Increased expression of putative cancer stem cell markers in primary prostate cancer is associated with progression of bone metastases

Colombel, Marc; Eaton, Colby L.; Hamdy, Freddie C.; Ricci, E.; Pluijm, Gabri van der; Cecchini, Marco; Mège‐Lechevallier, Florence; Clézardin, Philippe; Thalmann, George N.

doi:10.1002/pros.21473

Cited by 54 publications

(43 citation statements)

References 26 publications

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“…Enhanced integrin α 2 expression was shown to facilitate the adhesion and survival of PCa cells through activated FAK and Akt phosphorylation (Figure 2). High expression of integrin α 2 in metastatic PCa and its important role in cell survival and adhesion in the bone microenvironment is supported by recent experimental and clinical publications [53, 54]. 3) Concomitant with enhanced integrin α 2 expression, we also observed that LNCaP RANKL cells grown in 3-D suspension exhibited elevated functional AR expression, a result not seen in 2-D monolayer culture (Figure 3).…”

Section: Discussionsupporting

confidence: 80%

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Induction of integrin α2 in a highly bone metastatic human prostate cancer cell line: roles of RANKL and AR under three-dimensional suspension culture

Ziaee

Chung

2014

Mol Cancer

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BackgroundProstate cancer (PCa) bone metastasis can be markedly enhanced by increased receptor activator of NF kappa-B ligand (RANKL) expression in PCa cells. Molecular mechanisms that account for the increased predilection of PCa for bone include increased bone turnover, promotion of PCa cell growth and survival in the bone environment, and recruitment of bystander dormant cells to participate in bone metastasis. The current study tests the hypothesis that PCa cells acquire high adhesion to bone matrix proteins, which controls PCa bone colonization, under the RANKL/RANK and AR axes.MethodsWe used a highly bone metastatic RANKL-overexpressing LNCaP PCa cell line, LNCaPRANKL, as a model to pursue the molecular mechanisms underlying the increased adhesion of PCa cells to collagens. A three-dimensional (3-D) suspension PCa organoid model was developed. The functions of integrin α2 in cell adhesion and survival were evaluated by flow cytometry and western blot. AR expression and functionality were compared in 2-D monolayer versus 3-D suspension cultures using AR promoter- and PSA promoter-luciferase activity. AR role in cell adhesion was assessed using an adhesion assay.ResultsLNCaPRANKL cells were shown to adhere tightly to ColI matrix through increased α2 integrin expression. This increased adhesion, concomitant with activation of the FAK and Akt pathways, was further enhanced by culturing LNCaPRANKL cells in 3-D suspension. Under the influence of 3-D suspension culture, AR was restored in LNCaPRANKL cells via downregulation of AP-4 transcription factor, and supported increased α2 integrin expression and adhesion to ColI.Conclusion3-D suspension culture and in vivo PCa tumor growth restore AR through downregulation of AP-4, enhancing integrin α2 expression and adhesion to ColI which is rich in bone matrices. The interactions of PCa with ColI, mediated by integrin α2 and AR expression, could be a key molecular event accounting for PCa bone metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-208) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 80%

“…These results are in agreement with work of Colombel et al . [54] who showed that higher α 2 β 1 protein expression in primary PCa tissues correlates with bone metastasis. Additionally, Sottnik et al .…”

Section: Discussionmentioning

confidence: 99%

Induction of integrin α2 in a highly bone metastatic human prostate cancer cell line: roles of RANKL and AR under three-dimensional suspension culture

Ziaee

Chung

2014

Mol Cancer

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“…37). In addition, the signatures of PCSCs are associated with prostate cancer bone metastasis and poor prognosis (38,39).…”

Section: Discussionmentioning

confidence: 99%

Neural Cell Adhesion Protein CNTN1 Promotes the Metastatic Progression of Prostate Cancer

et al. 2016

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Prostate cancer metastasis is the main cause of disease-related mortality. Elucidating the mechanisms underlying prostate cancer metastasis is critical for effective therapeutic intervention. In this study, we performed gene-expression profiling of prostate cancer stem-like cells (PCSC) derived from DU145 human prostate cancer cells to identify factors involved in metastatic progression. Our studies revealed contactin 1 (CNTN1), a neural cell adhesion protein, to be a prostate cancer-promoting factor. CNTN1 knockdown reduced PCSC-mediated tumor initiation, whereas CNTN1 overexpression enhanced prostate cancer cell invasion in vitro and promoted xenograft tumor formation and lung metastasis in vivo. In addition, CNTN1 overexpression in DU145 cells and corresponding xenograft tumors resulted in elevated AKT activation and reduced E-cadherin (CDH1) expression. CNTN1 expression was not readily detected in normal prostate glands, but was clearly evident on prostate cancer cells in primary tumors and lymph node and bone metastases. Tumors from 637 patients expressing CNTN1 were associated with prostate cancer progression and worse biochemical recurrence-free survival following radical prostatectomy (P < 0.05). Collectively, our findings demonstrate that CNTN1 promotes prostate cancer progression and metastasis, prompting further investigation into the mechanisms that enable neural proteins to become aberrantly expressed in non-neural malignancies.

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“…The percentage of CSCs had a prognostic impact, particularly on the risk of progression of bone metastases. 32 The percentage of cells expressing a stem cell phenotype in bone marrow metastases of prostate cancer patients has been shown to be predictive of bone metastases progression. 33 There is also a small population of docetaxel-resistant cells, likely CSCs, that have been shown to be higher in metastasic compared to primary patient samples, and, in primary untreated samples, the percentage of these cells was associated with prognostic factors and time to biochemical relapse.…”

Section: Role Of Cscs In Prostate Cancermentioning

confidence: 99%

Metformin and prostate cancer stem cells: a novel therapeutic target

Mayer

Klotz

Venkateswaran

2015

Prostate Cancer Prostatic Dis

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Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies.

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Increased expression of putative cancer stem cell markers in primary prostate cancer is associated with progression of bone metastases

Abstract: It can be concluded that percentage of stem cell-like prostate cancer cells has a prognostic impact especially on the risk of metastatic bone progression.

Cited by 54 publications

References 26 publications

Induction of integrin α2 in a highly bone metastatic human prostate cancer cell line: roles of RANKL and AR under three-dimensional suspension culture

Induction of integrin α2 in a highly bone metastatic human prostate cancer cell line: roles of RANKL and AR under three-dimensional suspension culture

Neural Cell Adhesion Protein CNTN1 Promotes the Metastatic Progression of Prostate Cancer

Metformin and prostate cancer stem cells: a novel therapeutic target

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