Osteolytic Tumor Research Articles

Simultaneous C-arm Computed Tomography-Guided Microwave Ablation and Cementoplasty in Patients with Painful Osteolytic Bone Metastases: A Single-center Experience

To evaluate the clinical benefit of simultaneous percutaneous microwave ablation (PMA) and percutaneous cementoplasty (PC) for patients with painful osteolytic bone metastases under flat-detector C-arm computed tomography (CACT). Thirty patients (17 men and 13 women) with 42 osteolytic metastatic tumors were prospectively treated with PMA and PC simultaneously under CACT guidance. Technical success, major complications, local tumor control status, and daily morphine consumption were recorded. Visual analog scale, Oswestry disability index, and the short-form 36 questionnaire (SF-36, 8 domains) were used to evaluate pain, functional status, and quality of life (QoL), respectively. The technical success rate was 100% without major complications, and local tumor control rates were 100% and 75% for lesion diameter ≤3 cm and >3 cm, respectively. Daily morphine consumption, visual analog scale, and Oswestry disability index improved significantly from the respective pretreatment values of 75 mg, 7.4, and 59.2 to 17.3 mg, 1.7, and 22.9 at 1 week; 8.5 mg, 1.4, and 6.7 at 4 weeks; and 5.3 mg, 1.3, and 9.2 at 12 weeks, respectively (p< 0.01). The QoL assessments at 4 weeks showed significant improvements in physical function, role physical, bodily pain, general health and vitality (p < 0.05). Simultaneous PMA and PC under CACT guidance is effective to control pain and improve QoL in selective patients with painful osteolytic bone metastases.

DIFFERENTIAL DIAGNOSIS OF ODONTOGENIC KERATOCYST: A CASE REPORT

Cystic or neoplastic intraosseous pathologic entities that make a differential diagnosis with odontogenic keratocyst (OKC) share similar clinical characteristics and present as painless volume increase with facial asymmetry, with the mandible being the major site of involvement. Called osteolytic lesions (OL), they have similar radiographic patterns, being radiolucent or hypodense, unilocular or multilocular. The purpose of this paper is to describe the case of a 30-year-old male patient who presented painless volume increase located in the left mandibular region and facial asymmetry with 9 months of evolution. Radiographically, an extensive multilocular radiolucent lesion was observed, without root resorption and dental displacement. A CT scan confirmed the presence of osteolytic tumor with hypodense areas and rupture of the cortical bone. Biopsy confirmed the diagnosis of OKC. In this case, the clinical-behavioral characteristics of the OKC are presented to differentiate it from other OL.

Establishment and characterization of NCC-GCTB1-C1: a novel patient-derived cancer cell line of giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a rare osteolytic bone tumor, accounting for approximately 5% of all primary bone tumors. GCTB is characterized by unique giant cells. It is also characterized by recurrent mutations in the histone tail of the histone variant H3.3, H3F3A, on chromosome 1, therapeutic implications of which have not been established yet. There are few effective standardized treatments for GCTB, and a novel therapy has long been required. Patient-derived cancer cells have facilitated the understanding of mechanisms underlying the etiology and progression of multiple cancers. Thus far, only 10 GCTB cell lines have been reported, and none of them are publicly available. The aim of this study was to develop an accessible patient-derived cell line of GCTB, which could be used as a screening tool for drug development. Here, we describe the establishment of a cell line, designated NCC-GCTB1-C1, from the primary tumor tissue of a male patient with GCTB on the right distal radius. NCC-GCTB1-C1 cells were maintained as a monolayer culture for over 23 passages for 7months. These cells exhibited continuous growth, as well as spheroid formation and invasive ability. Using an oncology agent screen, we tested the effect of anticancer drugs on the proliferation of NCC-GCTB1-C1 cells. The cells displayed a remarkable response to romidepsin and vincristine. Thus, we established a novel GCTB cell line, NCC-GCTB1-C1, which could be a useful tool for studying GCTB tumorigenesis and the efficacy of anticancer drugs.

Bisphosphonate-functionalized micelles for targeted delivery of curcumin to metastatic bone cancer

Metastatic (secondary) bone cancer is one of the major causes of death in patients with advanced cancer. A lack of options for the targeted delivery of a desired therapeutic payload to multiple tumour modules located in the bone is still one of the foremost hurdles in the treatment/prevention of metastatic bone cancer. Curcumin has a proven anticancer potential with known challenges for application as a pharmaceutical agent. We have previously shown that micellar formulations could overcome some of these challenges and enhances its anti-cancer activity. In this study, we have developed a targeted drug delivery system using bisphosphonate (alendronate) conjugated Pluronic F127 micelles that could efficiently target, and specifically deliver curcumin to the osteolytic tumour microenvironment in the bone. Characterization of the formulation of curcumin-encapsulated alendronate-conjugated micelles demonstrated that the micelles have nanoscale size (∼27 nm) with a positive surface charge (+2.87 mV) and 4% drug loading. The alendronate-conjugated micelles showed significant bone-targeting potential. Rapid binding of the micelles to hydroxyapatite surface suggested that these nanoparticles are promising carriers for effective and targeted delivery of curcumin to osteolytic tumours in the bone.

Aggressive lytic lesion of lesser trochanter proximal femur in an eighteen year old male - A case report

Aneurysmal bone cyst (ABC) is an osteolytic benign tumour, which is usually situated in the metaphysis of long bones and mostly encountered in patients younger than 20 years old. Common treatment modalities include arterial embolization, curettage, intralesional injections and en-bloc resection with instrumentation. We present a case of an eighteen-year old male with an ABC involving lesser trochanter of left femur with impending pathological proximal femur fracture. We discuss treatment modalities and clinical outcome in our case. Keywords: Aneurysmal bone cyst, Expansile lytic cyst, Lesser trochanter tumour, Proximal femur.

Osteoclast Signal Transduction During Bone Metastasis Formation.

Osteoclasts are myeloid lineage-derived bone-resorbing cells of hematopoietic origin. They differentiate from myeloid precursors through a complex regulation process where the differentiation of preosteoclasts is followed by intercellular fusion to generate large multinucleated cells. Under physiological conditions, osteoclastogenesis is primarily directed by interactions between CSF-1R and macrophage colony-stimulating factor (M-CSF, CSF-1), receptor activator of nuclear factor NF-κB (RANK) and RANK ligand (RANKL), as well as adhesion receptors (e.g., integrins) and their ligands. Osteoclasts play a central role in physiological and pathological bone resorption and are also required for excessive bone loss during osteoporosis, inflammatory bone and joint diseases (such as rheumatoid arthritis) and cancer cell-induced osteolysis. Due to the major role of osteoclasts in these diseases the better understanding of their intracellular signaling pathways can lead to the identification of potential novel therapeutic targets. Non-receptor tyrosine kinases and lipid kinases play major roles in osteoclasts and small-molecule kinase inhibitors are emerging new therapeutics in diseases with pathological bone loss. During the last few years, we and others have shown that certain lipid (such as phosphoinositide 3-kinases PI3Kβ and PI3Kδ) and tyrosine (Src−family and Syk) kinases play a critical role in osteoclast differentiation and function in humans and mice. Some of these signaling pathways shows similarity to immunoreceptor-like receptor signaling and involves important other enzymes (e.g., PLCγ2) and adapter proteins (such as the ITAM−bearing adapters DAP12 and the Fc-receptor γ-chain). Here, we review recently identified osteoclast signaling pathways and their role in osteoclast differentiation and function as well as pathological bone loss associated with osteolytic tumors of the bone. A better understanding of osteoclast signaling may facilitate the design of novel and more efficient therapies for pathological bone resorption and osteolytic skeletal metastasis formation.

Generative approach for data augmentation for deep learning-based bone surface segmentation from ultrasound images.

Precise localization of cystic bone lesions is crucial for osteolytic bone tumor surgery. Recently, there is a move toward ultrasound imaging over plain radiographs (X-rays) for intra-operative navigation due to the radiation-free and cost-effectiveness of the modality. In this process, the intra-operative bone model reconstructed from the segmented ultrasound image is registered with the pre-operative bone model. Deep learning approaches have recently shown remarkable success in bone surface segmentation from ultrasound images. However, to train deep learning models effectively with limited dataset size, data augmentation is essential. This study investigates the applicability of the generative approach for data augmentation as well as identifies standard data augmentation approaches for bone surface segmentation from ultrasound images. The generative approach we used in our work is based on Pix2Pix image-to-image translation network. We have proposed a multiple-snapshot approach, which mitigates the uni-modal deterministic output issue in the Pix2Pix network without using any complex architecture and training process. We also identified standard data augmentation approaches necessary for ultrasound bone surface segmentation through experiments. We have evaluated our networks using 800 ultrasound images from trained regions (humerus bone) and 1200 ultrasound images from untrained regions (tibia and femur bones) using four different augmentation approaches. The results show that the generative augmentation approach has a positive impact on accuracy in both trained (+4.88%) and untrained regions (+25.84%) compared to using only standard augmentations. Moreover, compared to standard augmentation approaches, the addition of the generative augmentation approach also showed a similar trend in both trained (+8.74%) and untrained (+11.55%) regions. Generative approaches are very beneficial for data augmentation, where limited dataset size is prevalent, such as ultrasound bone segmentation. The proposed multiple-snapshot Pix2Pix approach has the potential to generate multimodal images, which enlarges the dataset considerably.

JZL184, A Monoacylglycerol Lipase Inhibitor, Induces Bone Loss in a Multiple Myeloma Model of Immunocompetent Mice

Multiple myeloma (MM) patients develop osteolysis characterised by excessive osteoclastic bone destruction and lack of osteoblast bone formation. Pharmacological manipulation of monoacylglycerol lipase (MAGL), an enzyme responsible for the degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG), reduced skeletal tumour burden and osteolysis associated with osteosarcoma and advanced breast and prostate cancers. MM and hematopoietic, immune and bone marrow cells express high levels of type 2 cannabinoid receptor and osteoblasts secrete 2-AG. However, the effects of MAGL manipulation on MM have not been investigated. Here, we report that treatment of pre-osteoclasts with non-cytotoxic concentrations of JZL184, a verified MAGL inhibitor, enhanced MM- and RANKL-induced osteoclast formation and size in vitro. Exposure of osteoblasts to JZL184 in the presence of MM cell-derived factors reduced osteoblast growth but had no effect on the ability of these cells to mature or form bone nodules. In vivo, administration of JZL184 induced a modest, yet significant, bone loss at both trabecular and cortical compartments of long bones of immunocompetent mice inoculated with the syngeneic 5TGM1-GFP MM cells. Notably, JZL184 failed to inhibit the in vitro growth of a panel of mouse and human MM cell lines, or reduce tumour burden in mice. Thus, MAGL inhibitors such as JZL184 can exacerbate MM-induced bone loss.

Multifocal Polyostotic Aneurysmal Bone Cyst of Pelvic Bones

Aneurysmal bone cyst (ABC) is a very rare benign osteolytic bone tumor representing less than 2% of all bone tumors and 5 to 6% of benign bone tumors. Atypical or unusual variants of ABC group together unusual clinical presentations, unusual complication, rare locations, and unusual age of occurrence, representing a real diagnostic challenge for clinicians. From all so-called unusual variants of ABC, multifocal one is particularly exceptional with only seven cases described metachronously in the world literature. We report the original case of a bifocal synchronous poly-ostotic and locally aggressive ABC involving the right ilium and the left superior pubic ramus in 19-year-old Tunisian man.

CS-01 GIANT CELL TUMOR IN THE SKULL BASE BONE TREATED WITH ANTI-RANKL INHIBITOR

Giant cell tumor of bone is a rare and osteolytic neoplasm that that usually affecting the epiphyses in long bones of the extremities. They seldom occur in the skull, preferentially affecting the sphenoid and temporal bones. Most pathologically benign, and total removal by surgery was regarded as the first treatment, however, it was very difficult in skull lesion. In 2014 the molecular targeting drug anti-RANKL inhibitor was approved in Japan. We report a case in which an anti-RANKL inhibitor was administered to a skull base bone giant cell tumor that was difficult to remove completely. A 56-year-old man with a sudden right neck pain followed by dysphoria and dysphagia was referred to our hospital. Computed tomography showed 4.4 x 2.0 cm osteolytic lesion involving the right occipital bone and occipital condyle. Magnetic resonance imaging demonstrated an extensive soft-tissue mass occupying. Surgical biopsy was performed and the pathological diagnosis was giant cell tumor. Patient received the anti-RANKL inhibitor (Denosumab®). After 4 weeks, ossification was observed, and neurological symptoms were improved after 12 weeks. Patient has been on good course for 5 years without recurrence and is still following-up.

Polymethylmethacrylate patient-matched implants (PMMA-PMI) for complex and revision cranioplasty: analysis of long-term complication rates and patient outcomes

ABSTRACTObjective: Cranioplasty (CP) is associated with high complication rates and patient-matched implants (PMI) are frequently used for CP. However, only limited data are available regarding complication rates of PMI-based CP after complex or failed primary CP. Here we report our experience with the use of polymethylmethacrylate (PMMA) PMI for this purpose.Method: We analyzed all patients with complex or failed primary CP and subsequent implantation of PMMA-PMI between 2010 and 2015 at our institution.Results: A total of 67 patients (29 females, 38 males) with a mean age of 43 years (range: 13–74 years) were included in the study. Primary PMI-CP was performed in 18 patients with destructive or osteolytic bone tumors. Secondary PMI-CP was performed in 49 patients. Complications occurred in 14 patients with an overall complication rate of 21.7% during a mean follow-up of 39.7 ± 23.4 month. Approximately two-thirds of the patients reported a good quality of life after the initial event and subsequent CP. The majority of patients (>90%) was satisfied with the cosmetic result.Conclusion: Surgical CP with PMMA-PMI appears to be a suitable method for patients with failed or complex CP. Complication rates are comparable to those reported for primary CP.

Mild hyperthermia by MR-guided focused ultrasound in an ex vivo model of osteolytic bone tumour: optimization of the spatio-temporal control of the delivered temperature

BackgroundMagnetic resonance guided focused ultrasound was suggested for the induction of deep localized hyperthermia adjuvant to radiation- or chemotherapy. In this study we are aiming to validate an experimental model for the induction of uniform temperature elevation in osteolytic bone tumours, using the natural acoustic window provided by the cortical breakthrough.Materials and methodsExperiments were conducted on ex vivo lamb shank by mimicking osteolytic bone tumours. The cortical breakthrough was exploited to induce hyperthermia inside the medullar cavity by delivering acoustic energy from a phased array HIFU transducer. MR thermometry data was acquired intra-operatory using the proton resonance frequency shift (PRFS) method. Active temperature control was achieved via a closed-loop predictive controller set at 6 °C above the baseline. Several beam geometries with respect to the cortical breakthrough were investigated. Numerical simulations were used to further explain the observed phenomena. Thermal safety of bone heating was assessed by cross-correlating MR thermometry data with the measurements from a fluoroptic temperature sensor inserted in the cortical bone.ResultsNumerical simulations and MR thermometry confirmed the feasibility of spatio-temporal uniform hyperthermia (± 0.5 °C) inside the medullar cavity using a fixed focal point sonication. This result was obtained by the combination of several factors: an optimal positioning of the focal spot in the plane of the cortical breakthrough, the direct absorption of the HIFU beam at the focal spot, the “acoustic oven effect” yielded by the beam interaction with the bone, and a predictive temperature controller. The fluoroptical sensor data revealed no heating risks for the bone and adjacent tissues and were in good agreement with the PRFS thermometry from measurable voxels adjacent to the periosteum.ConclusionTo our knowledge, this is the first study demonstrating the feasibility of MR-guided focused ultrasound hyperthermia inside the medullar cavity of bones affected by osteolytic tumours. Our results are considered a promising step for combining adjuvant mild hyperthermia to external beam radiation therapy for sustained pain relief in patients with symptomatic bone metastases.

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3.

Prostate cancer metastases primarily localize in the bone where they induce a unique osteoblastic response. Elevated Notch activity is associated with high-grade disease and metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in bone expressed 5–6 times more Notch3, than tumor cells that produce osteolytic lesions. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared to patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis. These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone metastases.

Mouse model recapitulates the phenotypic heterogeneity of human adult T-cell leukemia/lymphoma in bone

Adult T-cell leukemia/lymphoma has a unique relationship to bone including latency in the marrow, and development of bone invasion, osteolytic tumors and humoral hypercalcemia of malignancy. To study these conditions, we established and characterized a novel mouse model of ATL bone metastasis. Patient-derived ATL cell lines including three that do not express HTLV-1 oncoprotein Tax (ATL-ED, RV-ATL, TL-Om1), an in vitro transformed human T-cell line with high Tax expression (HT-1RV), and an HTLV-1 negative T-cell lymphoma (Jurkat) were injected intratibially into NSG mice, and were capable of proliferating and modifying the bone microenvironment. Radiography, μCT, histopathology, immunohistochemistry, plasma calcium concentrations, and qRT-PCR for several tumor-bone signaling mRNAs were performed. Luciferase-positive ATL-ED bone tumors allowed for in vivo imaging and visualization of bone tumor growth and metastasis over time. ATL-ED and HT-1RV cells caused mixed osteolytic/osteoblastic bone tumors, TL-Om1 cells exhibited minimal bone involvement and aggressive local invasion into the adjacent soft tissues, Jurkat cells proliferated within bone marrow and induced minimal bone cell response, and RV-ATL cells caused marked osteolysis. This mouse model revealed important mechanisms of human ATL bone neoplasms and will be useful to investigate biological interactions, potential therapeutic targets, and new bone-targeted agents for the prevention of ATL metastases to bone.

Protein Expression Profiles Corresponding to Histological Changes with Denosumab Treatment in Giant Cell Tumors of Bone.

Giant cell tumors of bone (GCTBs) are locally aggressive osteolytic bone tumors. Denosumab is a novel and effective therapeutic option for aggressive and recurrent GCTBs. Histologically, the post-denosumab-treated samples are characterized by two lesions: a residual stromal cell lesion with a few multinucleated giant cells (SL-lesion), and a fibro-osseous lesion (FO-lesion). To clarify the differences in the protein expression between the SL-lesion and FO-lesion in GCTB treated with denosumab, comparative proteomic studies are conducted using both lesions (12 pairs of pre- and post-denosumab treatment samples) by isobaric tags for relative and absolute quantification (i-TRAQ). Thirty-two consistently regulated proteins in the SL-lesions and 59 consistently regulated proteins in the FO-lesions are found. Twenty-one proteins in the SL-lesion and 48 proteins in the FO-lesion are independently expressed. These proteins may be involved in the process of the fibro-osseous reactions by denosumab treatment. In the software program used to establish these profiles, several canonical pathways are identified, including the unfolded protein response as an FO-lesion specific pathway. It is believed that the identified proteins and the results of the network analysis will provide a better understanding of the effects of denosumab in GCTB.

Abstract 2814: Systemic and local bone metastasis models for immuno-oncology drug development

Abstract Bone metastases are common and count 30-70% of metastases in breast, lung, and bladder cancer, and 80% of multiple myeloma patients have bone disease. Despite recent progress in cancer treatment, bone metastases remain incurable. Novel immunotherapies have the potential to cure also bone metastatic disease. Here we have established and validated syngeneic models with a focus on bone metastasis that could be used in preclinical efficacy studies. Syngeneic models were established for breast (4T1-GFP), multiple myeloma (5TGM1), bladder (MBT-2) and lung cancer (KLN-205). The cells were inoculated into systemic circulation (4T1 intracardially and 5TGM1 into tail vein) or bone marrow (MBT-2 and KLN-205). In the 4T1 model, tumor burden was assessed by ex vivo GFP imaging and in the 5TGM1 model by measuring serum IgG2b paraprotein levels during the study. Tumor-induced bone changes were followed by X-ray imaging in all models. Hind limbs were analyzed by histology and immunohistochemistry for tumor-infiltrating lymphocytes (TILs). The effects of standard-of-care compounds were assessed in the 4T1 (cyclophosphamide, 100 mg/kg or zoledronic acid, 0.1 mg/kg) and 5TGM1 (bortezomib, 1 mg/kg) models. The effect of anti-PD-1 treatment (200 µg/dose) was evaluated in the MBT-2 model. In the 4T1 model, osteolytic bone lesions formed within 13 days. In addition to bone metastases, about 50% of the mice had metastases in lungs, ovaries, kidneys and adrenal glands based on GFP imaging. Cyclophosphamide decreased the tumor burden and the area of osteolytic bone lesions. Zoledronic acid decreased the osteolytic lesion area but had no effect on tumor burden. Low number or no TILs were observed. In the 5TGM1 model, osteolytic lesions were observed and the study was ended at day 35. Metastases in ovaries, kidneys and adrenal glands were observed in about 30% of the mice. Bortezomib decreased serum paraprotein compared to vehicle treated mice. In both models, cachexia and paraplegia were occasionally observed. Moderate number of CD3+ TILs were observed in the tumors. In the intratibial MBT-2 and KLN-205 models, large osteolytic lesions were observed within 25 days, and in the KLN-205 model also lung metastases were observed. Anti-PD-1 treatment decreased osteolytic tumor area in the MBT-2 model. Moderate number of CD3+ and low number of CD4+ and CD8+ TILs were observed in the tumors growing in bone and also in the lung metastases. A high incidence of bone metastases was observed in all models. The use of systemic models allows studying the effects of test compounds in prevention or treatment of metastases. Intratibial models can be used when the primary interest is in tumor growth in bone microenvironment. Mimicking the clinical situation, none of the SOC compounds could prevent tumor growth completely, and therefore combination therapies are warranted for better overall efficacy. Citation Format: Tiina E. Kähkönen, Mari I. Suominen, Jenni H. Mäki-Jouppila, Jussi M. Halleen, Arne Scholz, Jenni Bernoulli. Systemic and local bone metastasis models for immuno-oncology drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2814.

KLF4 as a rheostat of osteolysis and osteogenesis in prostate tumors in the bone.

We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells to cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive and osteolytic tumors when injected into mouse femurs whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.

Regulation of Osteosclerosis by Inoculated Cd133+ PC3 Cells in Bone-marrow Microenvironmental Niches.

ABSTRACTBone is the most common site of prostate cancer (PC) metastasis. Studies suggest that cancer stem cells (CSCs) are associated with stemness characteristics, providing some support for the concept that CSCs act as osteosclerotic precursors in bone microenvironmental niches. Here, we asked whether ectopic overexpression of CD133 maintains stability of CSCs in human PC cell lines and induces the changes of molecular features in the bone microenvironment. Ectopic overexpression of CD133 in PC3 or DU145 cells led to increased expression of ALDHA1, OCT4, and NANOG, enhanced colony‐forming ability, and increased ALDH activity. In addition, micro‐CT imaging, confocal microscopy, and H&E staining of mouse tissue confirmed that CD133 overexpression in PC3 and DU145 led to marked osteolytic bone tumor. However, expression of osteoblastic markers such as collagen type I, bone sialoprotein, and osteocalcin (OC) at the tumor margin of CD133‐overexpressing PC3 tumors in mouse tibiae was higher than that of CD133‐overexpressing DU145 tumors with osteosclerotic molecular features. In addition, expression of osteopontin (OPN) mRNA/protein by CD133‐overexpressing PC3 cells was higher than that by DU145 cells. Especially, conditioned medium (CM) from PC3CD133+ cells increased osterix (OSX) activity in bone marrow stromal cells (BMSCs), resulting in increased expression of OC mRNA/protein resulted in increased staining of mineralized matrix by Alizarin red. However, CM from OPN silenced PC3CD133+ cells led to a reduction of OC mRNA and protein expression through OSX activity resulted in reduced amount of mineralized matrix. In conclusion, these findings suggest that CD133 plays a functional role in regulating CSC characteristics in PCs and modulates their abilities in which induce the osteosclerosis of BMSCs. In addition, OPN from CSCs acts as a niche component that promotes osteosclerosis by supporting osteoblastic differentiation of BMSCs. © 2019 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Diagnostic and Management Options of Osteoblastoma in the Spine.

BackgroundOsteoblastoma is a rare, benign, osteolytic neoplasm commonly found in the spine in early adulthood. Here, we review the clinical characteristics, radiographic findings, and surgical management of patients with spinal osteoblastoma.Material/MethodsThirteen patients with osteoblastoma who underwent surgery at our institute from June 2008 to November 2017 were enrolled in this study. The American Spinal Injury Association (ASIA) impairment scale was used to assess neurological function. All patients were treated with either total excision or intralesional piecemeal excision without postoperative radiotherapy. Clinical efficacy was evaluated by visual analog scale (VAS) scores, the Oswestry Disability Index (ODI) of nerve function, physical and radiographic examinations, bone fusion, and neurologic status.ResultsThe follow-up lasted 23–82 months (average, 43.8 months). The average surgical time was 178.1 minutes (range, 100–230 minutes), with an average intraoperative blood loss of 574 mL (range, 230–1100 mL). Postoperatively, VAS scores decreased from 6.2±1.7 to 0.5±0.7 (P<0.001). The preoperative and final ODI scores were 51.1±7.7 and 22.6±4.9, respectively, reflecting a significant decrease (P<0.001). According to the ASIA classification, 3 patients had grade C, 3 patients had grade D, and 7 patients had grade E disease. Three months postoperatively, 1 patient had grade D and 10 patients had grade E disease; ultimately, all cases were grade E disease. Only 1 patient experienced local recurrence and underwent en bloc marginal resection with postoperative radiotherapy. All patients remained neurologically stable without any major complications.ConclusionsAccurate intraoperative localization with complete resection is the key to preventing recurrence. Aggressive surgical resection can achieve satisfactory clinical and radiographic outcomes.

Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis

Bone is one of the preferred sites for the metastasis of malignant tumours, such as breast cancer, lung cancer and malignant melanoma. Tumour cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand (RANKL), which promotes osteoclast differentiation and activation. Tumour-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth, causing bone pain and hypercalcaemia. Furthermore, RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor, RANK. Thus inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis, and a human monoclonal anti-RANKL antibody, denosumab, has been used in the clinic. However, orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to patients. Here we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse models. Oral administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced osteolysis. AS2676293 suppressed RANKL-mediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10, which is known not to trigger osteoclast activation. Based on the results from this study, RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.