title: Hypoxia increases the motility of lung adenocarcinoma cell line A549 via activation of the epidermal growth factor receptor pathway.
abstract: Tumor hypoxia is associated with a malignant phenotype of cancer cells and poor patient prognosis. To investigate the role of hypoxia in tumor progression, we studied the effects of hypoxia in the A549 lung adenocarcinoma cell line. First, we showed that hypoxic treatment decreased cell-cell adhesion and induced a scattering of cancer cells. Concomitant with these morphological changes, the motility of cancer cells was increased, as demonstrated by the Boyden chamber assay. Then, we used oligonucleotide array analyses to identify the genes causally related to the hypoxia-induced motile phenotype. The results showed that the expression of approximately 100 genes was induced more than 5-fold by hypoxia. These included (among others) epidermal growth factor receptor (EGFR), as well as other well-known hypoxia-induced genes, such as vascular endothelial growth factor. Immunohistochemical analyses of primary lung adenocarcinomas confirmed the induction of EGFR in tumor cells in the vicinity of necrotic areas, a histological indicator of tumor hypoxia. Remarkably, the EGFR inhibitor AG1478 (10 microM) completely blocked the increased cell motility induced by hypoxia. Thus, the present study demonstrates the importance of the EGFR pathway in the increased motility of cancer cells that occurs in a hypoxic tumor environment.
authors.affiliation: Department of Human Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ota
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Etsuko
authors.initials: E
authors.lastname: Ohara
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Jun
authors.initials: J
authors.lastname: Nakajima
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011799:Quinazolines; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors