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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 16-21

Vasculogenic mimicry persists during glioblastoma xenograft growth


1 Department of Neurosurgery and Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Department of Neurosurgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
2 Department of Neurosurgery and Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
3 Department of Neurosurgery, The Eighth Affiliated Hospital of Sun Yat-sen University (Shenzhen Futian People's Hospital), Shenzhen, China; Department of Neurosurgery, Shenzhen Sixth People's Hospital (Nanshan Hospital), Shenzhen, China
4 Department of Neurosurgery, The Eighth Affiliated Hospital of Sun Yat-sen University (Shenzhen Futian People's Hospital), Shenzhen, China
5 Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China

Date of Web Publication28-Feb-2018

Correspondence Address:
Dr. Zhong-Ping Chen
Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_4_17

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  Abstract 

Background: Vasculogenic mimicry (VM) describes the functional plasticity of aggressive tumor cells to form newly recognized microcirculation, lined by tumor cells rather than endothelial cells, in solid tumors. The presence of VM in glioma is significantly associated with high tumor grade and poor prognosis. However, whether VM is a regular feature or only a temporary phenomenon during glioma growth is unknown. This study was designed to observe VM during the growth of subcutaneous and orthotopic xenograft glioma in Balb/c nude mice. Methods: The human glioblastoma cell line (U87) was used as xenografts in Balb/c nude mice models. The xenografts were obtained at different stages of tumor growth, and evaluated for VM and endothelium-dependent vessels by dual staining for endothelial marker CD34 and periodic acid-Schiff (PAS). Results: It was found that the PAS-positive patterns which were identified as VM were persistent during tumor growth of both subcutaneous and orthotropic xenografts. Further analysis showed that the microvessel density (MVD) of endothelium-dependent vessels was positively correlated with the tumor size of subcutaneous xenograft (r = 0.406, P = 0.009), while no significant correlation was found between VM density (VMD) and the tumor size (r = 0.107, P = 0.512). Furthermore, VMD was negatively correlated with MVD (r = −0.404, P = 0.010). Conclusion: The study results revealed that both VM and endothelium-dependent vessels coexist persistently during glioblastoma xenograft growth, indicating that VM may complement microcirculation in gliomas.

Keywords: Angiogenesis, glioma, vasculogenic mimicry


How to cite this article:
Li C, Chen YS, Zhang QP, Chen JL, Wang J, Chen FR, G HKN, Chen ZP. Vasculogenic mimicry persists during glioblastoma xenograft growth. Glioma 2018;1:16-21

How to cite this URL:
Li C, Chen YS, Zhang QP, Chen JL, Wang J, Chen FR, G HKN, Chen ZP. Vasculogenic mimicry persists during glioblastoma xenograft growth. Glioma [serial online] 2018 [cited 2022 Dec 7];1:16-21. Available from: http://www.jglioma.com/text.asp?2018/1/1/16/226433

Cong Li, Yin-Sheng Chen, and Qing-Ping Zhang have contributed equally.



  Introduction Top


During embryonic development, primary vascular networks are formed by two processes as follows: (1) vasculogenesis, the reorganization of randomly distributed cells into a network of blood vessels, and (2) angiogenesis, the sprouting of new vessels from the preexisting external vasculature, in response to chemical stimulation.[1] To maintain development and rapid growth, solid tumors need sufficient blood supply through angiogenesis.[2] Furthermore, angiogenesis is essential for tumor cells to invade surrounding tissues and also to metastasize to distant sites. Until recently, most of the tumor studies were focused on the role of angiogenesis, the recruitment of new vessels into a tumor from external vessels, in tumor biology.[3],[4] In 1999, Maniotis et al.[5] reported for the first time that highly aggressive uveal melanomas could form blood vessels by tumor cells instead of endothelial cells, similar to embryonic vasculogenesis, and named this phenomenon of tumor cell vascularization as vasculogenic mimicry (VM). This finding contributed to a new insight into tumor microcirculation. The histological structures of VM channels are patterned networks of interconnected loops of periodic acid-Schiff (PAS)-positive extracellular matrix formed by aggressive tumor cells rather than endothelial cells.[5],[6] Since then, VM has been described in several malignant tumors and the presence of VM is associated with more aggressive tumor biology and increased tumor-related mortality.[7]

Glioblastoma multiforme (GBM) remains the most malignant neoplasm of the central nervous system and has a dismal prognosis. Less than 10% of GBM patients survive for more than 5 years, despite the multimodality treatment including surgery, radiation, and chemotherapy.[8] Our previous studies revealed the existence of VM in gliomas and correlated with the poor outcome in glioma patients.[9],[10] Recent study showed that the classical angiogenesis-inhibitors endostatin and TNP-470 could not suppress melanoma VM as the tumor cells lack the appropriate receptors for the inhibitors to act effectively.[3] Anti-vascular endothelial growth therapy also showed limited efficacy in astrocytoma patients.[4] Therefore, it is essential to elaborate the biological behavior of tumor VM and the molecular mechanism regulating their formation for optimizing anti-vascular therapy in gliomas. However, whether VM is a regular feature or only a temporary phenomenon during glioma growth is unknown. In this study, human GBM cell line - U87, which can form VM structure in vitro,[11] was used as xenografts in Balb/c mice. VM and endothelium-dependent vessels were assessed during different stages of xenografts growth to see whether VM exists temporarily or persistently during the tumor growth.


  Materials and Methods Top


Glioblastoma multiforme cell culture

Human GBM cell line - U87 was used in this study. The cells were cultured in Gibco's Dulbecco's Modified Eagle's medium (DMEM) medium supplemented with 10% fetal bovine serum (Hyclone, Logan, UT, USA), 100 U/mL penicillin, and 100 mg/mL streptomycin, and incubated at 37°C in a 5% CO2 atmosphere.

Subcutaneous and orthotopic xenograft models

Forty 4-week old and thirty 6-week old male nude mice (Balb/c) were purchased from the Shanghai Slrc Laboratory Animal Co., Ltd., (Shanghai, China), and separately used for inducing flank subcutaneous xenografts and intracranial xenografts, respectively. The average weights of these mice were 12.76 ± 1.67 g and 18.40 ± 1.15 g, respectively. These athymic mice were bred at the Animal Center of Sun Yat-Sen University Cancer Center. All animal studies were performed according to the Institutional Ethical Guidelines for Experimental Animal Care of Sun Yat-Sen University Cancer Center.

For the subcutaneous xenograft model, single cell suspensions of U87 cells (2 × 106 tumor cells per 0.1 mL) were injected subcutaneously in each mouse flank. Post inoculation, every 5th day, up to the 40th day, a random group of five mice was sacrificed. The xenografts were removed, tumor diameter was measured, and fixed with formalin and embedded in paraffin.

For the orthotopic xenograft model, tumor cell suspensions (2 × 105 cells in 5 μL of DMEM) were inoculated into brains of anesthetized mice according to the standardized procedure.[12] In brief, target 1 mm to the right of the midline and 1 mm posterior to the coronal suture was identified for injection. After a small skin incision was made and a burr hole was created with a microsurgical drill, the microinjector was gently inserted into mice brain until it reached the depth of 3 mm from the skin. Tumor cells were injected at a slow speed, and the microinjector was maintained in the position for an additional 1 min before it was gently removed to avoid cell leak. The inoculated mice were monitored closely, and they were sacrificed every 5th day until the 30th day post inoculation. The whole brain was removed and formalin-fixed, cut into two coronal parts from the site of injection, then embedded in paraffin.

CD34 and periodic acid–Schiff dual staining

CD34 and PAS dual staining were performed as previously described, to evaluate the microcirculation patterns, the endothelium-dependent vessels and VM in xenografts samples.[9],[10] In brief, 5-μm thick tissue sections were cut from the paraffin-embedded xenografts specimens. After routine deparaffinization and dehydration, sections were immersed in a 3% hydrogen peroxide solution at room temperature for 20 min to block the endogenous peroxidase activity. Then, the sections were heated in citrate buffer solution (0.01 M, pH = 6.0) for 15 min in a microwave for antigen retrieval. After washing, three times with phosphate-buffered saline (PBS) for 5 min each, nonspecific binding was blocked with normal goat serum for 20 min at room temperature. The blocked sections were incubated with primary rabbit monoclonal anti-CD34 antibody (dilutions 1:1000; Epitomics Inc., CA, USA) overnight at 4°C. Then, the sections were briefly washed in PBS and incubated at room temperature with the secondary anti-rabbit IgG antibody (PV6001, Zhongshan Chemmical Co., Beijing, China) for 50 min. After washing in PBS, the sections were color-developed by DAB solution (Dako Corporation, Carpinteria, CA, USA). After rinsing with distilled water for 10 min, the slides were incubated with PAS for 12 min. Then, sections were washed with water and counter stained with Mayer's hematoxylin. The negative control was created by replacing the primary antibodies with PBS. Finally, the stained sections were viewed under a light microscope to detect CD34 and PAS signals.

Staining evaluation

Conventional blood vessels consist of endothelial cells which were CD34-positive, while VM consist of tumor cell instead of endothelial cells and they were CD34-negative and PAS-positive,[7],[9],[10] and hence, CD34 and PAS dual staining was used in this study to distinguish these two kinds of microcirculation patterns in xenografts tissues.

Micro-vessel density (MVD) was evaluated by counting CD34-positive channels in 5 selected fields at ×200 magnification, according to the protocol described by Weidner et al.,[13] and the average was then calculated. According to the criteria of Folberg, VM was identified when the vessels were CD34-negative and PAS-positive.[7] Vasculogenic mimicry density (VMD) was evaluated following the MVD evaluation method.

Statistical analysis

Statistical analyses were performed using SPSS version 13.0 software (SPSS Inc., Chicago, USA). Differences were considered as statistically significant when the values of P < 0.05.


  Results Top


Endothelium-dependent vessels and vasculogenic mimicry co-exist during orthotopic xenographs growth

Intracerebral xenograft models using human GBM cells, such as U87, well recapitulate the brain microenvironment with the blood-brain barrier. The tumor formation of the U87 orthotopic model showed by hematoxylin and eosin (H and E) staining is summarized in [Table 1]. U87 orthotopic xenografts showed a predominantly compact growth pattern histologically and were morphologically characterized by a single, densely cellular, well-demarcated nodular mass surrounded by a compact reaction of astrogliosis [Figure 1]A,[Figure 1]B,[Figure 1]C. Necrosis was seldom observed among the tumor mass. Nude mice showed obvious weight loss at 30 days after orthotopic inoculation.
Table 1: The frequency of orthotopic tumor formation after U87 cell inoculation

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Figure 1: U87 orthotopic xenografts, and periodic acid–Schiff-positive patterns during orthotopic xenografts growth. (A-C) U87 orthotopic nodular mass showed compact growth pattern and was clearly demarcated from surrounding brain tissue (B and C: H and E staining; Br: brain; Tu: tumor). (D-F) The periodic acid–Schiff-positive patterns were persistent during U87 orthotopic xenografts growth. Furthermore, the rich periodic acid–Schiff-positive patterns (Red arrows) were found in the center of tumor mass where the density of endothelium-dependent vessels (Blue arrows) was lower than the peripheral zone. (D-F: CD34 and PAS dual staining; 5, 15, and 25 days after orthotopic inoculation, respectively.)

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The endothelium-dependent vessels were confirmed by CD34-positivity, and the VM channels were PAS-positive but CD34-negative.[9],[10] As inoculation time passed, the tumor mass continuously grew and showed increased vascularization. However, as early as day 5 after U87 inoculation, even though tumor mass was very small, CD34-positive channels and PAS-positive patterns were both observed [Figure 1]D. In our observation, endothelial-lined vessels and PAS-positive patterns co-existed during the entire assessed time of tumor growth. Interestingly, PAS-positive patterns were mainly seen in the area with less endothelial-lined vessels [Figure 1]E and [Figure 1]F.

Endothelium-dependent vessels and vasculogenic mimicry co-exist during subcutaneous xenografts growth

Five days after subcutaneous inoculation of U87 cells, a tumor mass with an approximate diameter of 3 mm was observed at the site of injection. Up to day 40, tumor size reached approximately 17 mm in diameter, and rich blood vessels could be seen on the surface of tumors through the skin revealing that the xenografts had sufficient blood supply [Figure 2]A. The subcutaneous tumor mass was well demarcated, had an intact capsule and barely infiltrated the surrounding tissue. The median diameter of subcutaneous xenografts was 10.42 mm (range from 2.92 to 17.05 mm).
Figure 2: U87 subcutaneous xenografts, and periodic acid–Schiff-positive patterns during subcutaneous xenografts growth. (A) The subcutaneous tumors were compact nodule mass and were well demarcated from the surrounding tissue. (B) Morphologically, the spindle shaped cells (Black arrows) were arranged in the inner wall of blood sinusoids suggesting endothelial origin of the vessel. (C) The inner wall of a blood channel was lined by cells (Black arrows) similar to surrounding tumor cells in morphology, suggesting this channel was VM. (D-F) CD34-positive channels (Blue arrows) and periodic acid-Schiff-positive patterns (Red arrows) were observed in different diameter xenografts (D: 7.70 mm; E: 12.27 mm; F: 16.41 mm). (B and C: H and E staining; D-F: CD34 and PAS dual staining; B-F: ×400)

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No obvious necrosis was observed histologically in all the tumors, indicating that sufficient blood supply was provided for tumor growth. Rich blood sinusoids were observed in the H- and E-stained sections. Two kinds of blood vessels were seen, distinguished by morphologically different cells lining their inner wall; spindle-shaped cells indicated endothelium-dependent vessel [Figure 2]B and cells similar to the surrounding tumor cells in morphology suggested a VM [Figure 2]C. CD34-positive channels and PAS-positive but CD34-negative patterns were observed in all different size xenografts [Figure 2]D,[Figure 2]E,[Figure 2]F suggesting endothelium-dependent vessels and VM were concurrent during the observed growth period of the U87 xenografts.

Correlation between microvessel density, vasculogenic mimicry density and diameter of xenograft tumors

The density of CD34-positive vessels and VM was evaluated as mentioned above. We found that MVD was positively correlated with the diameter of the tumors (r = 0.406, P = 0.009) while there was no significant relationship between VMD and tumor size (r = 0.107, P = 0.512) [Figure 3]. These results suggest that endothelium-dependent vessels increased in numbers, while VM was relatively constant during tumor growth. Interestingly, VM patterns were more likely found in low MVD areas [Figure 1]E and [Figure 1]F. Further analysis showed that VMD was negatively correlated with MVD (r = −0.404, P = 0.010) [Figure 3], indicating that VM may play a supplementary role to the function of endothelium-dependent vessels.
Figure 3: Correlation of microvessel density and vasculogenic mimicry density with diameter of U87 subcutaneous xenografts. The micro-vessel density were positively correlated with the diameter of tumors (r = 0.406, P = 0.009) while for vasculogenic mimicry density there was no obvious correlation with tumor size (r = 0.107, P = 0.512). In addition, the vasculogenic mimicry density were negatively correlated with micro-vessel density (r = −0.404, P = 0.010)

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  Discussion Top


GBM possesses characteristics of high vascular proliferation, and sufficient blood supply is essential for maintaining tumor survival and rapid growth.[14] It is conventionally believed that oxygen and nutrition are provided by endothelium-dependent vessels where the inner walls are lined with endothelial cells.[15] However, recent studies revealed a new microcirculation pattern, termed VM, in some highly aggressive tumors.[5],[6],[7],[16],[17] In VM, characteristically tumor cells, instead of endothelial cells, constituted a wall and PAS-positive matrix-rich basement membrane. There are several evidences demonstrating that tumor cell-mediated VM plays an important role in the tumor development and has prognostic impact in breast cancer,[16] hepatocellular carcinoma,[17] and glioma.[10] Recent studies revealed that glioblastoma U87 cells can form VM tubules in vitro matrigel-based tube formation assay.[11] The present study revealed that U87 cells can also form VM channels under in vivo condition. Furthermore, subcutaneous and orthotopic xenografts generated by U87 cells concurrently presented PAS-positive patterns and CD34-positive vessels, suggesting that both endothelium-dependent vessels, as well as VM, persist during GBM xenograft growth. In addition, we found that the MVD is increased during xenografts growth demonstrating its angiogenic ability. However, VMD was mainly observed in the areas with less endothelium-dependent vessels, and VMD was negatively correlated with MVD, inferring that VM may complement the microcirculation during GBM growth.

Why GBM growth develops VM and what gives increase to this newly recognized pattern of microcirculation is unknown. Several studies have revealed that hypoxia plays an important role in VM formation.[18],[19],[20] Hypoxia is a characteristic feature of tumors and is associated with tumor growth. Especially, the local microenvironment of tumor center is often hypoxic or even anoxic. Studies have shown that the presence of necrotic cells also can stimulate tumor cells to acquire a tumor-derived endothelial cell phenotype and undergo VM.[21] In this study, the VM patterns were most frequently observed in the centers of tumor mass supporting the idea that hypoxia may induce VM formation. Tumor cells are mostly under hypoxic condition, due to fast growth, and to some extent this may account for the continued existence of VM during tumor growth.

VM describes the plastic and multipotent phenotype of highly aggressive tumor cells that can form functional vascular networks.[1] Cancer stem cells are thought to be refractory to therapies and are capable of regenerating tumor following treatment.[22] Glioblastoma cells may arise from cancer stem cells, which can modify the environment and induce plasticity in the cellular hierarchy.[23] Many studies reveal the potential of glioblastoma cells to mimic vascular endothelial cells and cancer stem cells play a pivotal role in glioblastoma VM formation, as glioblastoma stem cells (GSCs) can give rise to endothelial cells [24],[25],[26] and vascular pericytes.[27] A small population of GSCs can trans-differentiate into mural-like cells that co-express markers of neural and vascular lineages which can mediate VM in glioblastomas.[28] By live cell imaging, we have previously shown that GSCs may differentiate into endothelial cells and promote angiogenesis in glioblastomas.[29] A recent study revealed that the endothelial cells derived from GSCs can promote the invasion and recurrence of GBM, and contribute to the lethality of the condition.[30] In this regard, we theorize that VM may be a transition from GSCs to form tumor-derived endothelium-dependent vessels, which needs further evaluation. This theory can explain why MVD was increased and VMD was not significantly changed during the U87 xenografts growth observed in our study.

In conclusion, we have identified that VM persistently exists during glioblastoma U87 xenografts growth, which may complement the GBM microcirculation.

Financial support and sponsorship

The study was supported by National Natural Science Foundation of China (No. 30973478, 81372685), Natural Science Foundation of Guangdong Province (S2013040012894), Guangzhou Science Technology Project (No. 201508020125), Shenzhen Innovation Project of Scientific and Technology (JCYJ20140416094330210), and National Basic Research Program of China (No. 2015CB755505).

Conflicts of interest

There are no conflicts of interest.



 
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