In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgenindependence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR)
T. Nickerson et al., In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgenindependence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR), CANCER RES, 61(16), 2001, pp. 6276-6280
Androgen deprivation therapies for metastatic prostate cancer are useful in
itially, but progression to androgen independence usually results in relaps
e within 2 years. The molecular mechanisms underlying the clinically import
ant transition from androgen dependence to androgen independence are poorly
described. Several lines of investigation have suggested that insulin-like
growth factors (IGFs) are involved in the biology of prostate cancer, but
little is known about their relevance to progression to androgen independen
ce. We used three in vivo models of androgen-dependent (AD) human prostate
cancer to study this issue. Progression to androgen-independent (Al) growth
was associated with a 60-fold increase in expression of IGF-I mRNA in LAPC
-9 xenografts and a 28-fold increase in IGF-I expression in LNCAP xenograft
s, relative to the initial AD neoplasms. IGF type I receptor (IGF-IR) mRNA
levels were similar to2.5-fold and similar to5-fold higher, respectively, i
n Ai LAPC-9 and LNCaP tumors compared with the original AD neoplasms. AI gr
owth of these xenografts was also associated with significant reductions in
IGF binding protein-3 expression. LAPC-4 xenografts, which previously have
been shown to exhibit molecular pathology related to HER-2/neu expression
with progression to Al, showed relatively minor changes in expression of th
e genes investigated, but we nevertheless found evidence of increased IGF-I
R phosphorylation with progression to androgen independence in this model.
Taken together with prior observations, our results suggest that deregulati
on of expression of genes related to any one of several critical receptor t
yrosine kinase regulatory systems, including IGF signaling, may confer andr
ogen independence.