Abstract
BackgroundGenetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified HSPG2 (Perlecan) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in Drosophila. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer.ResultsHere we demonstrate Perlecan expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. Perlecan expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. Perlecan is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of Perlecan expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. Perlecan expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of Perlecan expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector GLI1 rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of Perlecan expression. Under low androgen, low growth factor conditions, Perlecan expression level correlates with the ability of the cells to maintain SHH signaling.ConclusionWe have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects.
Highlights
Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers
Perlecan is expressed in and associated with aggressive prostate cancers After identification of Perlecan as a candidate gene for the CAPB locus we sought to confirm the presence of Perlecan in primary prostate cancers
There was a significant increase in Perlecan levels in invasive tumors compared to either benign prostate tissue or the precancerous lesion high grade prostatic intraepithelial neoplasia (HGPIN)
Summary
Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. Molecular analyses of prostate tumors revealed that Su(fu) protein is absent in most highly aggressive tumors and somatic truncation mutations in the Su(fu) gene have been identified [8] consistent with the hypothesis that Su(fu) would act as a prostate tumor suppressor gene by inhibiting Sonic Hedgehog signaling These studies demonstrate the critical nature of Sonic Hedgehog signaling in tumorigenesis and metastasis. We demonstrate that Perlecan's effects on cell growth are independent of androgen signaling and occur through the binding of Sonic Hedgehog, resulting in modulation of the Sonic Hedgehog-Patched-Gli signaling pathway This data, along with data linking Perlecan to metastatic tumor environments such a bone matrix [13], presents a general model in which Perlecan expression by tumor cells under poor growth conditions enhances their ability to utilize growth factors until their spread to suitable metastatic tumor microenvironments for accelerated growth
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