Home Life Sciences Expression of Angiopoietin and VEGF in cervical cancer and its clinical significance
Article Open Access

Expression of Angiopoietin and VEGF in cervical cancer and its clinical significance

  • , EMAIL logo , , , , and
Published/Copyright: December 31, 2018
Download Article (PDF)
Open Life Sciences
From the journal Open Life Sciences Volume 13 Issue 1

Abstract

Objective

The aim of this study was to evaluate the expression of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) in cervical cancer and its clinical significance.

Methods

Immunohistochemical assay was used to examine the expression of Ang-1/2 and VEGF in tumor tissue from 56 cervical squamous cell carcinoma patients treated with operation only (SCC-O group), as well as 51 subjects with cervical squamous cell carcinoma treated with neoadjuvant radiotherapy (SCC-RCO group, n=28) or neoadjuvant chemotherapy (SCC-CO group, n=23). Both microvessel density (MVD) and lymphatic vessel density (LVD) were examined in the three groups through detection of CD34 and D2-40 expression in respective tissue samples.

Results

With the progression of cervical cancer, the positive expression scores of Ang-2 and VEGF were significantly increased (p<0.05). Compared with surgical intervention, neoadjuvant chemoradiotherapy significantly reduced the positive expression scores of Ang-1, Ang-2, and VEGF in cervical cancer tissues (p<0.05). The MVD values of the SCC-CO and SCC-RO groups were significantly reduced as compared to the SCC-O group (p<0.05). Similarly, the LVD values of the SCC-CO and SCC-RO groups were also significantly reduced when compared to those of the SCC-O group (p<0.05). However, LVD values of the SCC-CO and SCC-RO groups were not statistical different (p>0.05).

Conclusion

Ang-1, Ang-2 and VEGF may play an important role in the development of cervical cancer. Mutual synergism of Ang-2 and VEGF demonstrated a close relationship with the generation of cervical blood and lymphatic vessels. Cervical cancer radiotherapy and chemotherapy could significantly inhibit the formation of blood vessels and lymphatic vessels in tumor tissue.

Keywords: angiogenin; vascular endothelial growth factor; cervical cancer; microvessel density

1 Introduction

Carcinoma of uterine cervix is one of the most common malignant carcinomas that seriously threaten women’s lives, and ranks second to breast cancer in terms of morbidity, accounting for half of the malignant tumors occurring in the female reproductive system [1]. The morbidity and mortality of cervical cancer have decreased with the development of long-term and large-scale censuses and women’s health care in China [2]. Surgery, radiotherapy, and chemotherapy are the major treatments for cervical cancer. In recent years, several studies have verified that the occurrence, development, invasion, and metastasis of tumors are closely linked to angiogenesis [3, 4]. In the absence of blood vessel formation, tumor tissue stops growing when its diameter reaches 1 to 2 mm. Therefore, neoplastic angiogenesis is a prerequisite for tumor development. Angiogenesis is the synergistic effect of a series of vascular growth factors and vascular growth inhibitors [5]. The angiogenin and vascular endothelial cell growth factor (VEGF) family is essential to the mutual synergistic development of tumor invasion and metastasis. Moreover, angiogenesis and lymphatic circulation formation are closely related. The effect of the Ang family and VEGF in the angiogenesis in a tumor, especially cervical cancer, has been frequently discussed. In this study, the expression levels of Ang-1/2 and VEGF in the cervical squamous cell carcinoma were measured through the immunohistochemical assay. The influence of radiotherapy and chemotherapy on Ang-1/2 and VEGF expression were also determined, and the relationship between this effect and the formation of new blood vessels and lymphatics in cervical squamous cell carcinoma was analyzed.

2 Materials and methods

2.1 Patients

From March 2012 to February 2016, 107 paraffin embedded specimens of cervical cancer patients from our hospital were selected for this study, and all the specimens were classified as squamous carcinoma of cervix (SCC). Of the 107 specimens, 56 were samples of surgical resection of cervical cancer (SCC-O), 28 were samples of preoperative neoadjuvant chemotherapy (SCC-CO), and 23 were samples of neoadjuvant chemotherapy (SCC-RO).

SCC-O group: This group did not receive preoperative radiotherapy, chemotherapy, or immunotherapy. The age in this group ranged from 31 years to 68 years, and the median age was 47 years. 22 patients were less than 45 years old, and 34 patients were greater than 45 years old. According to the FIGO staging system [6], 27 cases were stage I and 29 cases were stage II. Fourteen cases of pelvic lymph node metastases, and 42 cases of no-metastases were also included.

SCC-CO group: The preoperative examination of patients all showed local cervical tumors with diameters of ≥4 cm. A course of DSA intubation chemotherapy was performed before surgery, which was performed 3–4 weeks after chemotherapy. The age range was 32–65 years, and the median age was 45 years. Eleven patients were less than 45 years old, and 18 were greater than 45 years old. FIGO staging showed 7 cases of stage I and 22 cases of stage II.

SCC-CO group: The preoperative examination of patients all showed local cervical tumors with diameters of ≥4 cm. All patients received radiotherapy 3–4 weeks before surgery. The age range was 29–66 years old, and the median age was 44 years old. 10 cases were less than 45 years old and 13 cases were greater than 45 years old. FIGO staging demonstrated 8 cases of staging I, 17 cases of stage II.

Informed consent: Informed consent has been obtained from all individuals included in this study.

Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the ethics committee of the Lishui People’s Hospital review board and the clinical study committee.

2.2 Reagent

Sheep anti-human Ang 1-2 polyclonal antibody was purchased from SANTA CRUZ Biotechnology Co., Ltd. (United States) and used at a working concentration of 1:100. Mouse anti-human VEGF monoclonal antibodies, mouse anti-human CD34 monoclonal antibodies, and mouse anti-human d2-40 monoclonal antibodies were purchased from Beijing Zhongshan Jinqiao Biotechnology Co., LTD, China, and used at a working concentration of 1:100. The ready-to-use Polink-2 Plus goat immunohistochemical staining kit with a hypersensitivity two-step method (Cat. No: PV-9003) and ready-to-use Immuno-Bridge + two-step method rat immunohistochemical kit (Cat. No: PV-9000) used in this study are products of GBI Biotechnology Co., Ltd (United States).

2.3 Immunohistochemical assay

The original paraffin sections of the above cases were re-examined and the paraffin specimens containing continuous cervical epithelium and cancer foci were selected. In each case, the paraffin tissues were successively sliced to 4 μm × 6 μm sections. One slice was stained with HE to determine the slice quality, which was further confirmed by a pathologist. Immunohistochemical staining was performed on the remaining sections according to the manufacturer’s instructions

2.4 Immunohistochemistry results evaluation

Instead of a monoclonal antibody, PBS was used as a negative control, and a known positive was used as the positive control. Immunohistochemical staining showed that the expression of Ang-2 or VEGF was positive when the cytoplasm or cell membrane was stained brown or brown yellow. For each section 5 high power fields (×400) were randomly selected, and the frequency of positive cells in 500 tumor cells was counted continuously. Determination of staining 1) 0-3 grades was divided according to the number of staining cells in the total number of visual field cells. Stage 0: 0, Stage 1: <25%, stage 2: 26%–50%, stage 3: >50%. 2) We divided 0–3 stages according to the staining strength of the stained cells: Stage 0: Negative, stage 1: Weak, faint yellow, stage 2: Medium, claybank, stage 3: Strong, sepia. Take 0-2 as the negative(-), >3 is the positive (+). Image Pro Plus (Media Cybemetics Inc USA) 8000 image analysis was used to analyze the expression level of each immunohistochemical slice, and input the slice images by the PC-Image analysis device through the image acquisition system with a ×20 objective lens. The corresponding part of each image was randomly selected, and the average optical (OD) of its positive positions was selected. The average value was used as the specimen result. MVD counting: CD34 positive reactant was indicated by the presence of light brown to dark brown particles, which localize in the vascular endothelial cell. Most of the stained capillaries and microvessels in tumor tissues were calculated using the Gasparini method [7]. The number of single endothelial cells or clusters of endothelial cells that were dyed brownish yellow in tumor areas were counted as single blood vessels. A lumen diameter of 50 Ixm was judged to be a microvessel, while vessels with >50 Ixm in diameter, or a lumen diameter of more than 8 red blood cells wide, or the wall of the tube containing the muscular layer was not counted as microvessels. Individual staining cells or groups of cells without lumina were counted as independent microvascular counts. Cases exhibiting tumor areas with the highest MVD under low power (×100) were selected. Then, five microvessels within the fields of vision under the high power (×400) were randomly counted, and the average value of the MVD was calculated. The method used for D2-40 markers and microlymphatic counting was similar to the above method.

2.5 Statistical analysis

Data were analyzed with SPSS 18.0 statistical software package (IBM, Armonk, NY, USA). Measurement data are expressed as mean ± standard deviation. Comparison of multiple groups was performed by one-way ANOVA, and the LSD method was used for comparison between groups. Enumeration data were expressed with a relative number, and the comparison between groups was made based on the c2 test. P<0.05 was considered to be statistically different.

3 Results

3.1 Ang-1, Ang-2 and VEGF expression

Ang-1 and Ang-2 showed expression in the cytoplasm or cell membrane as indicated by sepia or brown particles with uniform distribution. VEGF was mainly expressed in the cytoplasm, with some expression in the cell membrane, displaying brown particles (Figure 1).

Figure 1 Ang-1, Ang-2 and VEGF expression in cervical cancer (A: Ang-1 positive 400×; B: Ang-1 negative 400×; C: Ang-2 positive 400×; D: Ang-2 negative 400×; E: VEGF positive 400×; F: VEGF negative 400×; G: HE stain 200×; H: HE stain 400×)
Figure 1

Ang-1, Ang-2 and VEGF expression in cervical cancer (A: Ang-1 positive 400×; B: Ang-1 negative 400×; C: Ang-2 positive 400×; D: Ang-2 negative 400×; E: VEGF positive 400×; F: VEGF negative 400×; G: HE stain 200×; H: HE stain 400×)

3.2 Ang-1, Ang-2 and VEGF expression score of different groups

With the progression of cervical cancer, the positive scores of Ang-2 and VEGF were significantly increased (p<0.05; Table 1). Compared with surgery, we also observed that preoperative neoadjuvant chemoradiotherapy can significantly reduce the positive scores of Ang-1, Ang-2, and VEGF in cervical cancer tissues (p<0.05; Figure 2).

Figure 2 Bar plot of Ang-1, Ang-2 and VEGF expression score of different groups (*p<0.05; **p<0.01)
Figure 2

Bar plot of Ang-1, Ang-2 and VEGF expression score of different groups (*p<0.05; **p<0.01)

Table 1

Ang-1, Ang-2 and VEGF expression in SCC-O'SCC-CO'SCC-RO groups

GroupNAng-1Ang-2VEGF
SCC-O----
I2734.23±15.6638.64±16.2145.21±21.12
II2932.05±16.2258.66±18.5668.42±29.21
SCC-CO2826.23±12.2428.12±18.6526.41±17.36
SCC-RO2325.23±13.0424.35±16.5425.12±19.33

3.3 MVD and LVD scores in different groups

The MVD value of the SCC-CO and SCC-RO groups was significantly reduced as compared to the SCC-O group (p<0.05). Within this comparison, the SCC-RO group showed a greater reduction compared with the SCC-CO group, (p<0.05). The LVD values of the SCC-CO and SCC-RO groups were significantly reduced compared to that of the SCC-O group (p<0.05). However, the LVD values of the SCC-CO group and SCC-RO group were not statistically different (p>0.05), (Figure 3).

Figure 3 CD34 and D2-40 expression score of different groups (A: CD34 positive expression 400×; D2-40 positive expression 400×) (*p<0.05; **p<0.01)
Figure 3

CD34 and D2-40 expression score of different groups (A: CD34 positive expression 400×; D2-40 positive expression 400×) (*p<0.05; **p<0.01)

4 Discussion

The important effects of Ang-1 and Ang-2 on tumor progression have been verified in many solid malignant carcinomas [8, 9, 10]. High Ang-2 expression in tumors have been regarded as having a close relationship to angiogenesis, invasion, metastasis, and poor prognosis [11]. Previously, the mechanism of Ang-1 mediated promotion of vessel maturation and maintenance of vessel structure was conferred primarily through improving the viability of the vascular endothelial cell by inhibiting apoptosis and reducing vascular permeability and degeneration [12]. Ang-2, on the other hand, competitively inhibits the formation of unstable leaky blood vessels by specifically binding to Tie-1/2 receptors and preventing their phosphorylation. Published studies

have demonstrated that Ang-2 exhibited up-regulated expression at the protein and mRNA levels in prostate cancer, hepatocellular cancer, stomach cancer, and oral squamous cell carcinoma, without the expression decline of Ang-1 in the protein level and mRNA level [13, 14]

We found that Ang-1 and Ang-2 both have high expression levels in cervical cancer but showed different characteristics. With the progress of cervical cancer, the expression level of Ang-2 protein significantly increased from stage I to stage II, although the expression was considerably reduced by radiochemotherapy, and to a greater extent, by radiotherapy. However, with the progression of cervical cancer, Ang-1 displayed a reduction in protein expression level stage I to stage II, and radiochemotherapy also reduced expression, although the reduction was non-significant. The expression characteristics of VEGF are similar to those of Ang-2. The growth, invasion, and metastasis of malignant carcinomas was closely related to the generation of tumor vasculature, which was mainly dependent on the strict regulation of the promoting factor of vasculature generation and the inhibiting factor [15, 16]. Among these regulatory factors, VEGF and the Ang family are considered to be two independent and mutually affected vasculature systems. In the early stage of tumor development, tumor cells and the host select and form a vascular area with sufficient blood supply. Given that tumor tissues compete with healthy tissues for the same blood supply and tumor cells proliferate rapidly, the expression levels of VEGF in the body do not increase, whereas those of Ang-1 and Ang-2 increase significantly [17, 18]. Ang-2 showed antagonism to Ang-1 in the absence of VEGF, which produced damaged tumor blood vessels, loosened vasculature, eliminated the restriction of angiogenesis by the vascular basement membrane and surrounding cells, and activated endothelial cells. Under the stimulation of hypoxia, peripheral residual tumor cells produced an abundance of VEGF, concordant with activated endothelial cells becoming extremely sensitive to the effects of VEGF, thereby leading to rapid proliferation, invasion, and migration. Simultaneously, VEGF upregulated Ang-2 in the tumor adjacent to the vascular endothelial tissue through the VEGFR2/KER pathway. The overexpression of Ang-2 altered the balance between Ang-2 and Ang-1 and disrupted the interaction between Ang-1 and Tie-2 formation, leading to the loss of peripheral cells of the capillaries and loss of stability of the vascular walls [19, 20]. Meanwhile, as the continuous high expression of Ang-2 antagonizes the action of Ang-1, the vascular wall of new tumor is incomplete and its permeability is high. Continued production of VEGF can also induce lymph angiogenesis through the vegfr-3 signaling pathway [21].

Locally advanced cervical cancer is a group of high-risk cervical cancers with adverse prognostic factors. This type of cancer contains a large volume of local tumors and exhibits a high rate of lymphatic metastasis. Thus, direct surgical treatment is not suitable for this group. Radiotherapy is the standard treatment for cervical cancer in addition to surgery and can be applied at any stage, especially to patients with diagnosed advanced-stage cervical cancer [22, 23]. The ionizing radiation produced by radiotherapy exerts it’s effect on the DNA, RNA and protein of the tumor cells by inducing chromosomal aberrations, ultimately disrupting the cell cycle, and damaging the vessels in the lesion. After the radiotherapy, we observed that the expression rates of Ang-2 and VEGF in the tumor tissues were considerably reduced relative to those of the group that did not undergo radiochemotherapy. The protein expression of Ang-1 was reduced as well, but changes were not significant. The microvessel density and lymphatic vessel density after radiochemotherapy were reduced as well, suggesting that radiochemotherapy is an effective treatment for carcinoma of uterine cervix. Radiotherapy damages and kills tumor cells and therefore reduces Ang-1, Ang-2, and VEGF expression levels. Vascular and lymphatic vessel development in tumor tissues was decreased under the influence of relatively high Ang-1 and low Ang-2 and VEGF levels. Combined with the effect of radiotherapy on vascular lymphatic vessels, MVD and LVD also decreased. However, since radiotherapy only targets local lesions, it cannot control subclinical lesions or potential systemic subclinical metastases in patients with advanced cervical cancer.

Tumor vascularization is currently a popular area of investigation in antitumor therapy. By blocking tumor angiogenesis, tumor growth and metastasis can be effectively inhibited [24]. Under pathological situations, Ang-2 mainly is expressed in the relevant tissues of the tumor, and Ang-2 antibody treatment has good tumor targeting capability and few systemic side effects. Currently, Ang/Tie-2 receptor interaction is heavily studied and a biological agent of Ang/Tie-2 receptor has been successfully used for blocking angiogenesis. Given our improved understanding of the mechanisms of the gene expression regulation and signal transduction pathway of angiogen-promoting factors, such as VEGF, novel targets for angiopoietin may provide a promising new approach for the clinical treatment of tumors.

  1. Conflict of interest: Authors state no conflict of interest.

References

[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30.10.3322/caac.21442Search in Google Scholar PubMed

[2] Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115-32.10.3322/caac.21338Search in Google Scholar PubMed

[3] Tomao F, Papa A, Rossi L, Zaccarelli E, Caruso D, Zoratto F, et al. Angiogenesis and antiangiogenic agents in cervical cancer. Onco Targets Ther 2014;7:2237-48.10.2147/OTT.S68286Search in Google Scholar PubMed PubMed Central

[4] Minion LE, Tewari KS. Cervical cancer - State of the science: From angiogenesis blockade to checkpoint inhibition. Gynecol Oncol 2018;148:609-621.10.1016/j.ygyno.2018.01.009Search in Google Scholar PubMed PubMed Central

[5] Yu JQ, Zhou Q, Zhu H, Zheng FY, Chen ZW. Overexpression of astrocyte elevated gene-1 (AEG-1) in cervical cancer and its correlation with angiogenesis. Asian Pac J Cancer Prev 2015;16:2277-81.10.7314/APJCP.2015.16.6.2277Search in Google Scholar

[6] Horn LC, Schierle K, Schmidt D, Ulrich U, Liebmann A, Wittekind C. [Current TNM/FIGO classification for cervical and endometrial cancer as well as malignant mixed müllerian tumors. Facts and background]. Pathologe 2011;32:239-43.10.1007/s00292-010-1273-6Search in Google Scholar PubMed

[7] Gasparini G, Harris AL. Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. J Clin Oncol 1995;13:765-82.10.1200/JCO.1995.13.3.765Search in Google Scholar PubMed

[8] Ramanathan R, Olex AL, Dozmorov M, Bear HD, Fernandez LJ, Takabe K. Angiopoietin pathway gene expression associated with poor breast cancer survival. Breast Cancer Res Treat 2017;162:191-198.10.1007/s10549-017-4102-2Search in Google Scholar PubMed PubMed Central

[9] Chen JW, Luo YJ, Yang ZF, Wen LQ, Huang L. Knockdown of angiopoietin-like 4 inhibits the development of human gastric cancer. Oncol Rep 2018;39:1739-1746.10.3892/or.2018.6253Search in Google Scholar PubMed

[10] Carbone C, Piro G, Merz V, Simionato F, Santoro R, Zecchetto C, et al. Angiopoietin-Like Proteins in Angiogenesis, Inflammation and Cancer. Int J Mol Sci 2018;19.10.3390/ijms19020431Search in Google Scholar PubMed PubMed Central

[11] Chen JX, Stinnett A. Disruption of Ang-1/Tie-2 signaling contributes to the impaired myocardial vascular maturation and angiogenesis in type II diabetic mice. Arterioscler Thromb Vasc Biol 2008;28:1606-13.10.1161/ATVBAHA.108.169235Search in Google Scholar PubMed PubMed Central

[12] Oka N, Yamamoto Y, Takahashi M, Nishitani M, Kanayama HO, Kagawa S. Expression of angiopoietin-1 and -2, and its clinical significance in human bladder cancer. BJU Int 2005;95:660-3.10.1111/j.1464-410X.2005.05358.xSearch in Google Scholar PubMed

[13] Mitsuhashi N, Shimizu H, Ohtsuka M, Wakabayashi Y, Ito H, Kimura F, et al. Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma. Hepatology 2003;37:1105-13.10.1053/jhep.2003.50204Search in Google Scholar PubMed

[14] Kuboki S, Shimizu H, Mitsuhashi N, Kusashio K, Kimura F, Yoshidome H, et al. Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol 2008;23:e157-64.10.1111/j.1440-1746.2007.05175.xSearch in Google Scholar PubMed

[15] Chen HA, Kuo TC, Tseng CF, Ma JT, Yang ST, Yen CJ, et al. Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma. Hepatology 2016;64:1637-1651.10.1002/hep.28773Search in Google Scholar PubMed

[16] Faillaci F, Marzi L, Critelli R, Milosa F, Schepis F, Turola E, et al. Liver Angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after HCV direct-acting antivirals. Hepatology 2018.10.1002/hep.29911Search in Google Scholar PubMed PubMed Central

[17] Bessho H, Wong B, Huang D, Tan J, Ong CK, Iwamura M, et al. Effect of Ang-2-VEGF-A Bispecific Antibody in Renal Cell Carcinoma. Cancer Invest 2015;33:378-86.10.3109/07357907.2015.1047505Search in Google Scholar PubMed

[18] Chen ZB, Shen SQ, Ding YM, Wang WX, Tao JP, Liang LJ, et al. The angiogenic and prognostic implications of VEGF, Ang-1, Ang-2, and MMP-9 for hepatocellular carcinoma with background of hepatitis B virus. Med Oncol 2009;26:365-71.10.1007/s12032-008-9130-7Search in Google Scholar PubMed

[19] Tang KD, Holzapfel BM, Liu J, Lee TK, Ma S, Jovanovic L, et al. Tie-2 regulates the stemness and metastatic properties of prostate cancer cells. Oncotarget 2016;7:2572-84.10.18632/oncotarget.3950Search in Google Scholar PubMed PubMed Central

[20] Sun Y, Liu JH, Pan L, Jin L, Yang Y, Sui YX, et al. Modulatory effects of Beclin 1 on expression of angiopoietin and Tie-2 receptor in human cervical cancer cells. Asian Pac J Cancer Prev 2011;12:2985-90.Search in Google Scholar

[21] Zehnder-Fjällman AH, Marty C, Halin C, Hohn A, Schibli R, Ballmer-Hofer K, et al. Evaluation of anti-VEGFR-3 specific scFv antibodies as potential therapeutic and diagnostic tools for tumor lymph-angiogenesis. Oncol Rep 2007;18:933-41.10.3892/or.18.4.933Search in Google Scholar

[22] Huang K, Jia M, Li P, Han J, Zhang R, Li Q, et al. Radiotherapy Improves the Survival of Patients With Metastatic Cervical Cancer: A Propensity-Matched Analysis of SEER Database. Int J Gynecol Cancer 2018.10.1097/IGC.0000000000001313Search in Google Scholar PubMed

[23] Cibula D, Pötter R, Planchamp F, Avall-Lundqvist E, Fischerova D, Haie MC, et al. The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer. Radiother Oncol 2018;127:404-416.10.1016/j.radonc.2018.03.003Search in Google Scholar PubMed

[24] Alcázar JL, Jurado M, López-García G. Tumor vascularization in cervical cancer by 3-dimensional power Doppler angiography: correlation with tumor characteristics. Int J Gynecol Cancer 2010;20:393-7.10.1111/IGC.0b013e3181d159f9Search in Google Scholar PubMed

Received: 2018-07-31
Accepted: 2018-11-01
Published Online: 2018-12-31

© 2018 Qingyuan Lv et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Articles in the same Issue

  1. Research Article
  2. Purification of Tea saponins and Evaluation of its Effect on Alcohol Dehydrogenase Activity
  3. Runt-related transcription factor 3 promoter hypermethylation and gastric cancer risk: A meta-analysis
  4. Risk Factors for Venous Thromboembolism in Hospitalized Patients in the Chinese Population
  5. Value of Dual-energy Lung Perfusion Imaging Using a Dual-source CT System for the Pulmonary Embolism
  6. A new combination of substrates: biogas production and diversity of the methanogenic microorganisms
  7. mTOR modulates CD8+ T cell differentiation in mice with invasive pulmonary aspergillosis
  8. Direct Effects on Seed Germination of 17 Tree Species under Elevated Temperature and CO2 Conditions
  9. Role of water soluble vitamins in the reduction diet of an amateur sportsman
  10. Aberrant DNA methylation involved in obese women with systemic insulin resistance
  11. 16S ribosomal RNA-based gut microbiome composition analysis in infants with breast milk jaundice
  12. Characterization of Haemophilus parasuis Serovar 2 CL120103, a Moderately Virulent Strain in China
  13. MiRNA-145 induces apoptosis in a gallbladder carcinoma cell line by targeting DFF45
  14. Telmisartan induces osteosarcoma cells growth inhibition and apoptosis via suppressing mTOR pathway
  15. Optimizing the Formulation for Ginkgolide B Solid Dispersion
  16. Determination of the In Vitro Gas Production and Potential Feed Value of Olive, Mulberry and Sour Orange Tree Leaves
  17. Factors Influencing the Successful Isolation and Expansion of Aging Human Mesenchymal Stem Cells
  18. The Value of Diffusion-Weighted Magnetic Resonance Imaging in Predicting the Efficacy of Radiation and Chemotherapy in Cervical Cancer
  19. Chemical profile and antioxidant activity of Trollius europaeus under the influence of feeding aphids
  20. SSR Markers Suitable for Marker Assisted Selection in Sunflower for Downy Mildew Resistance
  21. A Fibroblast Growth Factor Antagonist Peptide Inhibits Breast Cancer in BALB/c Mice
  22. Antihyperglycemic and antihyperlipidemic effects of low-molecular-weight carrageenan in rats
  23. Microbial indicators and environmental relationships in the Umhlangane River, Durban, South Africa
  24. TUFT1 promotes osteosarcoma cell proliferation and predicts poor prognosis in osteosarcoma patients
  25. Long non-coding RNA-2271 promotes osteogenic differentiation in human bone marrow stem cells
  26. The prediction of cardiac events in patients with acute ST segment elevation myocardial infarction: A meta–analysis of serum uric acid
  27. Risk expansion of Cr through amphibious clonal plant from polluted aquatic to terrestrial habitats
  28. Overexpression of Zinc Finger Transcription Factor ZAT6 Enhances Salt Tolerance
  29. Sini decoction intervention on atherosclerosis via PPARγ-LXRα-ABCA1 pathway in rabbits
  30. Soluble myeloid triggering receptor expressed on myeloid cell 1 might have more diagnostic value for bacterial ascites than C-reactive protein
  31. A Preliminary Study on the Newly Isolated High Laccase-producing Fungi: Screening, Strain Characteristics and Induction of Laccase Production
  32. Hydrolytic Enzyme Production by Thermophilic Bacteria Isolated from Saudi Hot Springs
  33. Analysis of physiological parameters of Desulfovibrio strains from individuals with colitis
  34. Emodin promotes apoptosis of human endometrial cancer through regulating the MAPK and PI3K/ AKT pathways
  35. Down-regulation of miR-539 indicates poor prognosis in patients with pancreatic cancer
  36. Inhibitory activities of ethanolic extracts of two macrofungi against eggs and miracidia of Fasciola spp.
  37. PAQR6 expression enhancement suggests a worse prognosis in prostate cancer patients
  38. Characterization of a potential ripening regulator, SlNAC3, from Solanum lycopersicum
  39. Expression of Angiopoietin and VEGF in cervical cancer and its clinical significance
  40. Umbilical Cord Tissue Derived Mesenchymal Stem Cells Can Differentiate into Skin Cells
  41. Isolation and Characterization of a Phage to Control Vancomycin Resistant Enterococcus faecium
  42. Glycogen Phosphorylase Isoenzyme Bb, Myoglobin and BNP in ANT-Induced Cardiotoxicity
  43. BAG2 overexpression correlates with growth and poor prognosis of esophageal squamous cell carcinoma
  44. Relationship between climate trends and grassland yield across contrasting European locations
  45. Review Articles
  46. Mechanisms of salt tolerance in halophytes: current understanding and recent advances
  47. Salivary protein roles in oral health and as predictors of caries risk
  48. Nanoparticles as carriers of proteins, peptides and other therapeutic molecules
  49. Survival mechanisms to selective pressures and implications
  50. Up-regulation of key glycolysis proteins in cancer development
  51. Communications
  52. In vitro plant regeneration of Zenia insignis Chun
  53. DNA barcoding of online herbal supplements: crowd-sourcing pharmacovigilance in high school
  54. Case Reports
  55. Management of myasthenia gravis during pregnancy: A report of eight cases
  56. Three Cases of Extranodal Rosai-Dorfman Disease and Literature Review
  57. Letters to the Editor
  58. First report of Chlamydia psittaci seroprevalence in black-headed gulls (Larus ridibundus) at Dianchi Lake, China
  59. Special Issue on Agricultural and Biological Sciences - Part II
  60. Chemical composition of essential oil in Mosla chinensis Maxim cv. Jiangxiangru and its inhibitory effect on Staphylococcus aureus biofilm formation
  61. Secondary metabolites of Antarctic fungi antagonistic to aquatic pathogenic bacteria
  62. Study of Seizure-Manifested Hartnup Disorder Case Induced by Novel Mutations in SLC6A19
  63. Transcriptome analysis of Pinus massoniana Lamb. microstrobili during sexual reversal
  64. Mechanism of oxymatrine-induced human esophageal cancer cell apoptosis by the endoplasmic reticulum stress pathway
  65. Methylation pattern polymorphism of cyp19a in Nile tilapia and hybrids
  66. A Method of Biomedical Information Classification based on Particle Swarm Optimization with Inertia Weight and Mutation
  67. A novel TNNI3 gene mutation (c.235C>T/ p.Arg79Cys) found in a thirty-eight-year-old women with hypertrophic cardiomyopathy
  68. Remote Sensing-Based Extraction and Analysis of Temporal and Spatial Variations of Winter Wheat Planting Areas in the Henan Province of China
  69. Topical Issue on Precision Medicine
  70. Serum sTREM-1, PCT, CRP, Lac as biomarkers for death risk within 28 days in patients with severe sepsis
  71. IL-17 gene rs3748067 C>T polymorphism and gastric cancer risk: A meta-analysis
  72. Efficacy of Danhong injection on serum concentration of TNF-α, IL-6 and NF-κB in rats with intracerebral hemorrhage
  73. An ensemble method to predict target genes and pathways in uveal melanoma
  74. Evaluation of the quality of CT images acquired with smart metal artifact reduction software
  75. NPM1A in plasma is a potential prognostic biomarker in acute myeloid leukemia
  76. Arterial infusion of rapamycin in the treatment of rabbit hepatocellular carcinoma to improve the effect of TACE
  77. New progress in understanding the cellular mechanisms of anti-arrhythmic drugs
https://doi.org/10.1515/biol-2018-0063
Keywords for this article
angiogenin; vascular endothelial growth factor; cervical cancer; microvessel density
Creative Commons
BY-NC-ND 4.0

Articles in the same Issue

  1. Research Article
  2. Purification of Tea saponins and Evaluation of its Effect on Alcohol Dehydrogenase Activity
  3. Runt-related transcription factor 3 promoter hypermethylation and gastric cancer risk: A meta-analysis
  4. Risk Factors for Venous Thromboembolism in Hospitalized Patients in the Chinese Population
  5. Value of Dual-energy Lung Perfusion Imaging Using a Dual-source CT System for the Pulmonary Embolism
  6. A new combination of substrates: biogas production and diversity of the methanogenic microorganisms
  7. mTOR modulates CD8+ T cell differentiation in mice with invasive pulmonary aspergillosis
  8. Direct Effects on Seed Germination of 17 Tree Species under Elevated Temperature and CO2 Conditions
  9. Role of water soluble vitamins in the reduction diet of an amateur sportsman
  10. Aberrant DNA methylation involved in obese women with systemic insulin resistance
  11. 16S ribosomal RNA-based gut microbiome composition analysis in infants with breast milk jaundice
  12. Characterization of Haemophilus parasuis Serovar 2 CL120103, a Moderately Virulent Strain in China
  13. MiRNA-145 induces apoptosis in a gallbladder carcinoma cell line by targeting DFF45
  14. Telmisartan induces osteosarcoma cells growth inhibition and apoptosis via suppressing mTOR pathway
  15. Optimizing the Formulation for Ginkgolide B Solid Dispersion
  16. Determination of the In Vitro Gas Production and Potential Feed Value of Olive, Mulberry and Sour Orange Tree Leaves
  17. Factors Influencing the Successful Isolation and Expansion of Aging Human Mesenchymal Stem Cells
  18. The Value of Diffusion-Weighted Magnetic Resonance Imaging in Predicting the Efficacy of Radiation and Chemotherapy in Cervical Cancer
  19. Chemical profile and antioxidant activity of Trollius europaeus under the influence of feeding aphids
  20. SSR Markers Suitable for Marker Assisted Selection in Sunflower for Downy Mildew Resistance
  21. A Fibroblast Growth Factor Antagonist Peptide Inhibits Breast Cancer in BALB/c Mice
  22. Antihyperglycemic and antihyperlipidemic effects of low-molecular-weight carrageenan in rats
  23. Microbial indicators and environmental relationships in the Umhlangane River, Durban, South Africa
  24. TUFT1 promotes osteosarcoma cell proliferation and predicts poor prognosis in osteosarcoma patients
  25. Long non-coding RNA-2271 promotes osteogenic differentiation in human bone marrow stem cells
  26. The prediction of cardiac events in patients with acute ST segment elevation myocardial infarction: A meta–analysis of serum uric acid
  27. Risk expansion of Cr through amphibious clonal plant from polluted aquatic to terrestrial habitats
  28. Overexpression of Zinc Finger Transcription Factor ZAT6 Enhances Salt Tolerance
  29. Sini decoction intervention on atherosclerosis via PPARγ-LXRα-ABCA1 pathway in rabbits
  30. Soluble myeloid triggering receptor expressed on myeloid cell 1 might have more diagnostic value for bacterial ascites than C-reactive protein
  31. A Preliminary Study on the Newly Isolated High Laccase-producing Fungi: Screening, Strain Characteristics and Induction of Laccase Production
  32. Hydrolytic Enzyme Production by Thermophilic Bacteria Isolated from Saudi Hot Springs
  33. Analysis of physiological parameters of Desulfovibrio strains from individuals with colitis
  34. Emodin promotes apoptosis of human endometrial cancer through regulating the MAPK and PI3K/ AKT pathways
  35. Down-regulation of miR-539 indicates poor prognosis in patients with pancreatic cancer
  36. Inhibitory activities of ethanolic extracts of two macrofungi against eggs and miracidia of Fasciola spp.
  37. PAQR6 expression enhancement suggests a worse prognosis in prostate cancer patients
  38. Characterization of a potential ripening regulator, SlNAC3, from Solanum lycopersicum
  39. Expression of Angiopoietin and VEGF in cervical cancer and its clinical significance
  40. Umbilical Cord Tissue Derived Mesenchymal Stem Cells Can Differentiate into Skin Cells
  41. Isolation and Characterization of a Phage to Control Vancomycin Resistant Enterococcus faecium
  42. Glycogen Phosphorylase Isoenzyme Bb, Myoglobin and BNP in ANT-Induced Cardiotoxicity
  43. BAG2 overexpression correlates with growth and poor prognosis of esophageal squamous cell carcinoma
  44. Relationship between climate trends and grassland yield across contrasting European locations
  45. Review Articles
  46. Mechanisms of salt tolerance in halophytes: current understanding and recent advances
  47. Salivary protein roles in oral health and as predictors of caries risk
  48. Nanoparticles as carriers of proteins, peptides and other therapeutic molecules
  49. Survival mechanisms to selective pressures and implications
  50. Up-regulation of key glycolysis proteins in cancer development
  51. Communications
  52. In vitro plant regeneration of Zenia insignis Chun
  53. DNA barcoding of online herbal supplements: crowd-sourcing pharmacovigilance in high school
  54. Case Reports
  55. Management of myasthenia gravis during pregnancy: A report of eight cases
  56. Three Cases of Extranodal Rosai-Dorfman Disease and Literature Review
  57. Letters to the Editor
  58. First report of Chlamydia psittaci seroprevalence in black-headed gulls (Larus ridibundus) at Dianchi Lake, China
  59. Special Issue on Agricultural and Biological Sciences - Part II
  60. Chemical composition of essential oil in Mosla chinensis Maxim cv. Jiangxiangru and its inhibitory effect on Staphylococcus aureus biofilm formation
  61. Secondary metabolites of Antarctic fungi antagonistic to aquatic pathogenic bacteria
  62. Study of Seizure-Manifested Hartnup Disorder Case Induced by Novel Mutations in SLC6A19
  63. Transcriptome analysis of Pinus massoniana Lamb. microstrobili during sexual reversal
  64. Mechanism of oxymatrine-induced human esophageal cancer cell apoptosis by the endoplasmic reticulum stress pathway
  65. Methylation pattern polymorphism of cyp19a in Nile tilapia and hybrids
  66. A Method of Biomedical Information Classification based on Particle Swarm Optimization with Inertia Weight and Mutation
  67. A novel TNNI3 gene mutation (c.235C>T/ p.Arg79Cys) found in a thirty-eight-year-old women with hypertrophic cardiomyopathy
  68. Remote Sensing-Based Extraction and Analysis of Temporal and Spatial Variations of Winter Wheat Planting Areas in the Henan Province of China
  69. Topical Issue on Precision Medicine
  70. Serum sTREM-1, PCT, CRP, Lac as biomarkers for death risk within 28 days in patients with severe sepsis
  71. IL-17 gene rs3748067 C>T polymorphism and gastric cancer risk: A meta-analysis
  72. Efficacy of Danhong injection on serum concentration of TNF-α, IL-6 and NF-κB in rats with intracerebral hemorrhage
  73. An ensemble method to predict target genes and pathways in uveal melanoma
  74. Evaluation of the quality of CT images acquired with smart metal artifact reduction software
  75. NPM1A in plasma is a potential prognostic biomarker in acute myeloid leukemia
  76. Arterial infusion of rapamycin in the treatment of rabbit hepatocellular carcinoma to improve the effect of TACE
  77. New progress in understanding the cellular mechanisms of anti-arrhythmic drugs
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Winner of the OpenAthens UX Award 2026
Winner of the OpenAthens UX Award 2026
Have an idea on how to improve our website?
Please write us.
© 2026 De Gruyter Brill
Downloaded on 1.4.2026 from https://www.degruyterbrill.com/document/doi/10.1515/biol-2018-0063/html
Scroll to top button