Online first
Research paper
Published online: 2024-10-01
Endothelial progenitor cells as an angiogenic biomarker for the diagnosis and prognosis of lung cancer
Abstract
Background: Angiogenesis is mediated by endothelial progenitor cells (EPCs) derived from bone-marrow. In this prospective study, we tried to investigate the clinical utility of circulating EPCs in lung cancer (LC) patients.
Materials and methods: Flow cytometry technique was used to assess circulating EPCs according to the immuno-phenotype CD45– CD34+ CD133+ CD146+ mononuclear cells.
Results: Sixty patients and 30 controls were included in this prospective study. The mean of baseline EPC numbers was significantly higher in LC patients than in controls (p =0.003). Pretreatment EPC values were significantly correlated with primary tumor size (p = 0.05) and tumor response (p = 0.04). Receiver operating characteristics (ROC) curves were plotted to discriminate EPC numbers between patients and controls. Using ROC analysis, the optimal cutoff value was 125 cells/mL with a sensitivity and a specificity for baseline EPCs of 76.7% and 63.3%, respectively. According to this cutoff value, basal EPC values were significantly correlated with primary tumor size (p = 0.047) and response to chemotherapy (p = 0.034). High EPC levels were significantly associated with longer progression-free survival (PFS) and overall survival (OS) duration (p = 0.0043 and p = 0.02, respectively).
Conclusion: Increased baseline EPC values seem to be a useful biomarker for the prediction of prognosis and tumor response in LC patients. Furthermore, high EPC levels at diagnosis might be an indicator of tumor growth and longer survival in LC patients.
Keywords: endothelial progenitor cellscancer biomarkerlung cancerprognosis
References
- Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006; 24(28): 4539–4544.
- Gridelli C, Rossi A, Maione P. Treatment of non-small-cell lung cancer: state of the art and development of new biologic agents. Oncogene. 2003; 22(42): 6629–6638.
- Schiller JH, Harrington D, Belani CP, et al. Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002; 346(2): 92–98.
- Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55(2): 74–108.
- Li N, Shao K, Chen Z, et al. The impact of positive cancer family history on the clinical features and outcome of patients with non-small cell lung cancer. Fam Cancer. 2011; 10(2): 331–336.
- Vermeulen PB, Gasparini G, Fox SB, et al. Second international consensus on the methodology and criteria of evaluation of angiogenesis quantification in solid human tumours. Eur J Cancer. 2002; 38(12): 1564–1579.
- Ko EC, Raben D, Formenti SC. The Integration of Radiotherapy with Immunotherapy for the Treatment of Non-Small Cell Lung Cancer. Clin Cancer Res. 2018; 24(23): 5792–5806.
- Alaswad M. Locally advanced non-small cell lung cancer: current issues and recent trends. Rep Pract Oncol Radiother. 2023; 28(2): 286–303.
- Jung CW, Beard BC, Morris JC, et al. Hematopoietic stem cell engraftment: a direct comparison between intramarrow and intravenous injection in nonhuman primates. Exp Hematol. 2007; 35(7): 1132–1139.
- Asahara T, Kawamoto A, Masuda H. Concise review: Circulating endothelial progenitor cells for vascular medicine. Stem Cells. 2011; 29(11): 1650–1655.
- Aguirre A, Planell JA, Engel E. Dynamics of bone marrow-derived endothelial progenitor cell/mesenchymal stem cell interaction in co-culture and its implications in angiogenesis. Biochem Biophys Res Commun. 2010; 400(2): 284–291.
- Timmermans F, Plum J, Yöder MC, et al. Endothelial progenitor cells: identity defined? J Cell Mol Med. 2009; 13(1): 87–102.
- Flamini V, Jiang WG, Lane J, et al. Significance and therapeutic implications of endothelial progenitor cells in angiogenic-mediated tumour metastasis. Crit Rev Oncol Hematol. 2016; 100: 177–189.
- Rhone P, Ruszkowska-Ciastek B, Celmer M, et al. Increased number of endothelial progenitors in peripheral blood as a possible early marker of tumor growth in post-menopausal breast cancer patients. J Physiol Pharmacol. 2017; 68(1): 139–148.
- Jain S, Ward MM, O'Loughlin J, et al. Incremental increase in VEGFR1⁺ hematopoietic progenitor cells and VEGFR2⁺ endothelial progenitor cells predicts relapse and lack of tumor response in breast cancer patients. Breast Cancer Res Treat. 2012; 132(1): 235–242.
- Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001; 7(11): 1194–1201.
- Purhonen S, Palm J, Rossi D, et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci U S A. 2008; 105(18): 6620–6625.
- Urbich C, Aicher A, Heeschen C, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005; 39(5): 733–742.
- Yoon CH, Hur J, Park KW, et al. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation. 2005; 112(11): 1618–1627.
- Schillaci G, Rondelli F, Pirro M, et al. Endothelial progenitor cells are mobilized after major laparotomic surgery in patients with cancer. Int J Immunopathol Pharmacol. 2009; 22(4): 1035–1041.
- Duda DG, Cohen KS, di Tomaso E, et al. Differential CD146 expression on circulating versus tissue endothelial cells in rectal cancer patients: implications for circulating endothelial and progenitor cells as biomarkers for antiangiogenic therapy. J Clin Oncol. 2006; 24(9): 1449–1453.
- Hristov M, Erl W, Weber PC. Endothelial progenitor cells: isolation and characterization. Trends Cardiovasc Med. 2003; 13(5): 201–206.
- Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest. 1997; 111(6): 1710–1717.
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228–247.
- Mancuso P, Antoniotti P, Quarna J, et al. Validation of a standardized method for enumerating circulating endothelial cells and progenitors: flow cytometry and molecular and ultrastructural analyses. Clin Cancer Res. 2009; 15(1): 267–273.
- Masouleh BK, Baraniskin A, Schmiegel W, et al. Quantification of circulating endothelial progenitor cells in human peripheral blood: establishing a reliable flow cytometry protocol. J Immunol Methods. 2010; 357(1-2): 38–42.
- Ruszkowska-Ciastek B, Sokup A, Leszcz M, et al. The number of circulating endothelial progenitor cells in healthy individuals--effect of some anthropometric and environmental factors (a pilot study). Adv Med Sci. 2015; 60(1): 58–63.
- Folkman J. Angiogenesis and apoptosis. Semin Cancer Biol. 2003; 13(2): 159–167.
- Folkman J. Antiangiogenesis in cancer therapy--endostatin and its mechanisms of action. Exp Cell Res. 2006; 312(5): 594–607.
- Nowak K, Rafat N, Belle S, et al. Circulating endothelial progenitor cells are increased in human lung cancer and correlate with stage of disease. Eur J Cardiothorac Surg. 2010; 37(4): 758–763.
- Morita R, Sato K, Nakano M, et al. Endothelial progenitor cells are associated with response to chemotherapy in human non-small-cell lung cancer. J Cancer Res Clin Oncol. 2011; 137(12): 1849–1857.
- Ishiwata T, Takahashi K, Shimanuki Y, et al. Role of serum vascular endothelial growth factor in the prediction of angiogenesis and prognosis for non-small cell lung cancer. Lung. 2005; 183(1): 29–42.
- Chakra M, Pujol JL, Lamy PJ, et al. Circulating serum vascular endothelial growth factor is not a prognostic factor of non-small cell lung cancer. J Thorac Oncol. 2008; 3(10): 1119–1126.
- Tanaka S, Ueno T, Ishiguro H, et al. The lack of increases in circulating endothelial progenitor cell as a negative predictor for pathological response to neoadjuvant chemotherapy in breast cancer patients. NPJ Precis Oncol. 2017; 1(1): 6.
- Gkiozos I, Tsagouli S, Charpidou A, et al. Levels of vascular endothelial growth factor in serum and pleural fluid are independent predictors of survival in advanced non-small cell lung cancer: results of a prospective study. Anticancer Res. 2015; 35(2): 1129–1137.
- Dome B, Timar J, Dobos J, et al. Identification and clinical significance of circulating endothelial progenitor cells in human non-small cell lung cancer. Cancer Res. 2006; 66(14): 7341–7347.
- Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol. 2006; 7(4): 333–337.
- Hilbe W, Dirnhofer S, Oberwasserlechner F, et al. CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer. J Clin Pathol. 2004; 57(9): 965–969.
- Li B, Nie Z, Zhang D, et al. Roles of circulating endothelial progenitor cells and endothelial cells in gastric carcinoma. Oncol Lett. 2018; 15(1): 324–330.
- Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost. 2001; 86(1): 23–33.
- Li B, Nie Z, Zhang D, et al. Roles of circulating endothelial progenitor cells and endothelial cells in gastric carcinoma. Oncol Lett. 2018; 15(1): 324–330.
- Pirro M, Cagini L, Paciullo F, et al. Baseline and post-surgery endothelial progenitor cell levels in patients with early-stage non-small-cell lung carcinoma: impact on cancer recurrence and survival. Eur J Cardiothorac Surg. 2013; 44(4): e245–e252.
- Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000; 95(3): 952–958.
- Döme B, Hendrix MJC, Paku S, et al. Alternative vascularization mechanisms in cancer: Pathology and therapeutic implications. Am J Pathol. 2007; 170(1): 1–15.
- Maeda R, Ishii G, Ito M, et al. Number of circulating endothelial progenitor cells and intratumoral microvessel density in non-small cell lung cancer patients: differences in angiogenic status between adenocarcinoma histologic subtypes. J Thorac Oncol. 2012; 7(3): 503–511.
- Sudo K, Sato K, Sakamoto S, et al. Association Between Endothelial Progenitor Cells and Treatment Response in Non-Squamous Non-small Cell Lung Cancer Treated with Bevacizumab. Anticancer Res. 2017; 37(10): 5565–5571.
- Danova M, Comolli G, Manzoni M, et al. Flow cytometric analysis of circulating endothelial cells and endothelial progenitors for clinical purposes in oncology: A critical evaluation. Mol Clin Oncol. 2016; 4(6): 909–917.
- Rhone P, Bielawski K, Ziołkowska K, et al. Low Pre-Treatment Count of Circulating Endothelial Progenitors as a Prognostic Biomarker of the High Risk of Breast Cancer Recurrence. J Clin Med. 2019; 8(11).
- Woo S, Kim S. Determination of cutoff values for biomarkers in clinical studies. Precis Future Med. 2020; 4(1): 2–8.