Prostate Cancer Cells Promote Osteoblastic Bone Metastases through Wnts

Hall, Christopher L.; Bafico, Anna; Dai, Jinlu; Aaronson, Stuart A.; Keller, Evan T.

doi:10.1158/0008-5472.can-05-1317

Cited by 275 publications

(273 citation statements)

References 25 publications

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“…Subsequent studies implicated DKK1 in the pathogenesis of osteolytic lesions in patients with multiple myeloma (Tian et al, 2003). During our study, Hall et al (2005) reported that PC-3 prostate cancer cells express DKK1 and showed by genetic manipulation of DKK1 in C4-2b prostate cancer cells that WNT signaling participates in prostate cancerinduced new bone formation. Our observations are consistent with these findings and extend further to the identification of the expression of WNT7b and DKK1 in human prostate cancer specimens.…”

Section: Discussionmentioning

confidence: 51%

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Yang

Vázquez

et al. 2007

Oncogene

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The tendency of prostate cancer to produce osteoblastic bone metastases suggests that cancer cells and osteoblasts interact in ways that contribute to cancer progression. To identify factors that mediate these interactions, we compared gene expression patterns between two bonederived prostate cancer cell lines that produce osteoblastic (MDA PCa 2b) or osteolytic lesions (PC-3). Both cell lines expressed Wnt ligands, including WNT7b, a canonical Wnt implicated in osteogenesis. PC-3 cells expressed 50 times more Dickkopf-1 (DKK1), an inhibitor of Wnt pathways, than did MDA PCa 2b cells. Evaluation of the functional role of these factors (in cocultures of prostate cancer cells with primary mouse osteoblasts (PMOs) or in bone organ cultures) showed that MDA PCa 2b cells activated Wnt canonical signaling in PMOs and that DKK1 blocked osteoblast proliferation and new bone formation induced by MDA PCa 2b cells. MDA PCa 2b cells did not induce bone formation in calvaria from mice lacking the Wnt co-receptor Lrp5. In human specimens, WNT7b was not expressed in normal prostate but was expressed in areas of high-grade prostate intraepithelial neoplasia, in three of nine primary prostate tumor specimens and in 16 of 38 samples of bone metastases from prostate cancer. DKK1 was not expressed in normal or cancerous tissue but was expressed in two of three specimens of osteolytic bone metastases (P ¼ 0.0119). We conclude that MDA PCa 2b induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption that determines lesion phenotype.

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Section: Discussionmentioning

confidence: 51%

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Yang

Vázquez

et al. 2007

Oncogene

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“…In tumors with Wnt pathway defects, stabilized β-catenin interacts with TCF transcription factors to mediate increased expression of specific genes, at least some of which likely play critical roles in cancer pathogenesis (40). One of the well-known pathways that regulates oncogenesis in different organs is the Wnt signaling pathway (41). β-catenin is a downstream molecule in the Wnt signaling pathway and plays important roles in the structural organization and function of cell-to-cell adhesion and tumor invasion and metastasis (42).…”

Section: Discussionmentioning

confidence: 99%

shRNA against CD44 inhibits cell proliferation, invasion and migration, and promotes apoptosis of colon carcinoma cells

Park

Huh²,

Lee³

et al. 2011

Oncol Rep

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Abstract. CD44 is a causal factor for tumor invasion, metastasis and acquisition of resistance to apoptosis. CD44 knockdown using inducible short hairpin RNA (shRNA) significantly reduces cell growth and invasion. Short hairpin RNA against CD44 and pGFP-V-RS-vector was used for knockdown of CD44 expression in SW620 colon cancer cells. Cell growth, invasion and migration assay, immunofluorescence for β-catenin expression and Western blotting for Wnt signaling molecules were analyzed. Cell cycle analysis and Western blot analysis for apoptotic molecules were evaluated. Short hairpin RNA against CD44 reduced the expression of CD44. Cell proliferation, migration and invasion were markedly inhibited and apoptosis was increased in shRNA CD44-transfected cells. Knockdown of CD44 decreased the phosphorylation of PDK1, Akt and GSK3β, and β-catenin levels. Decreased phosphorylated Akt led to an increase in phosphorylated FoxO1 and induced cell cycle arrest in the G 0 -G 1 phase and a decrease in the S phase. The levels of Bcl-2 and Bcl-xL expression were down-regulated, while the levels of BAX expression and cleaved caspase-3, -8 and -9 were increased. CD44 knockdown by way of shRNA inhibited cell proliferation and induced cell apoptosis. This can be used as a therapeutic intervention with the anti-survival/pro-apoptotic machinery in human colon cancer.

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“…In instances of osteolytic tumours, the presence of Dkk-1 would be predicted to exacerbate lesion formation through inhibition of Wnt-dependent osteogenesis. This certainly seems probable since a recent study has demonstrated that prostate tumours-expressing high levels of Dkk-1 produce more extensive local bone destruction compared to controls that express lower levels (Hall et al, 2005). Reducing the osteoinhibitory effects of Dkk-1 would therefore be predicted to reduce local bone damage, and as a result, probably reduce the expansion of the tumour.…”

Section: Discussionmentioning

confidence: 99%

“…Examples include multiple myeloma (Tian et al, 2003) and some forms of prostate cancer (Hall et al, 2005). Damage of the bone by malignancy can increase the severity of the disease by providing a permissive microenvironment for tumour growth and metastatic events.…”

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confidence: 99%

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

et al. 2007

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Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3b inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immunodepletion of Dkk-1 or administration of GSK3b inhibitors could represent an adjunct therapy for this disease.

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Prostate Cancer Cells Promote Osteoblastic Bone Metastases through Wnts

Cited by 275 publications

References 25 publications

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

shRNA against CD44 inhibits cell proliferation, invasion and migration, and promotes apoptosis of colon carcinoma cells

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

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