Correlation of Angiogenic Biomarkers to Tumor Progression and Angiogenesis in Cervical Cancer Cell (CaSki)-implanted Nude Mice


  • Nakorn Mathuradavong Division of Physiology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
  • Umarat Srisawat Division of Physiology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
  • Bhornprom Yoysungnoen Division of Physiology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
  • Nattapon Sookprasert Division of Physiology, Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand



Angiogenic biomarkers, Cervical cancer, CaSki, Angiogenesis, Tumor progression


Introduction: Several studies have indicated that microvascular density (MVD) and the expressions of angiogenic biomarkers were associated with tumor growth and angiogenesis in cervical cancer. However, the results were incomplete and inconsistent.

Objectives: To determine the correlation of the angiogenic biomarkers, including vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1-alpha (HIF-1α), cyclooxygenase-2 (COX-2), and epidermal growth factor receptor (EGFR), to tumor progression and angiogenesis in cervical cancer cell (CaSki)-implanted nude mice model.

Methods: 10×106 of CaSki cells were injected into the female nude mice (n = 50) to establish subcutaneous tumors. The tumor size was measured every 3 days for one month. The MVD was evaluated using the CD31 expression. VEGF, HIF-1α, COX-2, and EGFR expression
were detected by immunohistochemistry.

Results: The results showed that HIF-1α (r = 0.979 and r = 0.942), VEGF (r = 0.972 and r = 0.929), COX-2 (r = 0.982 and r = 0.957), and EGFR (r = 0.993 and r = 0.971) closely correlated with tumor growth and tumor angiogenesis, respectively. Interestingly, EGFR was mostly involved in tumor growth and angiogenesis.

Conclusions: This study demonstrates that the HIF-1α, VEGF, COX-2, and EGFR are a set of biological markers which are strongly related to tumor progression and angiogenesis in cervical cancer.


Download data is not yet available.


Cuzick J, Arbyn M, Sankaranarayanan R, et al. Overview of human papillomavirusbased and other novel options for cervical cancer screening in developed and developing countries. Vaccine. 2008;26(S10):29-41.

Randall LM, Monk BJ, Darcy KM, et al. Markers of angiogenesis in high-risk, earlystage cervical cancer: A Gynecologic Oncology Group study. Gynecol Oncol. 2009;112(3):583-589.

Hu X, Liu H, Ye M, Zhu X. Prognostic value of microvessel density in cervical cancer. Cancer Cell Int. 2018;18:152.

Newman PJ, Berndt MC, Gorski J, et al. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science. 1990;247(4947):1219-1222.

Hendrix MJ, Seftor EA, Meltzer PS, et al. Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry. Proc Natl Acad Sci U S A. 2001;98(14):8018-8023.

Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399 (6733):271-275.

Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxiainducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997;57(23):5328-5335.

Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039-2049.

Ferrara N. Vascular endothelial growth factor: molecular and biological aspects. Curr Top Microbiol Immunol. 1999;237:1-30.

Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9(6):653-660.

Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207-214.

Cheng WF, Chen CA, Lee CN, Wei LH, Hsieh FJ, Hsieh CY. Vascular endothelial growth factor and prognosis of cervical carcinoma. Obstet Gynecol. 2000;96(5 Pt 1):721-726.

Kim MH, Seo SS, Song YS, et al. Expression of cyclooxygenase-1 and -2 associated with expression of VEGF in primary cervical cancer and at metastatic lymph nodes. Gynecol Oncol. 2003;90(1):83-90.

Lee CM, Shrieve DC, Zempolich KA, et al. Correlation between human epidermal growth factor receptor family (EGFR, HER2, HER3, HER4), phosphorylated Akt (P-Akt), and clinical outcomes after radiation therapy in carcinoma of the cervix. Gynecol Oncol. 2005;99(2):415-421.

Loncaster JA, Cooper RA, Logue JP, Davidson SE, Hunter RD, West CM. Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix. Br J Cancer. 2000;83(5):620-625.

Guidi AJ, Abu-Jawdeh G, Berse B, et al. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst. 1995;87(16):1237-1245.

Tang X, Zhang Q, Nishitani J, Brown J, Shi S, Le AD. Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxiainducible factor 1 alpha protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells. Clin Cancer Res. 2007;13(9):2568-2576.

Sheng H, Shao J, Washington MK, DuBois RN. Prostaglandin E2 increases growth and motility of colorectal carcinoma cells. J Biol Chem. 2001;276(21):18075-18081.

Dohadwala M, Luo J, Zhu L, et al. Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44. J Biol Chem. 2001;276(24):20809-20812.

Valverde A, Penarando J, Canas A, et al. Simultaneous inhibition of EGFR/VEGFR and cyclooxygenase-2 targets stemness-related pathways in colorectal cancer cells. PLoS One. 2015;10(6):131363.

Hugo HJ, Saunders C, Ramsay RG, Thompson EW. New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis. J Mammary Gland Biol Neoplasia. 2015;20(3-4):109-119.

Kang S, Kim MH, Park IA, et al. Elevation of cyclooxygenase-2 is related to lymph node metastasis in adenocarcinoma of uterine cervix. Cancer Lett. 2006;237(2):305-311.

Kulkarni S, Rader JS, Zhang F, et al. Cyclooxygenase-2 is overexpressed in human cervical cancer. Clin Cancer Res. 2001;7(2):429-434.

Rogers SJ, Harrington KJ, Rhys-Evans P, O-Charoenrat P, Eccles SA. Biological significance of c-erbB family oncogenes in head and neck cancer. Cancer Metastasis Rev. 2005;24(1):47-69.

Yoysungnoen-Chintana P, Bhattarakosol P, Patumraj S. Antitumor and antiangiogenic activities of curcumin in cervical cancer xenografts in nude mice. Biomed Res Int. 2014;2014:817972.

Sarkis SA, Abdullah BH, Abdul Majeed BA, Talabani NG. Immunohistochemical expression of epidermal growth factor receptor (EGFR) in oral squamous cell carcinoma in relation to proliferation, apoptosis, angiogenesis and lymphangiogenesis. Head Neck Oncol. 2010;2:13.

Kim MK, Kim HS, Kim SH, et al. Human papillomavirus type 16 E5 oncoprotein as a new target for cervical cancer treatment. Biochem Pharmacol. 2010;80(12):1930-1935.

Kim SH, Juhnn YS, Kang S, et al. Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ERK1,2 and PI3K/Akt. Cell Mol Life Sci. 2006;63(7-8):930-938.

Yoysungnoen B, Bhattarakosol P, Patumraj S, Changtam C. Effects of tetrahydro-curcumin on hypoxia-inducible factor-1α and vascular endothelial growth factor expression in cervical cancer cell-induced angiogenesis in nude mice. Biomed Res Int. 2015;2015:391748.

Mahasiripanth T, Hokputsa S, Niruthisard S, Bhattarakosol P, Patumraj S. Effects of Acanthus ebracteatus Vahl on tumor angiogenesis and on tumor growth in nude mice implanted with cervical cancer. Cancer Manag Res. 2012;4:269-279.

Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1-8.

Cairns RA, Hill RP. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical

carcinoma. Cancer Res. 2004;64(6):2054-2061.

Ziello JE, Jovin IS, Huang Y. HypoxiaInducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007;80(2):51-60.

Grau R, Punzon C, Fresno M, Iniguez MA. Peroxisome-proliferator-activated receptor alpha agonists inhibit cyclo-oxygenase 2

and vascular endothelial growth factor transcriptional activation in human colorectal carcinoma cells via inhibition of activator protein-1. Biochem J. 2006;395(1):81-88.




How to Cite

Mathuradavong, N., Srisawat, U., Yoysungnoen, B. and Sookprasert, N. 2022. Correlation of Angiogenic Biomarkers to Tumor Progression and Angiogenesis in Cervical Cancer Cell (CaSki)-implanted Nude Mice. Asian Medical Journal and Alternative Medicine. 22, 3 (Dec. 2022), 202–211. DOI:



Original Articles