Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis.
Epidermal growth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker of human glioblastoma multiforme (GBM). However, its functional role and biological significance in GBM remain elusive. Here, we show that multiple GBM cell subpopulations could be purified from the specimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFR and of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, are tumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them, EGFR-expressing tumor-initiating cells (TIC) display the most malignant functional and molecular phenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-function strategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting that EGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of new therapeutically relevant scenarios, as the presence of functionally heterogeneous EGFR(pos) and EGFR(neg) TIC subpopulations within the same tumor might affect clinical response to treatment.
Mazzoleni
Stefania
S
Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.
Politi
Letterio S
LS
Pala
Mauro
M
Cominelli
Manuela
M
Franzin
Alberto
A
Sergi Sergi
Lucia
L
Falini
Andrea
A
De Palma
Michele
M
Bulfone
Alessandro
A
Poliani
Pietro L
PL
Galli
Rossella
R
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D011799:Quinazolines; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology
D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors