Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer.
OBJECTIVE
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.


METHODS
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.
Renyi-Vamos
Ferenc
F
Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary.
Tovari
Jozsef
J
Fillinger
Janos
J
Timar
Jozsef
J
Paku
Sandor
S
Kenessey
Istvan
I
Ostoros
Gyula
G
Agocs
Laszlo
L
Soltesz
Ibolya
I
Dome
Balazs
B
D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011379:Prognosis; D016019:Survival Analysis; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis; D033921:Vesicular Transport Proteins; D000098853:Podoplanin
D006023:Glycoproteins; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C117468:PDPN protein, human; D000098853:Podoplanin