Epidermal growth factor up-regulates CD44-dependent astrocytoma invasion in vitro.
CD44/hyaluronan interactions and epidermal growth factor (EGF) stimulation are both known to enhance tumour invasion in vitro. The frequent amplification of the EGF receptor (EGFR) in high-grade astrocytomas led to the examination of the hypothesis that CD44-dependent astrocytoma invasion is regulated by EGF. It has been shown that human astrocytoma cells express only the standard (haemopoietic) form of CD44 (CD44s) and that EGF up-regulates CD44 mRNA and protein in a time- and dose-dependent (10-100 ng/ml) manner. EGF stimulation did not result in induction of additional splice variants. No EGF-induced increase in CD44s was observed after treatment of cells with the wild-type EGFR tyrosine kinase inhibitor Tyrphostin AG1478 (30 nM). Up-regulation of CD44 by EGF is also prevented by the transcriptional inhibitor actinomycin D (5 microg/ml) and by blocking the MAP kinase (MAPK) pathway using the MEK inibitor U0126 (100 microM). CD44 up-regulation was associated with a 50% increase in invasion through hyaluronan-supplemented Matrigel(trade mark), which was abrogated by ligating CD44 with the specific antibody KM201. These results suggest that increased CD44 expression in response to EGF stimulation plays a significant role in astrocytoma invasion.
Monaghan
M
M
Department of Oncology, Cancer Research Centre, The Queen's University of Belfast, Belfast City Hospital Tower, Lisburn Road, Belfast BT9 7AB, UK.
Mulligan
K A
KA
Gillespie
H
H
Trimble
A
A
Winter
P
P
Johnston
P G
PG
McCormick
D
D
D001254:Astrocytoma / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*
D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004815:Epidermal Growth Factor; D066246:ErbB Receptors