING WU, JIWEI XING, LISONG LIN, QINGLIANG ZHAO
In Vivo May 2024, 38 (3) 1192-1198; DOI: 10.21873/invivo.13554
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