Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis.
The insulin-like growth factor-1 (IGF-1) signaling axis is important for cell growth, differentiation and survival and increased serum IGF is a risk factor for prostate and other cancers. To study IGF-1 action on the prostate, we created transgenic (PB-Des) mice that specifically express human IGF-1(des) in prostate epithelial cells. This encodes a mature isoform of IGF-1 with decreased affinity for IGF binding proteins (IGFBP) due to a 3-amino acid deletion in the N terminus. Expression of IGF-1(des) was sufficient to cause hyperplastic lesions in all mice, however the well-differentiated lesions did not progress to adenocarcinoma within a year. Remarkably, crossing the PB-Des mice to an established model of prostate cancer delayed progression of organ-confined tumors and emergence of metastatic lesions in young mice. While dissemination of metastatic lesions was widespread in old bigenic mice we did not detect IGF-1(des) in poorly differentiated primary tumors or metastatic lesions. Expression of endogenous IGF-1 and levels of P-Akt and P-Erk were reduced independent of age. These data suggest that increased physiologic levels of IGF-1 facilitate the emergence of hyperplastic lesions while imposing a strong IGF-1-dependent differentiation block. Selection against IGF-1 action appears requisite for progression of localized disease and metastogenesis.
Kaplan-Lefko
P J
PJ
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Sutherland
B W
BW
Evangelou
A I
AI
Hadsell
D L
DL
Barrios
R J
RJ
Foster
B A
BA
Demayo
F
F
Greenberg
N M
NM
D000230:Adenocarcinoma / Q000556:secondary; D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary; D002454:Cell Differentiation / Q000502:physiology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006338:Heart Neoplasms / Q000556:secondary; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000378:metabolism* / Q000473:pathology*; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D013160:Splenic Neoplasms / Q000556:secondary; D013953:Thymus Neoplasms / Q000556:secondary; D014571:Urologic Neoplasms / Q000556:secondary
D007334:Insulin-Like Growth Factor I