β4 Integrin signaling induces expansion of prostate tumor progenitors.
The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that β4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.
Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA.
Toshiaki
T
Yoshioka
Javier
J
Otero
Yu
Y
Chen
Young-Mi
YM
Kim
Jason A
JA
Koutcher
Jaya
J
Satagopan
Victor
V
Reuter
Brett
B
Carver
Elisa
E
de Stanchina
Katsuhiko
K
Enomoto
Norman M
NM
Greenberg
Peter T
PT
Scardino
Howard I
HI
Scher
Charles L
CL
Sawyers
Filippo G
FG
Giancotti
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D018390:Gene Targeting; D006801:Humans; D039663:Integrin beta4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D039663:Integrin beta4; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse; C491743:MET protein, human