Lymphangiogenesis Correlates with Lymph Node Metastasis, Prognosis, and Angiogenic Phenotype in Human Non–Small Cell Lung Cancer

Abstract

Purpose: Recent experimental studies have revealed that lymphangiogenesis plays an important role in cancer progression, but its clinical significance in the case of non-small cell lung cancer (NSCLC) remains unclear. Our aim was to assess the lymphangiogenesis of human NSCLC, and to correlate this with angiogenic phenotype (angiogenic versus nonangiogenic growth pattern) and clinical behavior. Experimental Design: One hundred and three patients with NSCLC and complete follow-up information were included. Tumor samples were immunostained for vascular endothelial growth factor-C (VEGF-C), the lymphatic endothelial markers, LYVE-1 and D2-40/Podoplanin, and the panvascular marker, CD31. Lymphatic vessel density (LVD) and perimeters were evaluated within the tumor and peritumorally. Results: LVDs at the tumor periphery were significantly higher in lymph node metastatic tumors (P < 0.005) and high LVDs correlated with poor overall survival (P < 0.001). However, this tendency proved to be significant only in the angiogenic tumor group (P < 0.001). Although 68% of the patients with nonangiogenic tumors had lymph node metastasis (P = 0.0048 versus angiogenic tumors), in the patient group with nonangiogenic NSCLCs, there was no information from the LVDs in any investigated tumor area (P > 0.05). In contrast to angiogenic tumors, which had actively sprouting lymphatics in all of the investigated tumor areas, nonangiogenic tumors showed no Ki67 staining intratumorally. Conclusions: Our results reveal tumor lymphangiogenesis as a novel prognostic indicator for the risk of lymph node metastasis in NSCLC. Moreover, it also provides the first evidence that nonangiogenic NSCLCs mainly co-opt host tissue lymphatics during their growth, in contrast to most of the angiogenic tumors, which expand with concomitant lymphangiogenesis.

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma

“…Several studies have shown that peritumoral lymphatic vessels are associated with lymph node metastasis, 8,14,17,18,27,40,41 whereas other studies, only for head and neck squamous cell carcinoma, showed that intratumoral lymphatic vessels, and not peritumoral lymphatic vessel density, are important for lymphatic spreads. 3,14,15 Thus, we first examined the VEGF-C and D2-40 expression in cholangiocarcinoma S Aishima et al intratumoral or peritumoral lymphatic vessel density in intrahepatic cholangiocarcinomas, and detected the following: (1) lymphatic vessel density was much lower in the tumor center than in the tumor periphery; (2) lymphatic vessels in the tumor center were frequently collapsed, whereas peritumoral lymphatic vessels showed open lumen; and (3) lower lymphatic vessel density in the tumor center was significantly correlated with the presence of lymphatic invasion.…”

“…1,2 Several types of human cancer can induce the formation of lymphatic vessels, [3][4][5][6] whereas other cancers do not actively induce lymphangiogenesis and simply invade existing lymphatic vessels. [7][8][9][10][11][12][13] A positive relationship between the intratumoral or peritumoral lymphatic vessel density and lymphatic spreads has been reported in head and neck squamous cell carcinoma, 3,14,15 cutaneous melanoma, 16,17 lung cancer, 18 and pancreatic endocrine tumor. 19,20 Vascular endothelial growth factor-C (VEGF-C) has been found to be the common lymphangiogenetic factor, acting predominantly via VEGF receptor-3 (VEGFR-3), which is expressed by lymphatic endothelial cells, 21 and VEGF-C strongly promoted the growth of tumor-associated lymphatic vessels.…”

Lymphatic microvessel density as prognostic marker in colorectal cancer

“…Although it is claimed that LYVE-1 is a specific marker for lymphatic vessels, its value in identifying fully functional lymphatics, has been questioned. Two recent studies failed to detect lymphatics within the non-small-cell lung carcinoma using LYVE-1, 40,41 while were identified using podoplanin. 40 Another study was unable to detect LYVE-1 expression in the majority of the colorectal samples, but again showed podoplanin expression.…”

“…Two recent studies failed to detect lymphatics within the non-small-cell lung carcinoma using LYVE-1, 40,41 while were identified using podoplanin. 40 Another study was unable to detect LYVE-1 expression in the majority of the colorectal samples, but again showed podoplanin expression. 37 Therefore, LYVE-1 may not be expressed by functional lymphatics and stained nonfunctional intratumoral and peritumoral lymphatic vessels.…”

Targeting lymphangiogenesis to prevent tumour metastasis

“…Reliable assays to detect the presence of VEGF-C, VEGF-D and VEGFR-3, and also to detect intra-or peritumoural lymphangiogenesis must be in place. Approaches for detecting these by immunohistochemistry, including identification of lymphatic vessels by staining for markers such as LYVE-1 (Dadras et al, 2003) and podoplanin (Renyi-Vamos et al, 2005), have been described in the clinicopathological literature and may require further development to become sufficiently robust. Initial trials should be performed on cancers in which lymphangiogenesis can be detected in a reasonable proportion of cases.…”