Lymphangiogenic Markers and Their Impact on Nodal Metastasis and Survival in Non-Small Cell Lung Cancer--A Structured Review with Meta-Analysis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Aug 26

PMID 26305218

Citations 7

Authors

Thomas K Kilvaer

Erna-Elise Paulsen

Sigurd M Hald

Tom Wilsgaard

Roy M Bremnes

Lill-Tove Busund

Tom Donnem

Affiliations

Soon will be listed here.

Abstract

Background: In non-small cell lung cancer (NSCLC), nodal metastasis is an adverse prognostic factor. Several mediating factors have been implied in the development of nodal metastases and investigated for predictive and prognostic properties in NSCLC. However, study results differ. In this structured review and meta-analysis we explore the published literature on commonly recognized pathways for molecular regulation of lymphatic metastasis in NSCLC.

Methods: A structured PubMed search was conducted for papers reporting on the expression of known markers of lymhangiogenesis in NSCLC patients. Papers of sufficient quality, presenting survival and/or correlation data were included.

Results: High levels of vascular endothelial growth factor C (VEGF-C, HR 1.57 95% CI 1.34-1.84) and high lymphatic vascular density (LVD, HR 1.84 95% CI 1.18-2.87) were significant prognostic markers of poor survival and high expression of VEGF-C, vascular endothelial growth factor receptor 3 (VEGFR3) and LVD was associated with lymph node metastasis in NSCLC.

Conclusion: Lymphangiogenic markers are prognosticators of survival and correlate with lymph node metastasis in NSCLC. Their exact role and clinical implications should be further elucidated.

Citing Articles

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References

Jin S, Zhu W, Shi Q, Zhang Z, Guo R . Clinicopathological significance of lymphatic vessel density marked by D2-40 and E-cadherin expression in non-small-cell lung cancer. Med Oncol. 2012; 29(5):3157-61. DOI: 10.1007/s12032-012-0229-5. View

Takanami I . Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer. Oncol Rep. 2006; 15(2):437-42. View

Kadota K, Huang C, Liu D, Ueno M, Kushida Y, Haba R . The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients. Eur J Cancer. 2008; 44(7):1057-67. DOI: 10.1016/j.ejca.2008.03.012. View

Bolenz C, Fernandez M, Tilki D, Herrmann E, Heinzelbecker J, Ergun S . The role of lymphangiogenesis in lymphatic tumour spread of urological cancers. BJU Int. 2009; 104(5):592-7. DOI: 10.1111/j.1464-410X.2009.08704.x. View

Ogawa E, Takenaka K, Yanagihara K, Kurozumi M, Manabe T, Wada H . Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer. 2004; 91(3):498-503. PMC: 2409842. DOI: 10.1038/sj.bjc.6601992. View

Daly S, Kubasiak J, Rinewalt D, Pithadia R, Basu S, Fhied C . Circulating angiogenesis biomarkers are associated with disease progression in lung adenocarcinoma. Ann Thorac Surg. 2014; 98(6):1968-75. DOI: 10.1016/j.athoracsur.2014.06.071. View

Chen F, Takenaka K, Ogawa E, Yanagihara K, Otake Y, Wada H . Flt-4-positive endothelial cell density and its clinical significance in non-small cell lung cancer. Clin Cancer Res. 2004; 10(24):8548-53. DOI: 10.1158/1078-0432.CCR-04-0950. View

Yu M, Liu L, Liang C, Li P, Ma X, Zhang Q . Intratumoral vessel density as prognostic factors in head and neck squamous cell carcinoma: a meta-analysis of literature. Head Neck. 2013; 36(4):596-602. DOI: 10.1002/hed.23301. View

Li Q, Dong X, Gu W, Qiu X, Wang E . Clinical significance of co-expression of VEGF-C and VEGFR-3 in non-small cell lung cancer. Chin Med J (Engl). 2003; 116(5):727-30. View

10.

Kadota K, Huang C, Liu D, Nakashima N, Yokomise H, Ueno M . The clinical significance of the tumor cell D2-40 immunoreactivity in non-small cell lung cancer. Lung Cancer. 2010; 70(1):88-93. DOI: 10.1016/j.lungcan.2009.12.014. View

11.

Ko Y, Jung C, Lee M, Byun J, Kang J, Lee K . Clinical significance of vascular endothelial growth factors (VEGF)-C and -D in resected non-small cell lung cancer. Cancer Res Treat. 2009; 40(3):133-40. PMC: 2697470. DOI: 10.4143/crt.2008.40.3.133. View

12.

Higgins J, Thompson S . Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-58. DOI: 10.1002/sim.1186. View

13.

Enatsu S, Iwasaki A, Shirakusa T, Hamasaki M, Nabeshima K, Iwasaki H . Expression of hypoxia-inducible factor-1 alpha and its prognostic significance in small-sized adenocarcinomas of the lung. Eur J Cardiothorac Surg. 2006; 29(6):891-5. DOI: 10.1016/j.ejcts.2006.03.027. View

14.

Zhan P, Wang J, Lv X, Wang Q, Qiu L, Lin X . Prognostic value of vascular endothelial growth factor expression in patients with lung cancer: a systematic review with meta-analysis. J Thorac Oncol. 2009; 4(9):1094-103. DOI: 10.1097/JTO.0b013e3181a97e31. View

15.

Mollberg N, Bennette C, Howell E, Backhus L, Devine B, Ferguson M . Lymphovascular invasion as a prognostic indicator in stage I non-small cell lung cancer: a systematic review and meta-analysis. Ann Thorac Surg. 2014; 97(3):965-71. DOI: 10.1016/j.athoracsur.2013.11.002. View

16.

Maekawa S, Iwasaki A, Shirakusa T, Enatsu S, Kawakami T, Kuroki M . Correlation between lymph node metastasis and the expression of VEGF-C, VEGF-D and VEGFR-3 in T1 lung adenocarcinoma. Anticancer Res. 2007; 27(6A):3735-41. View

17.

Card C, Yu S, Swartz M . Emerging roles of lymphatic endothelium in regulating adaptive immunity. J Clin Invest. 2014; 124(3):943-52. PMC: 3938271. DOI: 10.1172/JCI73316. View

18.

Huang C, Liu D, Masuya D, Nakashima T, Kameyama K, Ishikawa S . Clinical application of biological markers for treatments of resectable non-small-cell lung cancers. Br J Cancer. 2005; 92(7):1231-9. PMC: 2361974. DOI: 10.1038/sj.bjc.6602481. View

19.

Su J, Shih J, Yen M, Jeng Y, Chang C, Hsieh C . Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res. 2004; 64(2):554-64. DOI: 10.1158/0008-5472.can-03-1301. View

20.

Jain R . Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307(5706):58-62. DOI: 10.1126/science.1104819. View