Elsevier

Lung Cancer

Volume 63, Issue 2, February 2009, Pages 277-283
Lung Cancer

VEGF-A and VEGFR-3 correlate with nodal status in operable non-small cell lung cancer: Inverse correlation between expression in tumor and stromal cells

https://doi.org/10.1016/j.lungcan.2008.05.022Get rights and content

Abstract

Background

Lymph node metastasis is an essential determinant for stage and clinical management of non-small cell lung cancer (NSCLC). The vascular endothelial growth factors (VEGFs) and receptors (VEGFRs) are fundamental molecules in angiogenesis and lymphangiogenesis. We aimed to explore the correlations between nodal metastasis and the expression of VEGFs and VEGFRs in tumor cells and in tumor-related stroma.

Patients and methods

Tumor tissue samples from 335 resected patients with stage I–IIIA NSCLC were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of VEGF-A, VEGF-C, and VEGF-D and VEGFR-1, VEGFR-2 and VEGFR-3.

Results

There were 232 N0 and 103 N+ patients (76 N1, 27 N2). In multivariate analyses, low stromal VEGF-A expression (P = 0.018) is associated with N+ status. In tumor cells, strong correlations exist between high VEGF-A expression (P = 0.032) and N+ status, and high VEGFR-3 expression (P < 0.001) and N2-status.

Conclusion

The converse impact by stromal VEGF-A versus tumor cell VEGF-A expression on nodal metastasis may allude the importance of the tumor–stroma interaction when trying to understand lymphatic metastasis in NSCLC.

Introduction

In non-small cell lung cancer (NSCLC), regional lymph node status (N-status) is a pivotal determinant for staging, clinical management, and survival of patients [1], [2].

In angiogenesis, one of the hallmarks in cancer development, VEGF-A and its receptors VEGFR-1 and VEGFR-2 appear to be the most significant signaling molecules [3], [4], [5], [6]. More recently, it has become clear that the basic mechanisms of hemangiogenesis also seem to apply to lymphangiogenesis and its role in regional metastasis, though the molecular mechanism of lymphatic metastasis is poorly understood [7], [8]. A lymphangiogenic role of VEGF-A is proposed, as preclinical and clinical studies indicate that VEGF-A promotes lymphatic metastasis [8], [9], [10].

The ligands VEGF-C and its close homolog VEGF-D exert their effects on endothelial cells via the receptors VEGFR-2 and VEGFR-3. Several preclinical and clinical studies have found VEGF-C, VEGF-D and VEGFR-3 to be important players in lymphangiogenesis [3], [7], [11], [12]. In clinical NSCLC studies, however, there is no consensus regarding the impact of VEGF-C, VEGF-D and VEGFR-3 on lymphangiogenesis [13], [14], [15], [16], [17], [18], [19], [20]. It has also been proposed that secreted VEGF-C primarily binds to VEGFR-3 on the tumor cells (autocrine loop) and that only residual VEGF-C binds to the VEGFR-3 receptors in lymphatic endothelial cells (paracrine pathway) to promote lymphangiogenesis [20].

A complex interplay between tumor, endothelial and stromal cells (e.g. macrophages, fibroblasts, lymphocytes, granulocytes and plasma cells) has been described in both angiogenesis and lymphangiogenesis [3], [5], [21], [22]. Most studies addressing VEGFs and VEGFRs significance in angiogenesis and lymphangiogenesis have focused on expression in tumor cells or endothelial cells, while the importance of the stromal component has been less studied.

In a large cohort of surgically resected NSCLC patients [23], we have previously reported on VEGF-A, VEGF-C and VEGF-D and VEGFR-1, VEGFR-2 and VEGFR-3 related to angiogenesis and their prognostic impact. As these markers are considered associated with both angio- and lymphangiogenesis, we now explore how their expression in tumor cells and stroma correlate with regional lymphatic metastasis.

Section snippets

Patients and clinical samples

Primary tumor tissues from anonymized patients diagnosed with NSCLC pathologic stage I–IIIA at the University Hospital of Northern Norway (UNN) and Nordland Central Hospital (NH) from 1990 through 2004 were used. In total, 371 patients were registered from the hospital database. Of these, 36 patients were excluded from the study due to: (i) radiotherapy or chemotherapy prior to surgery (n = 10); (ii) other malignancy within 5 years prior to NSCLC diagnosis (n = 13) and (iii) inadequate

Clinicopathologic variables

Demographic, clinical, and histopathologic variables and their relation to nodal status are shown in Table 1. With respect to lymph node metastasis, there were 232 lymph node negative and 103 node positive patients (N1, n = 76; N2, n = 27). The median age was 67 (range 28–85) years and the majority of the patients were male (76%). The NSCLC tumors comprised 191 squamous cell carcinomas (SCCs), 95 adenocarcinomas (ACs), 31 large-cell carcinomas (LCCs) and 18 bronchioalveolar carcinomas (BACs). Due

Discussion

We present a large-scale study using high-throughput TMA technology to investigate associations between lymphatic metastasis and the expression of angiogenic ligands and receptors in malignant cells and stroma of the lung. In tumor cells, strong positive correlations exist between high VEGF-A expression and N+ status and high VEGFR-3 expression and N2-positivity. Whereas in stroma, VEGF-A expression is inversely associated with lymph node metastasis. To our knowledge, this is the first

Conflict of interest

None declared.

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