8 results on '"Hongju Deng"'
Search Results
2. The bisphosphonate zoledronic acid decreases tumor growth in bone in mice with defective osteoclasts
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Zhiqiang Xu, Angela C. Hirbe, Anthony J. Apicelli, Anke J. Roelofs, Katherine N. Weilbaecher, Julie L. Prior, Michael J. Rogers, Mark C. Eagleton, David Piwnica-Worms, Stephanie N. Becker, Desiree H. Floyd, Hongju Deng, and Lisa G. Lanigan
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medicine.medical_specialty ,Histology ,Cell Survival ,Physiology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Protein Prenylation ,Osteoclasts ,Bone Neoplasms ,Mice, Transgenic ,Zoledronic Acid ,Article ,Mice ,Biphosphonate ,Osteoclast ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Neoplasm Metastasis ,Tartrate-resistant acid phosphatase ,Diphosphonates ,biology ,business.industry ,Imidazoles ,Bone metastasis ,Geranyltranstransferase ,Bisphosphonate ,medicine.disease ,Enzyme Activation ,Mice, Inbred C57BL ,Zoledronic acid ,medicine.anatomical_structure ,Endocrinology ,RANKL ,biology.protein ,Cancer research ,Protein prenylation ,business ,medicine.drug - Abstract
Bisphosphonates (BPs), bone targeted drugs that disrupt osteoclast function, are routinely used to treat complications of bone metastasis. Studies in preclinical models of cancer have shown that BPs reduce skeletal tumor burden and increase survival. Similarly, we observed in the present study that administration of the Nitrogen-containing BP (N-BP), zoledronic acid (ZA) to osteolytic tumor-bearing Tax+ mice beginning at 6 months of age led to resolution of radiographic skeletal lesions. N-BPs inhibit farnesyl diphosphate (FPP) synthase, thereby inhibiting protein prenylation and causing cellular toxicity. We found that ZA decreased Tax+ tumor and B16 melanoma viability and caused the accumulation of unprenylated Rap1a proteins in vitro. However, it is presently unclear whether N-BPs exert anti-tumor effects in bone independent of inhibition of osteoclast (OC) function in vivo. Therefore, we evaluated the impact of treatment with ZA on B16 melanoma bone tumor burden in irradiated mice transplanted with splenic cells from src(-/-) mice, which have non-functioning OCs. OC-defective mice treated with ZA demonstrated a significant 88% decrease in tumor growth in bone compared to vehicle-treated OC-defective mice. These data support an osteoclast-independent role for N-BP therapy in bone metastasis.
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- 2009
3. Interferon-γ Targets Cancer Cells and Osteoclasts to Prevent Tumor-associated Bone Loss and Bone Metastases
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Wessel P. Dirksen, Andrew Berdy, Özge Uluçkan, Sherry Shu, Thomas J. Rosol, Desiree H. Floyd, Michelle A. Hurchla, Emanuela Heller, Mark C. Eagleton, Fang Bu, Soledad Fernandez, Zhiqiang Xu, Yuetsu Tanaka, Hongju Deng, and Katherine N. Weilbaecher
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Osteolysis ,T cell ,Osteoclasts ,Bone Neoplasms ,Soft Tissue Neoplasms ,Biochemistry ,Bone resorption ,Interferon-gamma ,Mice ,Molecular Basis of Cell and Developmental Biology ,Osteoclast ,medicine ,Animals ,Humans ,Interferon gamma ,Bone Resorption ,Neoplasm Metastasis ,Progenitor cell ,Molecular Biology ,Mice, Knockout ,Human T-lymphotropic virus 1 ,Chemistry ,Gene Products, tax ,Cell Biology ,medicine.disease ,medicine.anatomical_structure ,Apoptosis ,Cancer cell ,Immunology ,Hypercalcemia ,Cancer research ,medicine.drug - Abstract
Interferon-gamma (IFN-gamma) has been shown to enhance anti-tumor immunity and inhibit the formation of bone-resorbing osteoclasts. We evaluated the role of IFN-gamma in bone metastases, tumor-associated bone destruction, and hypercalcemia in human T cell lymphotrophic virus type 1-Tax transgenic mice. Compared with Tax(+)IFN-gamma(+/+) mice, Tax(+)IFN-gamma(-/-) mice developed increased osteolytic bone lesions and soft tissue tumors, as well as increased osteoclast formation and activity. In vivo administration of IFN-gamma to tumor-bearing Tax(+)IFN-gamma(-/-) mice prevented new tumor development and resulted in decreased bromodeoxyuridine uptake by established tumors. In vitro, IFN-gamma directly decreased the viability of Tax(+) tumor cells through inhibition of proliferation, suppression of ERK phosphorylation, and induction of apoptosis and caspase 3 cleavage. IFN-gamma also inhibited macrophage colonystimulating factor-mediated proliferation and survival of osteoclast progenitors in vitro. Administration of IFN-gamma to C57BL/6 mice decreased Tax(+) tumor growth and prevented tumor-associated bone loss and hypercalcemia. In contrast, IFN-gamma treatment failed to protect IFN-gammaR1(-/-) mice from Tax(+) tumor-induced skeletal complications, despite decreasing tumor growth. These data demonstrate that IFN-gamma suppressed tumor-induced bone loss and hypercalcemia in Tax(+) mice by inhibiting both Tax(+) tumor cell growth and host-induced osteolysis. These data suggest a protective role for IFN-gamma in patients with bone metastases and hypercalcemia of malignancy.
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- 2009
4. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment
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Jochen G. Schneider, Sara Chen, Xinming Su, Leah Goldberg, Marcos Vidal, Emanuela Heller, Jingyu Xiang, Michelle A. Hurchla, Hongju Deng, Fanxin Long, Julie L. Prior, Mary C. Hornick, David Piwnica-Worms, Kyu Sang Joeng, Ross L. Cagan, and Katherine N. Weilbaecher
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Patched ,Patched Receptors ,Cancer Research ,medicine.medical_specialty ,Heterozygote ,Stromal cell ,Mice, Nude ,Osteoclasts ,Bone Neoplasms ,Receptors, Cell Surface ,Biology ,Bone and Bones ,Article ,Cell Line ,Receptors, G-Protein-Coupled ,Paracrine signalling ,Mice ,Osteoclast ,Internal medicine ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Hedgehog Proteins ,Tumor microenvironment ,Mice, Inbred BALB C ,Veratrum Alkaloids ,Neoplasms, Experimental ,Smoothened Receptor ,Hedgehog signaling pathway ,Patched-1 Receptor ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Cancer research ,Female ,Smoothened ,Signal Transduction - Abstract
Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1+/−) increased bone resorption, suggesting direct regulation of osteoclast (OC) activity by the Hh pathway. Ptch1+/− mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable SMO antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases. Cancer Res; 72(4); 897–907. ©2011 AACR.
- Published
- 2011
5. Targeting the alphavbeta3 integrin for small-animal PET/CT of osteolytic bone metastases
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Thaddeus J. Wadas, Carolyn J. Anderson, Alexander Zheleznyak, Katherine N. Weilbaecher, Hongju Deng, and Jennifer E. Sprague
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Tail ,Pathology ,medicine.medical_specialty ,Osteolysis ,Leukemia, T-Cell ,medicine.medical_treatment ,H&E stain ,Osteoclasts ,Standardized uptake value ,Bone Neoplasms ,Article ,Metastasis ,Diagnosis, Differential ,Mice ,Osteoclast ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Receptors, Vitronectin ,Diphosphonates ,business.industry ,Gene Products, tax ,Bisphosphonate ,medicine.disease ,Spine ,Gene Expression Regulation, Neoplastic ,Leukemia ,medicine.anatomical_structure ,Zoledronic acid ,Treatment Outcome ,Copper Radioisotopes ,Positron-Emission Tomography ,business ,Multiple Myeloma ,Tomography, X-Ray Computed ,Oligopeptides ,medicine.drug - Abstract
This article describes the evaluation of the radiopharmaceutical (64)Cu-CB-TE2A-c(RGDyK) ((64)Cu-RGD) as an imaging agent for osteolytic bone metastases and their associated inflammation by targeting of the alpha(v)beta(3) integrin on osteoclasts and the proinflammatory cells involved at the bone metastatic site.The (64)Cu-RGD radiotracer was evaluated in the transgenic mouse expressing Tax (Tax(+)), which spontaneously develops osteolytic tumors throughout the vertebrae and hind limbs, using biodistribution studies and small-animal PET/CT. Histologic analysis was also performed on Tax(+) mouse tails, using hematoxylin and eosin and tartrate-resistant acid phosphatase to confirm the presence of osteolytic bone lesions and the presence of osteoclasts, respectively. Additionally, a proof-of-principle study was conducted with a small group of Tax(+) animals presenting with osteolytic lesions. These animals were treated with the bisphosphonate zoledronic acid and imaged with (64)Cu-RGD to determine whether this radiopharmaceutical was sensitive enough to detect a response to the bisphosphonate therapy.Biodistribution studies using (64)Cu-RGD demonstrated that Tax(+) mice between the ages of 6 and 12 mo had a greater accumulation of activity in their tail vertebrae than did the wild-type (WT) cohort (P = 0.013). Additionally, Tax(+) mice between the ages of 6 and 12 mo had significantly more tracer activity associated with their tail vertebrae than did Tax(+) mice older than 12 mo (P = 0.003), suggesting that earlier bone metastases cause an increased recruitment of alpha(v)beta(3)-expressing cells. Small-animal PET/CT with (64)Cu-RGD was conducted on Tax(+) and WT mice. On the basis of standardized uptake value analysis, Tax(+) mice had approximately 2-fold more tail-associated activity than did WT animals (P = 0.0157). Additionally, decreases in uptake were observed in the tails of Tax(+) mice after treatment with the osteoclast inhibitor zoledronic acid, and histologic analysis of Tax(+) mouse-tail vertebrae revealed the presence of Tax(+) tumor cells, osteoclasts, and proinflammatory cells within the bone microenvironment.Together, these data suggest that (64)Cu-RGD has the potential to effectively image osteolytic bone metastases and monitor the physiologic changes in the bone metastatic microenvironment after osteoclast-inhibiting bisphosphonate therapy.
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- 2009
6. CD47 regulates bone mass and tumor metastasis to bone
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William A. Frazier, Wei Zou, David Piwnica-Worms, Stephanie N. Becker, Özge Uluçkan, Katherine N. Weilbaecher, Julie L. Prior, and Hongju Deng
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musculoskeletal diseases ,Male ,Cancer Research ,Cellular differentiation ,Melanoma, Experimental ,Osteoclasts ,Bone Neoplasms ,CD47 Antigen ,Mice, Transgenic ,Biology ,Article ,Metastasis ,Mice ,Osteoclast ,medicine ,Animals ,Humans ,CD47 ,Macrophages ,RANK Ligand ,Integrin beta3 ,Bone metastasis ,Cell Differentiation ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Oncology ,RANKL ,Cancer research ,biology.protein ,Bone marrow ,Nitric Oxide Synthase - Abstract
CD47, also called integrin-associated protein, plays a critical role in the innate immune response and is an atypical member of the immunoglobulin superfamily that interacts with and activates β3 integrins. β3 integrin−/− mice have defective platelet and osteoclast function and are protected from bone metastasis. The role of CD47 in skeletal homeostasis and bone metastasis has not been described. CD47−/− mice had increased bone mass and defective osteoclast function in vivo. Although the number of functional osteoclasts formed by differentiating CD47−/− bone marrow macrophages was decreased, high doses of RANKL rescued differentiation and function of CD47−/− osteoclasts ex vivo and rescued the osteoclast defect in CD47−/− mice. Inhibition of nitric oxide (NO) synthase, which is expressed at higher levels in CD47−/− osteoclasts, also rescued the osteoclast defect in CD47−/− cells. We then examined the consequences of this osteoclast defect in bone metastasis. In a model of tumor metastasis to bone, bone tumor burden was decreased in the CD47−/− mice compared with wild-type (WT) controls, with no decrease in s.c. tumor growth in CD47−/− mice. There was decreased tumor-associated bone destruction in the CD47−/− mice compared with WT controls, consistent with a defect in osteoclast function that was not rescued by the presence of tumor. Our data show that CD47 regulates osteoclastogenesis, in part, via regulation of NO production, and its disruption leads to a decrease in tumor bone metastasis. CD47 is a novel therapeutic target to strengthen bone mass and diminish metastatic tumor growth in bone. [Cancer Res 2009;69(7):3196–204]
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- 2009
7. HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by osteoclast inhibition
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Katherine N. Weilbaecher, Lee Ratner, Angela C. Hirbe, Ling Gao, John C. S. Harding, Hongju Deng, and Haibo Zhao
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musculoskeletal diseases ,Bone disease ,Large granular lymphocytic leukemia ,Immunology ,Organophosphonates ,Osteoclasts ,Bone Neoplasms ,Mice, Transgenic ,Biochemistry ,Metastasis ,Mice ,Osteoprotegerin ,Osteoclast ,Bone Density ,Medicine ,Animals ,Lymphocytes ,Cells, Cultured ,Human T-lymphotropic virus 1 ,Lymphokines ,Neoplasia ,business.industry ,Interleukin-6 ,Bone metastasis ,Cell Biology ,Hematology ,Gene Products, tax ,medicine.disease ,Lymphoma ,Leukemia ,medicine.anatomical_structure ,Gene Expression Regulation ,Hypercalcemia ,business - Abstract
One in 20 carriers of human T-cell leukemia virus type 1 (HTLV-1) will develop adult T-cell leukemia/lymphoma (ATL), a disease frequently associated with hypercalcemia, bone destruction, and a fatal course refractory to current therapies. Overexpression of the HTLV-1–encoded Tax oncoprotein under the human granzyme B promoter causes large granular lymphocytic leukemia/lymphomas in mice. We found that Tax+ mice spontaneously developed hypercalcemia, high-frequency osteolytic bone metastases, and enhanced osteoclast activity. We evaluated Tax tumors for the production of osteoclast-activating factors. Purification of Tax+ tumor cells and nonmalignant tumor-infiltrating lymphocytes demonstrated that each of these populations expressed transcripts for distinct osteoclast-activating factors. We then evaluated the effect of osteoclast inhibition on tumor formation. Mice doubly transgenic for Tax and the osteoclast inhibitory factor, osteoprotegerin, were protected from osteolytic bone disease and developed fewer soft-tissue tumors. Likewise, osteoclast inhibition with bone-targeted zoledronic acid protected Tax+ mice from bone and soft-tissue tumors and prolonged survival. Tax+ mice represent the first animal model of high-penetrance spontaneous osteolytic bone metastasis and underscore the critical role of nonmalignant host cells recruited by tumor cells in the process of cancer progression and metastasis.
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- 2005
8. The ARF Tumor Suppressor Regulates Bone Remodeling and Osteosarcoma Development in Mice
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Jason D. Weber, Katherine N. Weilbaecher, Thomas J. Rosol, Daniel Rauch, David Piwnica-Worms, Stefan Niewiesk, Michael Dale Lairmore, Lee Ratner, John C. S. Harding, Michelle A. Hurchla, Lauren Shea, Mark C. Eagleton, and Hongju Deng
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Anatomy and Physiology ,Mouse ,Tumor Physiology ,medicine.medical_treatment ,lcsh:Medicine ,Osteoclasts ,Zoledronic Acid ,Bone remodeling ,Mice ,0302 clinical medicine ,Molecular Cell Biology ,Basic Cancer Research ,Bone and Soft Tissue Sarcomas ,Tumor Suppressor Protein p14ARF ,lcsh:Science ,Musculoskeletal System ,Osteosarcoma ,0303 health sciences ,Multidisciplinary ,Diphosphonates ,Cancer Risk Factors ,Imidazoles ,Osteoblast ,Animal Models ,Gene Products, tax ,Primary tumor ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Bone Remodeling ,Cellular Types ,Cancer Prevention ,Research Article ,Heterozygote ,medicine.medical_specialty ,Transgene ,Bone Marrow Cells ,Mice, Transgenic ,Biology ,Predisposing Conditions and Syndromes ,03 medical and health sciences ,Model Organisms ,Osteoclast ,Internal medicine ,medicine ,Animals ,Bone ,030304 developmental biology ,Osteoblasts ,Models, Genetic ,Oncogene ,lcsh:R ,Carcinoma ,Cancers and Neoplasms ,Bisphosphonate ,Genes, p53 ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,Cancer research ,lcsh:Q ,Tumor Suppressor Protein p53 - Abstract
The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf(-/-) mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf(-/-) mice had increased expression of OB genes while Arf(-/-) OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf(-/-) mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf(-/-) tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf(+/-) mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf(-/-) mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS.
- Published
- 2010
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