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(American Journal of Pathology. 2006;168:991-1003.)
© 2006 American Society for Investigative Pathology

Laminin 2 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

Domenico Vitolo^*, Luciano Ciocci^*, Gloria Deriu^*, Silvia Spinelli^*, Stefania Cortese^*, Laura Masuelli^*, Stefania Morrone^*, Mary Jo Filice, Giorgio Furio Coloni, Pier Giorgio Natali and Carlo Davide Baroni^*

From the Department of Experimental Medicine and Pathology^* and the Division of Thorax Surgery, University of Rome "La Sapienza," Rome; and the Regina Elena Cancer Institute, Rome, Italy

Capillaries expressing the laminin 2 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 2 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 2 chain rather than through the laminin ß1 chain and fibronectin. AE-2 cells constitutively expressed all EGF receptors and the 6ß1 integrin, which is one of the laminin 2 chain receptors. EGF up-regulated 6ß1 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-6 integrin chain monoclonal antibody. These data indicate that laminin 2 chain and 6ß1 may be mutually involved in EGF-dependent migration of AE-2 cells and that laminin 2 chain-positive vessels may favor metastasis of EGF-dependent tumors.