Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis

Abstract

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 welldifferentiated 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.

Conditional Deletion of Insulin-like Growth Factor-I Receptor in Prostate Epithelium

“…Recently, we reported that enforced expression of IGF-I in prostate epithelium could promote preneoplastic growth but was insufficient to cause carcinoma (18). As well, crossing the lit mice with TRAMP (28) showed that although chronically reduced systemic IGF-I and GH expression could significantly delay tumor-related death, the direct role of IGF-I signaling at the level of the prostate epithelium was not specifically addressed nor was the relative contribution of reduced GH levels to prolonged survival.…”

“…Second, our data indicate that any decrease in circulating IGF-I in combination with changes to p53 that would physiologically accompany normal aging would provide selective advantage to transformed epithelial cells that could overcome the IGF-IR-mediated differentiation block and progress toward more invasive and disseminated forms of carcinoma. We have previously proposed the hurdle hypothesis to explain how factors that contribute to the height of the differentiation ''hurdle'' in essence will determine how aggressive a cancer must become to overcome the differentiation barrier/blockade to achieve malignant transformation (18). Because abrogation of functional IGF-IR expression actually promoted earlier emergence of more aggressive, less-differentiated carcinomas in a p53-compromised model of prostate cancer, the current data support the hypothesis that titration of IGF-IR signaling reduces the prodifferentiation block.…”

“…We have recently shown that enforced IGF-I signals can cause spontaneous preneoplastic changes in the prostate in a genetically engineered mouse (GEM) model and that selection against this same signal was concomitant with the emergence of more aggressive metastatic states (18), consistent with clinical data (14). Based on these findings, we proposed the ''hurdle hypothesis'' to explain how the strength of the IGF-I signal can help define the height of a differentiation hurdle that in turn determines how aggressive a cancer must become to achieve malignancy (18).…”

Interleukin-Driven Insulin-Like Growth Factor Promotes Prostatic Inflammatory Hyperplasia

“…IGF promotes epithelial growth in tissue culture studies and in vivo (Cohen et al, 1991;Plymate et al, 1996). IGF overexpression exhibits a potent growth-promoting effect for IGF in the prostate and results in hyperplasia (DiGiovanni et al, 2000;Kaplan-Lefko et al, 2008). Further, Ruan and Kleinberg demonstrated that IGF-I is required for prostate development (Ruan et al, 1999).…”

Lipids in the Pathogenesis of Benign Prostatic Hyperplasia: Emerging Connections

“…Augmented steroidal signaling and mesenchymal-epithelial interactions are required for the normal as well as pathological growth of the prostate gland (Marker et al, 2003). However, current literature indicates that apart from steroids, peptides and lipids are also playing a crucial role in the pathogenesis of BPH (Cai et al, 2001;Culig et al, 1996;Escobar et al, 2009;Kaplan-Lefko et al, 2008;Rahman et al, 2007;Rick et al, 2011;Story, 1995;Vikram et al, 2010c). Even if the effects of peptides and lipids on the growth of the gland is milder as compared to that of steroids, chronic change in their levels either due to dietary habit or genetic predispositions can significantly contribute to the initiation and/or progression of the disease over a period of time.…”