Laminin 5 expression protects against anoikis at aerogenous spread and lepidic growth of human lung adenocarcinoma.
Adenocarcinoma of the lung is characterized by frequent aerogenous spread (AE) and advancement along the alveolar wall (BAC growth). To elucidate the mechanism of AE metastasis and BAC growth in human lung adenocarcinoma, we established an in vivo orthotopic animal model and an in vitro culture. Investigation of expression levels of integrins, laminins and Type IV collagens, which are the major regulating molecules for cell attachment and anoikis was carried out and a clear correlation between the expression level of laminin 5 (LN5) and the BAC growth was observed using an orthotopic animal model. Introduction of LN5 cDNA to A549 cells increased anoikis resistance in an expression dependent manner. Cells with LN5 overexpression resisted with anoikis after treatment with PI3K-Akt and ERK inhibitors. The amount of phosphorylated focal adhesion kinase (FAK) was also higher in LN5 overexpressing cells. Major tyrosine residues of the EGF receptor at 1068, 1086 and 1173, except at 1148, remained phosphorylated only in the LN5 overexpressing cells even without EGF stimulation, that indicates the ligand independent activation of EGF receptor. BAC growth ratio and AE was confirmed to be significantly correlated with LN5 expression in surgically resected human lung adenocarcinomas by immunohistochemistry. Our results indicate that the activation of the EGF receptor by overexpressing LN5-integrin-FAK signaling pathway may play a crucial role in BAC growth and AE metastasis in human lung adenocarcinoma.
Kodama
Keiji
K
Pathology Division, National Cancer Center Research Institute East, Chiba, Japan.
Ishii
Gen'ichiro
G
Miyamoto
Shin'ichi
S
Goya
Masato
M
Zhang
Shi-Chuan
SC
Sangai
Takafumi
T
Yoshikawa
Takeshi
T
Hasebe
Takahiro
T
Hitomi
Yoshiaki
Y
Izumi
Keisuke
K
Ochiai
Atsushi
A
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D023102:Anoikis / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D017931:DNA Primers; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000235:genetics; D007797:Laminin / Q000235:genetics*; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D014183:Transplantation, Heterologous
D017931:DNA Primers; D016023:Integrins; C478221:LAMB1 protein, human; C513277:Lamb1 protein, mouse; D007797:Laminin; D012333:RNA, Messenger; C095567:laminin alpha 3