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Year : 2019  |  Volume : 15  |  Issue : 6  |  Page : 1282-1287

Resistance to bevacizumab in ovarian cancer SKOV3 xenograft due to EphB4 overexpression

Department of Obstetrics and Gynecology, Binzhou Medical University Hospital, Binzhou, Shandong, P.R. China

Date of Submission27-Sep-2016
Date of Decision22-Oct-2016
Date of Acceptance13-Nov-2016
Date of Web Publication24-Dec-2019

Correspondence Address:
Dr. Li Li
Department of Obstetrics and Gynecology, Binzhou Medical University Hospital, Binzhou, Shandong 256603
P.R. China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.204896

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 > Abstract 

Aim of Study: Bevacizumab (BV) is broadly used to treat a number of cancers; however, BV resistance mechanisms and strategies to overcome this resistance are yet to be determined.
Materials and Methods: In this study, we used ovarian xenograft model to evaluate the underlying resistance mechanisms of BV in ovarian cancer treatment.
Results: Our results showed that EphB4 was overexpressed in BV-resistant xenograft models instead of other common receptor tyrosine kinases. In addition, when coadministrated with EphB4 blocker NVP-BHG712, the antitumor effect of BV was significantly enhanced in the resistant model, further confirmed the role of EphB4 in BV-resistant ovarian cancer. These results indicate that NVP-BHG712 reverses EphB4 overexpression-mediated resistance to BV.
Conclusion: These findings represent a guide for the design of future medication strategy and may be useful in guiding the use of BV in combination with NVP-BHG712 in patients with resistance or intolerance ovarian cancer.

Keywords: Bevacizumab, EphB4, ovarian cancer cells, xenograft

How to cite this article:
Li L, Nan F, Guo Q, Guan D, Zhou C. Resistance to bevacizumab in ovarian cancer SKOV3 xenograft due to EphB4 overexpression. J Can Res Ther 2019;15:1282-7

How to cite this URL:
Li L, Nan F, Guo Q, Guan D, Zhou C. Resistance to bevacizumab in ovarian cancer SKOV3 xenograft due to EphB4 overexpression. J Can Res Ther [serial online] 2019 [cited 2022 May 27];15:1282-7. Available from: https://www.cancerjournal.net/text.asp?2019/15/6/1282/204896

 > Introduction Top

In 2012, around 238,000 women were diagnosed with ovarian cancer, the most lethal of all gynecologic malignancies.[1] About 151,000 women dead in the same year from this indication.[2] At present, the aggressive cytoreductive surgery, followed by platinum and taxane combination chemotherapy, is regarded as the standard treatment for ovarian cancer.[3] Through taking the standard treatment, 70% of ovarian cancer patients will experience a significant clinical remission after the initial therapy; however, most ovarian cancer patients will ultimately experience progression and succumb.[2] For patients with advanced ovarian cancer, the standard treatment, maximal surgical cytoreduction, following with platinum-containing chemotherapy, have reached overall response rates of 60%–75% with initial therapy; however, the majority of women with epithelial ovarian cancer (EOC) will relapse and demand for retreatment with a platinum-based chemotherapy regimen.[3] Therefore, further treatments of ovarian cancer are very necessary to get rid of poor long-term prognosis. To improve the prognoses of ovarian cancer patients, plenty of clinical research has been carried out to explore new therapies, including antiangiogenesis therapy.[4]

Bevacizumab (BV) is known as the most widely studied antiangiogenesis agent across tumor types and also specifically in epithelial ovarian cancer (EOC). The US Food and Drug Administration approved BV for the treatment of platinum-resistant EOC in November 2014.[5] BV (Avastin ®) is a recombinant, humanized, monoclonal immunoglobulin G1 antibody targeted at vascular endothelial growth factor A (VEGF-A). Binding to and neutralizing all biologically active forms of VEGF-A, BV suppresses the growth of tumors and inhibits progression of metastatic disease.[6] The objective response rate of BV can extend 16% of patients with recurrent ovarian cancer and stabilized disease for 5.5 months in 50% of patients.[7] As already demonstrated and approved in several countries, the application of BV has already been the first-line treatment as well as the first-targeted antiangiogenic therapy for ovarian cancer patients.[8]

While we are enjoying BV anticancer benefits, BV resistances as well as the poor knowledge of BV resistance mechanism are still remaining incompletely understood.[9],[10] Adaptive resistance and escape from antiangiogenesis therapy limit the anti-angiogenesis therapy progress.[11] The research of mechanism for overcoming resistance to anti-VEGF drugs, especially BV in ovarian cancer, is increasingly important. The purpose of current study is to investigate the underlying mechanisms of BV resistance in ovarian cancer, which would shed new lights on treatment strategy.

 > Materials and Methods Top

SKOV3 cell line and culture condition

SKOV3 human ovarian cancer cell line was purchased from the American Type Culture Collection (Rockville, MD, USA) and cultured in Minimum Essential Alpha RPMI-1640 Medium (Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (HyClone, Logan, UT, USA) at 37°C in a humidified atmosphere with 5% CO2.

Bevacizumab-resistant ovarian cancer xenograft model establishment

Fifteen of 6–7-week-old athymic BALB/c nude mice were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China). The mice were maintained under super pathogen-free conditions and housed in barrier facilities on a 12-h light/dark cycle, with free access to food and water. All animal experiments were performed in accordance with protocols approved by the Huazhong University Experimental Animal Care and Use Committee. 5 × 106 SKOV3 cells were subcutaneously injected into each nude mouse. Tumor size and width were measured once every 5 weeks since the day of SKOV3 cell implantation. Tumor sizes were calculated by the standard formula of tumor size = length × width 2/ 2. When tumor size reached 150 mm 3, the mice were administrated with BV (Roche, Basel, Switzerland) as a liquid and fine powder at 5 mg/kg. Twenty-five weeks after the first injection, all mice were euthanized by carbon dioxide asphyxiation and the tumor tissues were harvested for weight measurement, microarray analysis, real-time polymerase chain reaction (PCR) analysis, and Western blot analysis.

Microarray-based gene expression profiling and analysis

The GeneChip Human Genome U133 Plus 2.0 Arrays (Affymetrix, Santa Clara, CA, USA) were used to analyze the genomic gene copy number and gene expression in ovarian xenograft tumors. Gene profiling comparison was achieved by calculating the fold change of the copy number and gene expression between these tumors. The data were processed using the aroma. ScanArray Express Scanner (PerkinElmer) was used to scan hybridization signals. GenePix Pro version 5.0 (Molecular Devices, Sunnyvale, CA, USA) was used for the signal process. The raw data normalization of each spot was taken by subtracting from the mean intensity of the background signal, determined by the 95% confidence intervals of the signal intensities of all of the blank spots.

Quantitative real-time reverse transcription polymerase chain reaction analysis

Quantitative real-time reverse-transcriptase PCR (RT-PCR) was performed with TaqMan probes on an ABI Prism 7500 system (Applied Biosystems). The TaqMan probes were purchased from Applied Biosystems. For each sample, the final numerical value (v) was calculated according to the following function: V = tumor (PRAME or CTAG1B messenger RNA [mRNA] value/glyceraldehyde-3-phosphate dehydrogenase [GAPDH] mRNA value)/testis (PRAME or CTAG1B mRNA value/GAPDH mRNA value). Complementary DNA (cDNA) was prepared from total RNA isolated from cell pellets (Qiagen RNeasy Kit), using SuperScript III and oligo dTs (Thermo Fisher Scientific, Waltham, MA, USA). After DNase treatment (Ambion), cDNA was used as the template for quantitative PCR on a BioRad CFX Connect Real-time System and SsoAdvanced Universal SYBR Green Supermix (BioRad, Hercules, CA, USA). mRNA levels were calculated by the 2− ΔΔ Ct method and presented as fold changes of relevant controls.

Western blotting analysis

To confirm gene overexpression involved in BV-resistant tumor, Western blot was performed. The tumor tissues were isolated at 2 h after the last treatment with BV or/and NVP-BHG712 on day 21 of the efficacy studies. Following the harvest, tumors tissues were homogenized and lysed in cell lysis buffer (Bio-Rad Laboratories, Hercules, CA, USA) with phosphatase inhibitor cocktail and proteinase inhibitor cocktail (Sigma, St. Louis, MO, USA). The lysates were centrifuged at 13,000 rpm for 20 min. Extracts were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (10% acrylamide) and transferred onto nitrocellulose membranes by electrophoretic transfer (Hybond TM-C super, Amersham, UK). Primary antibodies were added and incubated overnight at 4°C. Then, the membranes were blocked in TBST (0.2M NaCl, 10 mM Tris, pH 7.4, 0.2% Tween-20). The membranes were then conjugated with secondary antibodies of EphB4. Membranes were then washed with 1 × PBST three times and visualized with enhanced chemiluminescence (Amersham, GE Healthcare, Little Chalfont, UK).

In vivo efficacy study

NVP-BHG712 was acquired from MedChem Express (Monmouth Junction, NJ, USA).

Tumor tissue isolated from mouse 8 was cut into 2 × 2 mm 3 pieces; the necrotic part was removed and subcutaneously implanted to nude mice. After tumor size had reached 150 mm 3, the mice were then randomized into four groups (each group included ten mice): BV group that treated with a single intraperitoneal injection of 5 mg/kg BV, NVP-BHG712 group that treated with a single subcutaneous injection of 10 mg/kg. BV blocking group that treated with a single subcutaneous injection of BV + NVP-BHG712. The vehicle group was treated with a single injection of intraperitoneal 0.05 ml saline.

Statistical analysis of the data

All data were presented as mean ± standard deviation for the indicated number of independently performed experiments. The statistical analysis was carried out using the Student's t-test. P < 0.05 was considered to be statistically significant.

 > Results Top

Bevacizumab-resistant ovarian cancer xenograft model establishment

We injected female BALB/c nude mice with SKOV3 human ovarian cancer cell line and established the ovarian cancer xenograft model. When the average tumor volume reached approximately 150 mm 3, eight mice were randomly picked up and treated with BV. The antitumor activity of BV was examined in these eight ovarian cancer xenograft models. Acquisition of resistance to BV was evaluated by comparing the differences in tumor volume and weight growth during the treatment overtime. BV exhibited significant antitumor activity in all of the eight models until evaluated in week 10. However, the tumor volume of mouse 3 and mouse 8 significantly increased in week 20 after BV administration [Figure 1]a, indicated acquirement of BV resistance. To confirm tumor volume increase of mouse 3 and mouse 8, all 8 mice were sacrificed in week 25 to measure the tumor weight. The tumor weight of mouse 3 and mouse 8 was over 0.5 g, significantly higher than tumor tissue weight of other mice [Figure 1]b. These in vivo findings demonstrated that tumor tissue of mouse 3 and mouse 8 acquired the resistance to BV and, therefore, could be used as BV-resistant ovarian cancer xenograft models for the following studies.
Figure 1: Tumor growth inhibition resistance of bevacizumab was observed. (a) Bevacizumab inhibited tumor growth in ovarian cancer models. 1–8, nude mice bearing ovarian tumors were once-daily dosed with bevacizumab at the indicated dose after tumor reached 150 mm3 for up to 25 weeks. (b) The weights of ovarian tumors from all Avastin-treated groups at week 25 were measured

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Gene expression profiling and analysis to disclose the mechanism of bevacizumab-resistant tumor

To explore the gene expression mechanism of BV-resistant ovarian cancer xenograft model, we used microarray with the U133+2.0 gene chips to compare the genome-wide gene profile of all eight ovarian cancer xenograft models. We screened and selected the genes with different elevated RNA transcription levels of BV-resistant xenograft tumors compared with the nonresistant ovarian tumor tissues. Four genes were identified including estimated glomerular filtration rate (eGFR), c-Met, insulin-like growth factor (IGF), and EphB4. The microarray data showed that EphB4 was significantly amplified and highly expressed in mouse 3 and mouse 8 [Figure 2]a. From this result, we could see that EphB4 was overexpressed in the two BV-resistant ovarian cancer xenograft models (mouse 3 and mouse 8).
Figure 2: The drug resistance mechanism of bevacizumab was explored and confirmed by microarray, reverse-transcriptase polymerase chain reaction, and Western blot analysis. Tumor 1–8 were resected from xenografts, respectively, and then suffered to gene chips, reverse-transcriptase polymerase chain reaction, and Western blot. (a) The amplification and expression of estimated glomerular filtration rate, c-Met, insulin-like growth factor, and EphB4 in all eight ovarian cancer models were analyzed with the SNP6.0 and U133+2.0 gene chips. (b) A comparison of messenger RNA expression level of EphB4 in eight ovarian cancer models was taken by reverse-transcriptase polymerase chain reaction. (c) The expression level of pEphB4 was further analyzed by Western blot in mouse 3 and 8 tumor tissues. β-actin was used as a loading control

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This gene profiling result was confirmed by the RT-PCR analysis and Western blot analysis [Figure 2]b. EphB4 mRNA gene expression was evaluated by quantitative real-time PCR analysis [Figure 2]b. Quantification of mRNA relative expression showed a significant higher expression of EphB4 gene in BV-resistant tissues in comparison to other normal groups. The high EphB4 expression was confirmed in BV-resistant ovarian cancer model mouse 3 and mouse 8.

To further explore expression level of EphB4 protein in all eight ovarian cancer models to find BV-resistant mechanism, Western blot analysis was performed. Western blot result also revealed the similar result: EphB4 was overexpressed in BV-resistant ovarian cancer tissue 3 and 8, suggesting the association of EphB4 overexpression with BV resistance mechanism [Figure 2]c. Taken above results together, we focused on EphB4 as a candidate molecule for acquired BV resistance.

EphB4 blocker NVP-BHG712 reversed bevacizumab resistance

NVP-BHG712 is cloned from erythropoietin-producing hepatocellular carcinoma, specific receptor blocking EphB4.[12] Based on microarray and RT-PCR, we found that the expression of EphB4 was overexpression in BV-resistant cancer. To verify the efficacy of EphB4 in BV resistance, ovarian tumor-bearing mice were treated with the EphB4 inhibitor NVP-BHG712 in combination with BV. BV at a concentration of 5 mg/Kg was used after a series of pilot experiments indicated that this concentration was able to produce significant resistance in ovarian cancer xenograft model. NVP-BHG712 at a concentration of 10 mg/kg or in combination with BV did not result in toxicity in ovarian xenograft. The combination treatment of BV and NVP-BHG712 further prolonged the tumor growth inhibition effect compared with the BV alone. Saline- and NVP-BHG712-treated mice were used as control groups. In addition, tumor size, weight, and volume significantly reduced by NVP-BHG712 in combination with BV [Figure 3]a, [Figure 3]b, [Figure 3]c. The combination treatment of NVP-BHG712 neutralized EphB4 overexpression. Taken all results together, overexpressed EphB4 plays a key role in the resistance to antitumor therapy of BV.
Figure 3: EphB4 blocker NVP-BHG712 reversed bevacizumab resistance in ovarian cancer xenograft model. NVP-BHG712 in combination with bevacizumab reduced tumor size and volume. (a) Tumor volume changes over time following implantation. Data points represent mean tumor volume of each treatment group (n = 8). Error bars represent standard deviation. (b) Images of excised SKOV3 tumors implanted subcutaneously in thymic BALB/c nude mice that were treated with normal saline, bevacizumab, NVP-BHG712, and combination of NVP-BHG712 plus bevacizumab at the end of the 5-week treatment period, n = 8. (c) Mean weight of the excised SKOV3 tumors from the mice treated with normal saline, bevacizumab, NVP-BHG712, and the combination of NVP-BHG712 with bevacizumab at the end of the study. Error bars represent standard deviation. **P < 0.01 versus the bevacizumab group

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 > Discussion Top

Even BV is broadly used for multiple cancers treatment, BV resistance, and its mechanism has not been revealed yet.[9] In this study, we found that NVP-BHG712 in combination with BV significantly attenuated tumor growth in ovarian tumor xenograft model. Our study is helpful to gain more insights into the mechanisms of acquired BV resistance. EphB4 overexpression was found and was responsible for the resistance of antitumor activity of BV. NVP-BHG712 reversed this resistance by blocking the Eph 4, providing a promising strategy to restore BV sensitivity in ovarian cancer treatment.

Although many studies have been done on BV resistance mechanism research, the specific molecular mechanisms causing the resistance to a BV have not been well understood yet. According to a previous study, ovarian cancer cells induced resistance to BV via activating Akt phosphorylation in endothelial cells.[13] Another study reported that increased tumor hypoxia and hence elevated hypoxia-inducible factor-1α (HIF1α) limit the efficacy of VEGF pathway-targeting drugs through upregulating adaptive resistance genes.[14] This study was further confirmed by another study of Deng in 2016. Deng found that TCEB2 gene was significantly upregulated in resistance-acquired ovarian cancer cells and caused BV resistance through promoting HIF-1α degradation and suppressing VEGF-A expression.[15] The strategy to reverse the resistance should be combined antiangiogenic drugs with agents suppressing HIF1α.[14] Our finding is different from previous points; the possible reason would be due to different cancer type, and the relationship behind them needed further investigation.

Some previous studies have been done on EphB4 to explore and improve ovarian cancer treatment effect, leading to promising ovarian cancer treatment strategies. JI-101, as an inhibitor of EphB4, was used in combination with everolimus as a single dose in an ovarian cancer treatment pilot study.[16] The suppression of EphB4 inhibited the growth of ovarian cancer cells SKVO3 by downregulation of the phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin (mTOR) pathway, as well as reverse Akt phosphorylation induced by mTOR small hairpin RNA.[17] EphB4 gene silencing and inhibition strategies enhanced tumor cell apoptosis and decreased ovarian cancer migration, invasion and deducted tumor weight.[18],[19] All these studies mentioned above also identified EphB4 as a valuable therapeutic target in ovarian cancer.

 > Conclusion Top

EphB4 overexpression in BV resistance-acquired ovarian tumors helped us know more about molecular mechanisms of resistance to anti-VEGF therapies. The coadministration with EphB4 blocker shed light on another potential treatment strategy to reverse BV resistance. However, the molecular mechanism underlying the overexpression of EphB4 in BV resistance-acquired ovarian tumors is not known. However, the pharmacokinetic study, safety study, and phenotypic effect study of the coadministration of BV with NVP-BHG712 still need to be further investigated.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

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Werner TL, Wade ML, Agarwal N, Boucher K, Patel J, Luebke A, et al. A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-ß, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort. Invest New Drugs 2015;33:1217-24.  Back to cited text no. 16
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Kumar SR, Masood R, Spannuth WA, Singh J, Scehnet J, Kleiber G, et al. The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome. Br J Cancer 2007;96:1083-91.  Back to cited text no. 19


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