Bone Abstracts

Tumor development occurs often by over-activation of members of the RAS-oncogene family (small GTPases (sGTPs)). By blocking the mevalonate pathway, aminobisphosphonates (BPs), and statines prevent activation of GTPs by inhibiting their post-translational prenylation. As we have shown, this induces apoptosis in U2OS osteosarcoma cells by re-activation of FAS expression via epigenetic DNA demethylation (1).The histone demethylase JHD...

Tumors contain a small population of cancer stem cells (CSC) proposed to be responsible for tumor maintenance and relapse. Aldehyde dehydrogenase 1 (ALDH1) activity has been used as a functional stem cell marker to isolate CSCs in different cancer types. This study used the Aldefluor assay and fluorescence-activated cell sorting (FACS) analysis to isolate ALDH1high cells from five human sarcoma cell lines and one primary chordoma cell line. ALDH1high cell...

Chordomas are rare, low to intermediate grade malignant bone tumors of the axial skeleton. Current treatment options are limited to surgical procedures as chordomas are largely resistant to conventional radiation and chemotherapy. Cell lines are valuable tools to explore molecular mechanisms involved in tumorigenesis and they have a fundamental impact on the development of new anticancer agents. We established a novel chordoma cell-line, MUG-Chor1, from a recurrent morphologic...

Introduction: The interaction between RANK/RANKL is critical for the regulation of osteoclastogenesis and bone resorption. Inhibition of this interaction helps restore the balance between bone resorption and formation. ALX-0141, a novel biological agent (Nanobody) that specifically targets RANKL, was studied in a Phase I trial to assess the safety, tolerability, immunogenicity and PK after single injection.Methods: Forty-two healthy postmenopausal women ...

Tumour stromal macrophages differentiate into tumour associated macrophages (TAMs), with characteristics resembling the immunosuppressive M2 polarization instead of the pro-inflammatory M1. TAMs have a central role in promoting tumour vascularization, cancer cell dissemination and suppression of anti-cancer immune response. Cancer cell dissemination leads to metastasis formation which, e.g. in breast cancer often happens in bone marrow. We have studied the in vitro mo...

Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, zoledronic acid triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), whi...

Chondrosarcomas are cartilage-forming, poorly vascularized tumors. With an estimated annual incidence of 1 in 200 000, they represent the second malignant primary bone tumor of adults after osteosarcoma. These tumors are resistant to chemotherapy and radiotherapy, surgical excision remaining the only therapeutic option. However, very few cell lines and animal models are available, and the mechanisms behind their chemoresistance remain largely unknown. Our goal was to establish...

It has been established that disturbances of intracellular signaling pathways strongly contribute to the oncologic process. Indeed, phosphatidylinositol-3-kinase (PI3K) became a key target in cancer therapy, due to its high frequency of mutation and/or gain of function of its catalytic subunits in cancer cells. In this context, we investigated the in vitro and in vivo effects of a new PI3Kα inhibitor, BYL719 (Novartis Pharma), on bone cells and its thera...

Osteosarcoma is the most common primary malignant bone tumor, characterized by osteoid production and/or osteolytic lesions of bone. Despite recent improvements in chemotherapy and surgery, the problem of non-response to chemotherapy remains and constitutes a poor prognosis parameter. Consequently new therapeutic strategies aim to improve the overall rate of survival. The present work investigated the therapeutic interest of a dual phosphatidylinositol-3-kinase (PI3K)/mammalia...

Osteosarcoma is the most common primary malignant bone tumor, characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments points out the importance of exploring new therapeutic ways. Imatinib Mesylate (Glivec, Novartis Pharma), a tyrosine kinase inhibitor, has been originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that Imatinib Mesylate inhibits osteoclast differentiation th...

Osteosarcoma, the main malignant primary bone tumor, affects a ‘young’ population composed of children and young adults. Current treatment consists of tumor resection associated with chemotherapy. Unfortunately in many cases, a lack of response to anti-tumor drugs is observed, leading to development of metastases and to the patient’s death. Because TGF-β promotes metastases from many solid epithelial tumors, we investigated the effect of inhibitory Smad7 ov...

An IgM monoclonal gammopathy (MGUS) is often the first sign of a lymphomonocytic B-lymphoma (Waldenström macroglobulinemia-WD). Osteolytic lesions can occur in B cell malignancies (WD, hairy cell leukemia, LLC\..) but are less frequent than in myeloma. In addition, bone remodeling in WD is poorly understood. However, an osteoporosis is often observed in MGUS patients. We studied a series of bone biopsies performed in patients with an IgM gammopathy by histomorphometry, mi...

Osteosarcoma is the most frequent primary bone tumor that develops mainly in young adults. The survival rate at 5 years is below 30% for patients with poor response to treatment or with metastasis.The histones modifications are of critical importance in maintaining the transcription program of both normal and tumor cells. The bromodomain and extra-terminal domain (BET) protein family is an important class of ‘histone reading protein’ capable to...

Introduction: Bone metastases represent a frequent complication of breast cancer and are characterized by increased tumour-driven activation of osteoclasts and subsequent bone loss. Aminobisphosphonates inhibit osteoclast function and are established therapies of skeletal metastases. Similar to statins, they block the mevalonate pathway and are thought to have direct anti-tumour effects. Here, we report on the anti-tumour potential of a sequential inhibition of the mevalonate ...

Multiple myeloma is an incurable neoplastic disorder of plasma cells, which invade the bone marrow, secrete monoclonal immunoglobulins, and induce bone lesions, hypercalcemia, anemia and renal failure. The development of myeloma relies on vicious interactions with the bone microenvironment, a deeper knowledge of which is needed to identify prognostic markers and potential therapeutic targets. To achieve an unbiased, comprehensive assessment of the extracellular milieu of myelo...

Bone is the primary site of metastasis for breast cancer, which leads mainly to osteolytic lesions, Cancer cells can expand into the bone for their ability to ‘dialogue’ with resident cells, interfering with the physiological processes of bone turnover. In this study, a large-scale analysis comparing gene expression of biopsies of bone and visceral metastases from human breast cancer patients showed that the receptor (G protein-coupled) activity modifying protein-2 (...

Objective: To examine the efficacy and safety of direct administration of zoledronate acid (ZOL) on local osteoporotic lesion of ovariectomized rats.Methods: Six weeks later after ovariectomy, 16 6-month-old female S.D. rats were divided into the two groups with no differences of body weight and BMD of the proximal tibia. In the group L, 50 μl ZOL at a dose of 67 μg/kg were locally injected into the bone marrow between the two dr...

Marine cyanobacteria have been recognized as an important source of bioactive compounds. The cytotoxicity on cancer cell lines has been extensively explored and several cyanobacteria metabolites are already described as potential anticancer compounds or are considered useful templates for the design of new anticancer drugs. The majority of compounds have been isolated from filamentous or colonial cyanobacteria that growth in high densities along shores. In contrast, picoplankt...

Proton pump inhibitors (PPIs) are a class of drugs particularly used in gastric disorders. They promote a decrease on gastric acid secretion by inhibiting the H+/K+ ATPases. Osteoclasts are cells specialized in bone resorption by H+ translocation to the bone surface. Thus, PPIs might be regarded as potential tools to modulate osteoclast resorption activity, particularly in conditions that are associated with a hyperactivation of osteoclasts, li...

The skeleton is a preferred site of metastasis in patients with advanced breast cancer, and bone loss is one of the major complications of breast cancer metastasis. Therefore, prevention of bone metastasis is clinically important. Our previous observation of an anti-osteoclastic activity of Trolox, a vitamin E analogue, led us to investigate whether Trolox could inhibit bone metastasis and bone destruction induced by breast cancer. I.P. administration of Trolox markedly inhibi...

Introduction: The bone mineral density loss may be related to cancer. A specific correlation in the neuroendocrine tumors (NET) is not fully described yet.Aim: The analyze DXA in patients with or without NET.Material and method: We perfomed central DXA (spine and hip) with a GE Lunar device in post-menopausal women. None of them were previously treated with anti-osteoporotics drugs. The study groups included women with carcinoid tu...

Different results might be registered in DXA assessment in patients with neuroendocrine tumors (NET) since various factors induce bone disturbances as bone metastases, vitamin D hypovitaminosis, etc.Aim: The analyze DXA in NET.Material and method: The patients (p) were evaluated between 2008 and 2013. The diagnosis of NET was histological confirmed. We also included medullar thyroid cancer (MTC) with distance metastases and carcino...

Emerging evidence suggests that miRNAs (miR) can modulate a complex gene network in a cell-intrinsic and non-cell autonomous manner. We previously identified by transcriptomic analysis miR-192 to be heavily downregulated in different highly metastatic subpopulations (HMS) isolated from bone metastases in a lung cancer mice model, but its mechanistic contribution to the prometastatic activity remains unknown.To delineate the pleiotropic functions elicited...

There is increasing evidence for the key role of osteocytes in the regulation of bone remodeling. One of the main products of these cells, sclerostin, inhibits bone formation and may also stimulate bone resorption. To our knowledge, there are few data in prostate cancer (PC) patients especially in patients with hypogonadism related to androgen deprivation therapy (ADT). The aim of this study was to compare serum levels of sclerostin in ADT-treated and untreated PC patients wit...

Background: Besides the classic actions of vitamin D on bone metabolism and calcium homeostasis, there is evidence emphasizing its antiproliferative and proapoptotic activities. Data coming mostly from Northern regions suggest an effect of 25-hydroxyvitamin D (25(OH)D) serum concentrations on breast cancer prevention. We aimed to study the association between 25(OH)D concentrations and breast cancer risk in a Mediterranean population (Spain).Methods: We ...

Metastases to the bone are the incurable final outcomes of cancer, reducing both length and quality of life in an aggressive way. Despite the discoveries of many factors involved, no cure has been found. Metastatic outgrow starts in interaction with the bone micro-environment. The first attachment in bone is with the osteoblasts lining the endosteal surface. Our aim is to study the role of the osteoblasts in metastatic tumor spread and growth.We used an ...

Receptor activity modifying proteins (RAMPs 1, 2 and 3) are a class of important accessory proteins that interact and regulate several G-protein coupled receptor (GPCR) activity by finely modulating ligand interaction and in some cases trafficking receptors to cell surface.Predominant roles of RAMPs include ligand selectivity in receptors for Calcitonin (CT) family of peptides that comprise calcitonin, calcitonin gene related peptide, amylin and Adrenome...

Introduction: Patients with multiple myeloma (MM) commonly present with devastating bone disease mediated by increased bone resorption and suppressed bone formation. We have previously shown that blocking activity of the Wnt antagonist Dkk-1 promotes osteoblastogenesis and inhibits development of bone lesions in experimental models of MM. In the 5T murine models of MM, tumour cells home to the bone marrow. Injection of 5T2MM cells into C57BLKalwRij mice results in bone disease...

Glycosphingolipids (GSL) are essential structural components of mammalian cell membranes and lipid rafts that exert pleiotropic effects on cell survival, proliferation, and differentiation. Cancer associated GSL have been shown to promote tumor growth, angiogenesis, and metastasis; however their role in osteoclast (OC) activation and the development of osteolytic bone diseases such as multiple myeloma are not known. We investigated the hypothesis that GSL contribute to OC acti...

Introduction: Bone mineral density (BMD) evaluations have shown that adjuvant chemotherapy or endocrine therapy (ET) for early breast cancer (BC) is associated with accelerated BMD loss and increased fracture risk. In recent studies, zoledronic acid (ZOL) increased BMD in premenopausal and postmenopausal women with BC, and improved disease-free survival in some patient subsets compared with no ZOL. The purpose of the current study was to investigate the effect of adjuvant trea...

Introduction: The prospective, single-arm, open-label ZOTECT study was designed to assess the effect of zoledronic acid (ZOL) on bone-marker levels and potential correlations with disease outcomes in bisphosphonate-naive patients with bone metastases.Methods: Patients with bone metastases from prostate cancer (PC; n=301) or breast cancer (BC; n=99) who have not received bisphosphonates for ≥6 months were enrolled at 98 sites in Ge...