In:
Cancer Discovery, American Association for Cancer Research (AACR), Vol. 2, No. 10 ( 2012-10-01), p. 906-921
Abstract:
We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1–mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo. Significance: These results identify a causal role for NRP2 and VEGF/NRP2 signaling in the behavior of aggressive prostate cancers by a mechanism that involves regulation of Bmi-1, a transcriptional repressor implicated in the etiology of prostate cancer induced by loss of PTEN function, and the repression of the IGF-IR. The therapeutic implications are significant because combined inhibition of NRP2 and IGF-IR overcomes the resistance induced by targeting each receptor individually. Cancer Discov; 2(10); 906–21. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 857.
Type of Medium:
Online Resource
ISSN:
2159-8274
,
2159-8290
DOI:
10.1158/2159-8290.CD-12-0085
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2607892-2
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