Laminin α2 Chain-Positive Vessels and Epidermal Growth Factor in Lung Neuroendocrine Carcinoma : A Model of a Novel Cooperative Role of Laminin-2 and Epidermal Growth Factor in Vessel Neoplastic Invasion and Metastasis

Capillaries expressing the laminin α2 chain in basement membranes may be considered early developing vessels in normal and neoplastic human tissues. Therefore, we investigated whether up-regulation of this extracellular matrix protein favors transendothelial migration of neoplastic cells and then metastasis. In lung small and large cell neuroendocrine carcinomas, which exhibit a stronger metastatic tendency among carcinomas, laminin α2 chain-positive vessels were more numerous than in carcinoid tumors and supraglottis, breast, and lung non-small cell carcinomas, suggesting a direct relationship between these vessels and metastasis. In vitro studies showed that epidermal growth factor (EGF) induced a more efficient migration of the AE-2 lung neuroendocrine carcinoma cell line through the purified laminin α2 chain rather than through the laminin β1 chain and fibronectin. AE-2 cells constitutively expressed all EGF receptors and the α6β1 integrin, which is one of the laminin α2 chain receptors. EGF up-regulated α6β1 expression in several tumors. In this regard, we show that EGF increased the chemo-kinetic migration of AE-2 cells through EAHY endothelial monolayers, which was inhibited by the anti-α6 integrin chain monoclonal antibody. These data indicate that laminin α2 chain and α6β1 may be mutually involved in EGF-dependent migration of AE-2 cells and that laminin α2 chain-positive vessels may favor metastasis of EGF-dependent tumors.