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Abraham Schneider

Publications and source records attributed to Abraham Schneider.

10 recordsLinked to original sources
PubMed2006

Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis.

Prostate cancer almost exclusively metastasizes to skeletal sites, indicating that the bone provides a favorable microenvironment for its localization and progression. A natural yet understudied factor in bone that could facilitate tumor localization is elevated extracellular calcium ([Ca2+]o). The present study found that elevated [Ca2+]o (2.5 mmol/L) enhanced proliferation of skeletal metastatic prostate cell lines (PC-3 and C4-2B), but not the nonskeletal metastatic, epithelial-derived prostate cell line LNCaP. The proliferative effect of elevated [Ca2+]o was associated with higher expression of the calcium-sensing receptor (CaSR), a heterotrimeric G-protein-coupled receptor that is the predominant cell-surface sensor for [Ca2+]o. Knockdown of the CaSR via RNA interference reduced cell proliferation in vitro and metastatic progression in vivo. CaSR signaling in PC-3 cells was evaluated by measuring the elevated [Ca2+]o-dependent inhibition of cyclic AMP accumulation, induced by either prostaglandin E2 or forskolin. Elevated [Ca2+]o stabilized expression of cyclin D1, a protein required for cell cycle transition. Furthermore, elevated [Ca2+]o triggered activation of the Akt signaling pathway and enhanced PC-3 cell attachment. Both pertussis toxin (a G-protein inhibitor) and LY294002 (an inhibitor of Akt signaling) reduced cell attachment. These data suggest that elevated [Ca2+]o following increased bone remodeling could facilitate metastatic localization of prostate cancer via the CaSR and the Akt signaling pathway. Taken together, [Ca2+]o is a candidate mediator of prostate cancer bone metastasis.

Bone Neoplasms↗
PubMed2006

Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors.

PURPOSE: To describe the clinical, radiologic, and pathologic features and risk factors for osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients. PATIENTS AND METHODS: A retrospective review of 90 MM patients who had dental assessments, including 22 patients with ONJ. There were 62 men; the median age was 61 years in ONJ patients and 58 years among the rest. Prior MM therapy included thalidomide (n = 67) and stem-cell transplantation (n = 72). Bisphosphonate therapy included zoledronate (n = 34) or pamidronate (n = 17) and pamidronate followed by zoledronate (n = 33). Twenty-seven patients had recent dental extraction, including 12 patients in the ONJ group. Median time from MM diagnosis to ONJ was 8.4 years for the whole group. RESULTS: Patients usually presented with pain. ONJ occurred posterior to the cuspids (n = 20) mostly in the mandible. Debridement and sequestrectomy with primary closure were performed in 14 patients; of these, four patients had major infections and four patients had recurrent ONJ. Bone histology revealed necrosis and osteomyelitis. Microbiology showed actinomycetes (n = 7) and mixed bacteria (n = 9). More than a third of ONJ patients also suffered from long bone fractures (n = 4) and/or avascular necrosis of the hip (n = 4). The variables predictive of developing ONJ were dental extraction (P = .009), treatment with pamidronate/zoledronate (P = .009), longer follow-up time (P = .03), and older age at diagnosis of MM (P = .006). CONCLUSION: ONJ appears to be time-dependent with higher risk after long-term use of bisphosphonates in older MM patients often after dental extractions. No satisfactory therapy is currently available. Trials addressing the benefits/risks of continuing bisphosphonate therapy are needed.

Adult↗
PubMed2005

Bone turnover mediates preferential localization of prostate cancer in the skeleton.

Bone metastasis is a common untreatable complication associated with prostate cancer. Metastatic cells seed in skeletal sites under active turnover containing dense marrow cellularity. We hypothesized that differences in these skeletal-specific processes are among the critical factors that facilitate the preferential localization of metastatic prostate cancer in bone. To test this, athymic mice were administered PTH to induce bone turnover and increase marrow cellularity daily 1 wk before and after intracardiac inoculation of luciferase-tagged PC-3 cells. Tumor localization was monitored by bioluminescence imaging weekly for 5 wk. At the time of tumor inoculation, PTH-treated mice demonstrated significant increases in serum levels of bone turnover markers such as osteocalcin and tartrate-resistant acid phosphatase 5b and in the number of tartrate-resistant acid phosphatase-positive osteoclasts per millimeter of bone when compared with the other groups. Likewise, PTH treatment stimulated a qualitative increase in marrow cellular proliferation as determined by 5-bromo-2'-deoxyuridine immunostaining. Skeletal metastases formed in the hind limb and craniofacial regions of young mice with no difference between groups. In adult mice, however, bioluminescent signals in the hind limb and craniofacial regions were 3-fold higher in PTH-treated mice vs. controls. Fluorochrome labeling revealed increased bone formation activity in trabecular bone adjacent to tumors. When zoledronic acid, a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, was administered concurrently with PTH, a significant reduction in the incidence of bone tumors was observed. Overall, these studies provide new evidence that skeletal sites rich in marrow cellularity under active turnover offer a more congenial microenvironment to facilitate cancer localization in the skeleton.

Acid Phosphatase↗
PubMed2005

Anabolic actions of PTH (1-34): use of a novel tissue engineering model to investigate temporal effects on bone.

PTH is in clinical use for the treatment of osteoporosis and is under intensive investigation for its potential in applications of tissue engineering, fracture healing, and implant integration. However, the mechanisms of its action to stimulate bone formation are still unclear. A novel bone tissue engineering model was used to elucidate basic mechanisms of PTH anabolic actions. Ectopic ossicles containing cortical bone, trabecular bone, and a hematopoietic marrow were generated from implanted bone marrow stromal cells (BMSC). One week after implantation, nude mice were administered PTH or vehicle for 1 week (group 1), 3 weeks (group 2), or 7 weeks (group 3). Another group was also treated for 3 weeks, initiated 12 weeks after implantation (group 4). Micro-radiography and histomorphometry revealed increased marrow cellularity in group 1 PTH-treated ossicles, increased bone in group 2 PTH-treated ossicles, and similar amounts of bone in both group 3 and 4 ossicles regardless of treatment. Incidence of phosphate mineral and phosphate mineral to hydroxyproline ratio via Raman spectroscopy were significantly higher after 3 weeks versus 1 week of PTH treatment, but there was no difference between PTH- and vehicle-treated ossicles. Early events of PTH action in group 1 ossicles and the effects of a single injection of PTH on 1- and 2-week-old ossicles were evaluated by Northern blot analysis. Osteocalcin (OC) mRNA was increased after 1 week of intermittent PTH treatment in ossicles and calvaria but an acute injection did not alter OC mRNA. In contrast, a single injection of PTH increased matrix gamma-carboxyglutamic acid protein (MGP) mRNA in 2-week-old ossicles. Differential and temporal-dependent effects of PTH on OC and MGP suggest at the molecular level, that PTH acts to inhibit osteoblast mineralization. However, this does not translate into tissue level alterations. These data indicate that anabolic actions of PTH in ectopic ossicles are temporally dependent on the BMSC implanted and suggest that cell implantation strategies are particularly responsive to PTH.

Adipocytes↗
PubMed2004

Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo.

UNLABELLED: To delineate the role of SDF-1 and CXCR4 in metastatic prostate cancer (CaP), positive correlations were established between SDF-1 levels and tumor metastasis. Neutralization of CXCR4 limited the number and the growth of intraosseous metastasis in vivo. Together, these in vivo metastasis data provide critical support that SDF-1/CXCR4 plays a role in skeletal metastasis. INTRODUCTION: Previously we determined that the stromal-derived factor-1 (SDF-1)/CXCR4 chemokine axis is activated in prostate cancer (CaP) metastasis to bone. To delineate the role of SDF-1/CXCR4 in CaP, we evaluated SDF-1 levels in a variety of tissues and whether neutralization of SDF-1 prevented metastasis and/or intraosseous growth of CaPs. MATERIALS AND METHODS: SDF-1 levels were established in various mouse tissues by ELISA, immunohistochemistry, and in situ hybridization. To assess the role of SDF-1/CXCR4 in metastasis, bone metastases were established by administering CaP cells into the left cardiac ventricle of nude animals in the presence or absence of neutralizing CXCR4 antibody. The effect of SDF-1 on intraosseous growth of CaP cells was determined using intratibial injections and anti-CXCR4 antibodies and peptides. RESULTS: There was a positive correlation between the levels of SDF-1 and tissues in which metastatic CaP lesions were observed. SDF-1 levels were highest in the pelvis, tibia, femur, liver, and adrenal/kidneys compared with the lungs, tongue, and eye, suggesting a selective effect. SDF-1 staining was generally low or undetectable in the center of the marrow and in the diaphysis. SDF-1 mRNA was localized to the metaphysis of the long bones nearest to the growth plate where intense expression was observed near the endosteal surfaces covered by osteoblastic and lining cells. Antibody to CXCR4 significantly reduced the total metastatic load compared with IgG control-treated animals. Direct intratibial injection of tumor cells followed by neutralizing CXCR4 antibody or a specific peptide that blocks CXCR4 also decreased the size of the tumors compared with controls. CONCLUSIONS: These data provide critical support for a role of SDF-1/CXCR4 in skeletal metastasis. Importantly, these data show that SDF-1/CXCR4 participate in localizing tumors to the bone marrow for prostate cancer.

Amino Acids↗
PubMed2004

Animal models of bone metastasis.

Animal models will continue to be indispensable to investigate the pathogenesis of bone metastasis in vivo, conduct preclinical chemotherapeutic, chemoprevention and genetic therapy studies, test gene delivery mechanisms, and identify metastasis suppressor and inducer genes. It is likely that the bone marrow microenvironment, such as the endothelial cells, stromal cells, hematopoietic cells, bone cells, and the intercellular matrix play important roles in the localization and clonal growth of cancer cells in bone. Given the complexity of bone metastasis, many genes are expected to be involved in the pathogenesis and few are likely indispensable. The use of genomic and proteomic approaches to study these animal models will identify key targets for therapeutic intervention. As we further refine these models and use imaging for real-time evaluation of cells, and eventually target genes, these models will more closely mirror human disease and will hopefully become more predictive of the human response to therapy.

Bone Neoplasms↗
PubMed2003

Skeletal homeostasis in tissue-engineered bone.

Tissue-engineering strategies to stimulate bone regeneration may offer an alternative approach to conventional orthopaedic and maxillofacial surgical therapies. Over the last decade, significant advances have been accomplished in developing biomimetic matrices, growth factors, cell transplantation and gene delivery therapeutics to support new bone growth. However, it is not known if tissue-engineered bone recapitulates the biology of normal skeletal tissue in response to physiologic cues. Here, we report that bone formed by the differentiation of transplanted murine bone marrow stromal cells (BMSCs) responds to a systemically delivered calciotropic hormone. Ectopic ossicles in mice exposed to catabolic doses of parathyroid hormone (PTH) had increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts as compared to control mice. In contrast, treatment with anabolic doses of PTH promoted a marked increase in trabecular bone mass as analyzed by microcomputed tomography and histomorphometry. Our findings demonstrate that bone formed from transplanted BMSCs is responsive to normal physiologic signals, and can be augmented by the addition of a systemic anabolic agent. Because multiple and distinct ossicles can be generated in a single animal, this versatile system may be used to: (a) elucidate cellular/molecular mechanisms in bone regeneration; (b) study cell-to-cell interactions in the bone marrow microenvironment in health and disease; and (c) evaluate the efficacy of osteotropic agents that modulate bone turnover in vivo.

Acid Phosphatase↗
PubMed2002

Parathyroid hormone and parathyroid hormone-related protein exert both pro- and anti-apoptotic effects in mesenchymal cells.

During bone formation, multipotential mesenchymal cells proliferate and differentiate into osteoblasts, and subsequently many die because of apoptosis. Evidence suggests that the receptor for parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), the PTH-1 receptor (PTH-1R), plays an important role in this process. Multipotential mesenchymal cells (C3H10T1/2) transfected with normal or mutant PTH-1Rs and MC3T3-E1 osteoblastic cells were used to explore the roles of PTH, PTHrP, and the PTH-1R in cell viability relative to osteoblastic differentiation. Overexpression of wild-type PTH-1R increased cell numbers and promoted osteocalcin gene expression versus inactivated mutant receptors. Furthermore, the effects of PTH and PTHrP on apoptosis were dramatically dependent on cell status. In preconfluent C3H10T1/2 and MC3T3-E1 cells, PTH and PTHrP protected against dexamethasone-induced reduction in cell viability, which was dependent on cAMP activation. Conversely, PTH and PTHrP resulted in reduced cell viability in postconfluent cells, which was also dependent on cAMP activation. Further, the proapoptotic-like effects were associated with an inhibition of Akt phosphorylation. These data suggest that parathyroid hormones accelerate turnover of osteoblasts by promoting cell viability early and promoting cell departure from the differentiation program later in their developmental scheme. Both of these actions occur at least in part via the protein kinase A pathway.

3T3 Cells↗
PubMedDate not supplied

In vivo visualization of metastatic prostate cancer and quantitation of disease progression in immunocompromised mice.

While survival periods for patients with localized prostate cancer have increased, there is still no curative therapy for metastatic disease. Using non-invasive bioluminescent imaging, we designed a comprehensive murine model to monitor tumor location and expansion. We detected micrometastases after one week that correlated by gross necropsy, autoradiography, and histopathology with organ and skeletal lesions seen clinically. We calculated in vivo kinetics for tumor growth based on biophoton emissions and observed significantly faster growth of bone lesions and of overall tumor burden in young mice compared to old mice. This model provides a controllable biological system for further investigation into the pathogenesis of metastatic prostate cancer and evaluation of new therapies.

Animals↗