Publications (16) View all
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Article: TGFβ1-Endo180-dependent collagen deposition is dysregulated at the tumour-stromal interface in bone metastasis.
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ABSTRACT: Cellular niches in adult tissue can harbour dysregulated microenvironments that become the driving force behind disease progression. The major environmental change when metastatic cells arrive in the bone is the destruction of mineralized type I collagen matrix. Once metastatic niches establish in bone, the invading tumour cells initiate a vicious cycle of osteolytic lesion formation via the dysregulation of paracrine signals and uncoupling of normal bone resorption and production. Here we report that the collagen receptor Endo180 (CD280, MRC2, uPARAP) participates in collagen deposition by primary human osteoblasts during de novo osteoid formation. This newly recognized function of Endo180 was suppressed in osteoblasts following heterotypic direct cell-cell contact in co-culture with prostate tumour cells. Reciprocal Endo180 up-regulation in osteolytic prostate tumour cells (PC3 and DU145) followed their direct contact with osteoblasts and promoted de novo collagen internalization, which is a previously characterized function of the constitutively recycling Endo180 receptor. The osteoblastic suppression and tumour cell-associated enhancement of Endo180 expression were equally sustained in these direct co-cultures. These findings are the first to demonstrate that increased tumour cell participation in collagen degradation and decreased collagen formation by osteoblasts in the osteolytic microenvironment are linked to the divergent regulation of a collagen-binding receptor. Immunohistochemical analysis of core biopsies from bone metastasis revealed higher levels of Endo180 expression in tumour cell foci than cells in the surrounding stroma. Additional experiments in prostate cell-osteoblast co-cultures indicate that divergent regulation of Endo180 is the result of dysregulated TGFβ1 signalling. The findings of this study provide a rationale for targeting collagen remodelling by Endo180 in bone metastases and other collagen matrix pathologies.The Journal of Pathology 11/2011; 226(5):775-83. · 6.32 Impact Factor -
Article: Authors' reply: Expanding horizons in metastatic prostate cancer treatment.
Nature Reviews Clinical Oncology 08/2011; · 11.96 Impact Factor -
Article: Bone metastasis in prostate cancer: emerging therapeutic strategies.
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ABSTRACT: Metastatic bone disease (MBD) in advanced-stage cancer increases the risk of intractable bone pain, pathological skeletal fracture, spinal-cord compression and decreased survival. The disease manifestation course during MBD is largely driven by homotypic and heterotypic cellular interactions between invading tumor cells, osteoblasts and osteoclasts. The outcome is a sustained vicious cycle of bone matrix remodeling. Osteoclast-mediated bone degradation and subsequent bone loss are the hallmarks of secondary bone metastases from most solid tumors. An additional complication in prostate cancer is the predominance of osteosclerotic lesions typified by inappropriate bone production. Successful therapeutic strategies for the treatment of osteolytic MBD include the administration of intravenous bisphosphonates or subcutaneous inhibitors of receptor activator of nuclear factor κB ligand (RANKL). Inhibitors of SRC and cABL kinases and cathepsin K are under clinical investigation as potential anti-osteolytics. In contrast to the rapid progress being made in the development of anti-osteolytic therapies, the treatment of osteosclerotic MBD remains restricted to palliative radiotherapy for symptomatic solitary lesions and systemic taxane-based chemotherapy for widespread multiple lesions. This Review discusses the complex pathology of bone lesions in metastatic castration-resistant prostate cancer and focuses on new therapeutic strategies and targets that are emerging in preclinical studies.Nature Reviews Clinical Oncology 06/2011; 8(6):357-68. · 11.96 Impact Factor -
Article: Bone metastasis in prostate cancer: emerging therapeutic strategies.
Nature Reviews Clinical Oncology 01/2011; 8(10):568. · 11.96 Impact Factor -
Article: Biological and clinical implications of nicastrin expression in invasive breast cancer.
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ABSTRACT: Nicastrin is an essential component of the gamma secretase (GS) enzyme complex, required for its synthesis and recognition of substrates for proteolytic cleavage. The purpose of this study was to investigate whether nicastrin has prognostic value or potential as a therapeutic target in breast cancer (BC). The suitability of nicastrin as a target in BC was assessed using BC tissue microarrays (TMAs) (n = 1050), and its biological role in vitro was evaluated in BC cell lines following gene silencing. Nicastrin blocking antibodies were developed and evaluated for their suitability as potential clinical therapeutics. TMA and cell line analysis confirmed that nicastrin expression was upregulated in BC compared to normal breast cells. In TMA patient samples, high nicastrin expression was observed in 47.5% of cases and correlated with ERα expression, patient age, and tumor grade. In pre-defined subset analysis, high nicastrin expression predicted for worse BC specific survival in the ERα -ve cohort. In vitro gene silencing of nicastrin resulted in disruption of the GS complex and a decrease in notch1 cleavage. This was sufficient to increase E-cadherin expression and its co-localization with p120 catenin at cell-cell junctions in MCF7 cells. Nicastrin silencing in invasive MDA-MB-231 cells resulted in loss of vimentin expression and a marked reduction in both cell motility and invasion; which was concomitant with the de novo formation of cell-cell junctions characterized by the colocalization of p120 catenin and F-actin. These data indicate that nicastrin can function to maintain epithelial to mesenchymal transition during BC progression. Anti-nicastrin polyclonal and monoclonal antibodies were able to decrease notch1 and vimentin expression and reduced the invasive capacity of BC cells in vitro. This supports our hypothesis that a nicastrin blocking antibody could be used to limit metastatic dissemination in invasive BC.Breast Cancer Research and Treatment 03/2010; 125(1):43-53. · 4.43 Impact Factor
