Browsing by Author "Zayzafoon, Majd"

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    Perlecan/HSPG2 and matrilysin/MMP-7 as indices of tissue invasion: tissue localization and circulating perlecan fragments in a cohort of 288 radical prostatectomy patients
    (Impact Journals, LLC, 2016) Grindel, Brian J.; Li, Quanlin; Arnold, Rebecca; Petros, John; Zayzafoon, Majd; Muldoon, Mark; Stave, James; Chung, Leland W.K.; Farach-Carson, Mary C.
    Prostate cancer (PCa) cells use matrix metalloproteinases (MMPs) to degrade tissue during invasion. Perlecan/HSPG2 is degraded at basement membranes, in reactive stroma and in bone marrow during metastasis. We previously showed MMP-7 efficiently degrades perlecan. We now analyzed PCa tissue and serum from 288 prostatectomy patients of various Gleason grades to decipher the relationship between perlecan and MMP-7 in invasive PCa. In 157 prostatectomy specimens examined by tissue microarray, perlecan levels were 18% higher than their normal counterparts. In Gleason grade 4 tissues, MMP-7 and perlecan immunostaining levels were highly correlated with each other (average correlation coefficient of 0.52) in PCa tissue, regardless of grade. Serial sections showed intense, but non-overlapping, immunostaining for MMP-7 and perlecan at adjacent borders, reflecting the protease-substrate relationship. Using a capture assay, analysis of 288 PCa sera collected at prostatectomy showed elevated levels of perlecan fragments, with most derived from domain IV. Perlecan fragments in PCa sera were associated with overall MMP-7 staining levels in PCa tissues. Domain IV perlecan fragments were present in stage IV, but absent in normal, sera, suggesting perlecan degradation during metastasis. Together, perlecan fragments in sera and MMP-7 in tissues of PCa patients are measures of invasive PCa.
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    RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization
    (Bioscientifica Ltd., 2014) Chu, Gina Chia-Yi; Zhau, Haiyen E.; Wang, Ruoxiang; Rogatko, André; Feng, Xu; Zayzafoon, Majd; Liu, Youhua; Farach-Carson, Mary C.; You, Sungyong; Kim, Jayoung; Freeman, Michael R.; Chung, Leland W.K.
    Prostate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model to study the mechanisms underlying the metastatic process. Here we report that receptor activator of NF-κB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor deletion/interference assays identified common transcription factor complexes (TFs), c-Myc/Max and AP4, as critical regulatory nodes. RANKL-RANK signaling activated a number of master regulator TFs that control the epithelial-mesenchymal transition (EMT) (Twist1, Slug, Zeb1, Zeb2), stem cell properties (Sox2, Myc, Oct3/4 and Nanog), neuroendocrine differentiation (Sox 9, HIF-1α and FoxA2) and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network, minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non-tumorigenic LNCaP cells to express RANKL, c-Met/activated c-Met, while downregulating AR expression. These initially non-tumorigenic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK-RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic cells.