Osteolytic Bone Metastases Research Articles

Subjective and objective evaluation of response to radiotherapy after different radiotherapy dose - fraction schemes in osteolytic bone metastases

Subjective and objective evaluation of response to radiotherapy after different radiotherapy dose - fraction schemes in osteolytic bone metastases

Calvarial Bone Implantation and in vivo Imaging of Tumor Cells in Mice

Bone is one of common metastasis sites for many types of cancer. In bone metastatic microenvironment, tumor-bone interactions play a significant role in the regulation of osteolytic or osteoblastic bone metastasis. In order to investigate the direct interaction between tumor cells and bone tissue, it is essential to generate appropriate animal models that mimic the behavior of tumor cells in bone metastatic lesions. Calvarial implantation model (bone invasion model) is a newly-established animal model that accurately recapitulates the behavior of tumor cells in the tumor-bone microenvironment. The surgical technique for tumor cell implantation is simpler than intracardiac, intra-arterial, or intraosseous injection techniques. This model can be useful for the identification of key factors driving tumor-induced osteolytic or osteoblastic changes.

Hip Pain Revealing Metastatic Prostate Cancer

Background: Prostate cancer is the most common malignant tumor and the second most common cause of cancer associated mortality in males. Bone metastasis is frequent, usually multiple and osteoplastic. Presentation of a pure osteolytic and solitary metastasis from a prostate carcinoma is extremely rare.Methodology: We report a case of prostate cancer in a 54-year-old man who presented with progressive severe right hip pain and stiffness with no urinary symptom. An MRI of the pelvis revealed a metastasis to the right hip. A prostate biopsy revealed prostate adenocarcinoma.Results: In the literature, there are few cases of a solitary osteolytic bone metastasis from carcinoma of the prostate, and especially in the pelvis. only one such case seems to be reporting.

Blockade of Mer By the Small Molecule Inhibitor R992 Inhibits Multiple Myeloma and Its Associated Bone Disease By Restoring the Perturbed Bone Homeostasis

Despite many therapeutic advances in recent years Multiple Myeloma (MM) still remains incurable in the majority of the patients. In addition, MM patients suffer significantly from co-morbidities including bone pain and renal insufficiency. Therefore, the development of novel treatments is warranted. The TAMR family consists of Tyro3, Axl and Mer which represent evolving targets in cancer. We demonstrated that the role of TAMR is non-redundant in hematologic malignancies, with Axl exerting an important function in AML, but not in MM, where Mer represents a novel target.Therefore, we tested the therapeutic potential of the Mer-inhibitor R992, which has an 8-fold selectivity over Tyro3 and a 13-fold selectivity over Axl in preclinical MM models (Rigel, San Francisco, USA).R992 exerted a dose-dependent growth inhibition of U266, JJN3 and RPMI8226 cells in vitro (n=3, *p<0.001). Mechanistically, Mer blockade inhibited proliferation in 5-bromo-2′-deoxyuridine assays and induced apoptosis as shown by increased numbers of Annexin V+ cells (n=3,*p<0.05 and *p<0.001, respectively). To delineate signaling pathways mediating the biological effects of Mer blockade in MM cells we investigated key mediators of MM cell proliferation and survival. Here, we found reduced phosphorylation of Akt upon Mer inhibition with R992. Furthermore, R992 inhibited mitogen-activated protein kinase (MAPK) pathways Erk and p38. Subsequently, we investigated whether inhibition of Mer signaling increases chemosensitivity of MM cells. Combination treatment of R992 with bortezomib and cyclophosphamide demonstrated that Mer inhibition significantly increased sensitivity of MM cells to these established MM therapies.Oral administration of 60mg/kg R992 BID to mice significantly reduced tumor burden in the U266 systemic myeloma mouse model. The λ light chain concentration and the CD138+ MM cell load was reduced 2-fold in R992 treated mice compared to placebo-treated mice 8 weeks after injection (n=5/5, *p<0.05 and n=4/5, *p<0.05, respectively). Importantly, treatment with R992 resulted in a significant prolongation of overall survival by 15 days in the U266 model (median OS 73 vs. 88 days (n=13/12, *p<0.05). In addition, treatment with R992 prolonged survival in the more aggressive JJN3 model (median OS 24 vs. 27 days, n=9/7, *p<0.005).For further phenotyping of the effects of R992 we performed microcomputed tomography (µCT) and histological analysis of the tibias in the U266 model. µCT analysis of proximal tibia metaphyses revealed, that bone volume and bone mineral density (BMD) were significantly increased by R992 (n=7/7, *p<0.05). Moreover, analysis of the metaphyseal spongiosa showed that R992 could retard myeloma-mediated destruction of trabecular bone area measured by increased trabecular number and increased trabecular thickness (n=7/7, *p<0.05). Interestingly, R992 could also enlarge the metaphyseal diameter due to thickened cortical bone. Vice versa, overexpression of the Mer ligands Gas6 and Pros1 in U266 and JJN3 cells led to increased osteoclast and decreased osteoblast differentiation in vitro and more rapid and destructive myeloma bone disease in vivo. These data suggest that the expression of Mer ligands represent thus far unrecognized mediators of MM-induced perturbed bone homeostasis.To directly assess the effect of R992 on osteoclasts, we treated osteoclast cultures with R992 and observed an inhibition of osteoclast differentiation by R992 alone and in co-culture with myeloma cells. Western blot analysis confirmed, that Mer phosphorylation was reduced by R992, whereas the phosphorylation of Tyro3 was not altered. Concomitantly, phosphorylation of p38 and activation of non-canonical NFκB pathway showed a dose dependent reduction after Mer blockade. Interestingly, R992 led also to increased osteoblast differentiation and could restore myeloma mediated osteoblast inhibition in co-cultures of MM cells and osteoblasts.In summary, our data suggest that Mer blockade leads to inhibition of MM and its associated bone disease. Furthermore, the function of Mer in bone homeostasis promoting osteoclast and inhibiting osteoblast activity leads to the potential application of Mer inhibitors also in osteolytic bone metastases or osteoporosis. DisclosuresDarwish:Rigel Pharmaceuticals: Employment. Bhamidipati:Rigel Pharmaceuticals: Employment. Masuda:Rigel Pharmaceuticals: Employment, Equity Ownership. Loges:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Complete Recalcification Following Arterial Embolization of Massive Osteolytic Bone Metastasis From NSCLC

Complete Recalcification Following Arterial Embolization of Massive Osteolytic Bone Metastasis From NSCLC

1828P - Role of SPECT-CT somatostatin-receptor scintigraphy in the management of medullary thyroid cancer (MTC)

Background: The MTC arises from the parafollicular, calcitonin-secreting malignant transformed thyroid C-cells who express on the surface somatostatin SSTR receptors. The most of aggressive locally advanced/metastatic MTC tumors, found to be positive for RET proto-oncogene mutation, are treated with Vandetanib. SPECT-CT somatostatin-receptor scintigraphy with 99mTc-Tektrotyd should be considered for MTC imaging before and after therapy for exact staging and follow-up of the disease due to its highly sensitivity and specificity for detection of neuroendocrine tumors, expressed SSTR. The aim of this study was to evaluate clinical role of SPECT-CT scintigraphy with 99mTc-Tektrotyd in the management of patients with MTC. Methods: 25pts (7M;18F) with MTC were studied; whole body somatostatin scintigraphy followed by target SPECT-CT studies were performed 2-4 hrs post i.v.inj. of 740 MBq 99mTc-Tektrotyd (Polatom). SPECT-CT camera Symbia T2, Siemens was used. Three of them were studied for initial pre-operative N/M-staging, 17 were follow-up after surgery. In 5 patients with metastatic disease SPECT-CT with 99mTc-Tektrotyd were performed before and after target therapy with Caprelsa (Vandetanib), 300mg/d orally. Results: Initial pre-operative staging showed 3 positive results for the primary tumor and metastatic lymph nodes and 2 false negative imaging of small 1-4 mm lung metastases. True negative results were obtained in 5 cases after thyroidectomy. True positive results were obtained in 17 cases with local recurrence in the thyroid bed, lymphadenopathy, osteolytic bone metastases, lung and subcutaneous lesions. False positive result was in 1 case with benign ovary cyst. Plasma levels of calcitonin vary from 94 to 5496 pg/ml in all 17 patients with local recurrence and/or metastatic lesions. In 5/17 cases SPECT-CT studies were used to evaluate effect of target therapy, respectively: partial response – in 2 cases, stable disease – in 2 cases and progressive disease – in 1 cases. Conclusions: SPECT-CT somatostatin-receptor scintigraphy with 99mTc-Tektrotyd is very useful functional imaging modality in patients with MTC in order to determinate personalized therapeutic disease approach. Legal entity responsible for the study: Sonya Sergieva. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

MiR-214 is an important regulator of the musculoskeletal metabolism and disease.

MiR-214 belongs to a family of microRNA (small, highly conserved noncoding RNA molecules) precursors that play a pivotal role in biological functions, such as cellular function, tissue development, tissue homeostasis, and pathogenesis of diseases. Recently, miR-214 emerged as a critical regulator of musculoskeletal metabolism. Specifically, miR-214 can mediate skeletal muscle myogenesis and vascular smooth muscle cell proliferation, migration, and differentiation. MiR-214 also modulates osteoblast function by targeting specific molecular pathways and the expression of various osteoblast-related genes; promotes osteoclast activity by targeting phosphatase and tensin homolog (Pten); and mediates osteoclast-osteoblast intercellular crosstalk via an exosomal miRNA paracrine mechanism. Importantly, dysregulation in miR-214 expression is associated with pathological bone conditions such as osteoporosis, osteosarcoma, multiple myeloma, and osteolytic bone metastasis of breast cancer. This review discusses the cellular targets of miR-214 in bone, the molecular mechanisms governing the activities of miR-214 in the musculoskeletal system, and the putative role of miR-214 in skeletal diseases. Understanding the biology of miR-214 could potentially lead to the development of miR-214 as a possible biomarker and a therapeutic target for musculoskeletal diseases.

Abstract 38: Mitophagy deficiency promotes osteolytic bone metastasis in breast cancer

Abstract Introduction: Metastasis of breast cancer to the bone is a common complication and occurs in 65-80% of late-stage patients. Specifically, the development of osteolytic bone lesions increases patient morbidity and mortality with debilitating skeletal complications. Mitophagy is a selective form of autophagy that removes damaged or excessive mitochondria in response to various metabolic stresses. However, the role of mitophagy in development of cancer remains largely unclear. The Janus-faced role of mitophagy during tumorigenesis leads to a novel challenge when targeting it for cancer therapies. This study focuses on the role of mitophagy deficiency in breast cancer osteolytic bone metastasis, and explores the potential of rescuing mitophagy deficiency as possible therapeutic targets for metastatic disease. Methods: Specific single-guide RNAs (sgRNAs) were used to deplete ULK1 expression in breast cancer cell lines. Mitophagy was monitored by detecting Tom20 and Hsp60. In addition, mitochondrial DNA (mtDNA) was used to further confirm the reduction of mitochondrial mass. For bone metastasis studies, luciferase-tagged tumor cells were injected into the left cardiac ventricle of anesthetized female nude mice. Metastatic progression was monitored by bioluminescence imaging (BLI). Micro-CT imaging was used to detect bone volume, cortical wall thickness, trabecular thickness and number in mice of tibia. TRAP assay was used to detect osteoclast differentiation assays. Results: We found that the core Atg protein ULK1 was not only expressed at low level in breast cancer, but also required for hypoxia-induced mitophagy. ULK1-related mitophagy deficiency promoted the formation of metastatic osteolytic lesions in experimental bone metastasis mouse model with MDA-MB-231 cells. TRAP staining revealed that mature osteoclasts significantly increased in RAW264.7 cells treated with CM from ULK1-knockout breast cancer cells. In addition, MEK inhibitor trametinib was sufficient to upregulate the expression of ULK1 and reduced the release of cytokines, which is key to osteoclast differentiation via triggering mitophagy, thereby effectively blocking breast cancer osteolytic bone metastasis. Conclusion: In conclusion, we demonstrate the functional importance of mitophagy defect in breast cancer for promoting osteolytic bone metastasis. We also provide strong preclinical evidence for using MEK-ERK pathway inhibitors to disrupt ERK kinase-involved ULK1 degradation and induce mitophagy as a breast cancer bone metastasis therapy. Citation Format: Rong Deng, Hai-Liang Zhang, Rui-Zhao Cai, Jun Tang, Xiao-Feng Zhu. Mitophagy deficiency promotes osteolytic bone metastasis in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 38.

Diagnosis and treatment of osteoblastic metastasis in patients with breast cancer

Osteoblastic metastasis of breast cancer is relatively rare, but there are cases of misdiagnosis and mistreatment in clinical treatment. They can only be diagnosed by X ray or CT bone scan and must be identified from bone repair after effective treatment in patients with osteolytic or mixed bone metastases. Bone metastasis is often seen in the disease-free condition of breast cancer, and very few can occur in stage Ⅳ lesions prior to surgery. Based on the analysis of clinical phenomena, we questioned the evaluation criteria of the therapeutic effect on bone metastasis of breast cancer created by the World Health Organization and the MD Anderson Cancer Center and concluded the formation mechanism of bone metastasis. For patients with simple osteoblastic bone metastasis, we broke through the recommendations of the National Comprehensive Cancer Network guideline and advocated the concept of "noninterference" . Patients with positive hormone receptor can be treated with traditional endocrine therapy. Hormone receptor negative and/or human epidermal growth factor receptor 2 positive patients can be observed first, followed by chemotherapy and/or targeted therapy when there is osteolytic bone metastasis or visceral metastasis. Furthermore, bisphosphonates are not required since osteoblastic bone metastasis is generally not associated with the risk of bone related events. The active treatment of primary lesion should be taken into account in stage Ⅳ patient before operation.

Osteolytic cancer cells induce vascular/axon guidance processes in the bone/bone marrow stroma

Prostate and breast cancers frequently metastasize to bone. The physiological bone homeostasis is perturbed once cancer cells proliferate at the bone metastatic site. Tumors are complex structures consisting of cancer cells and numerous stroma cells.In this study, we show that osteolytic cancer cells (PC-3 and MDA-MB231) induce transcriptome changes in the bone/bone marrow microenvironment (stroma). This stroma transcriptome differs from the previously reported stroma transcriptome of osteoinductive cancer cells (VCaP). While the biological process “angiogenesis/vasculogenesis” is enriched in both transcriptomes, the “vascular/axon guidance” process is a unique process that characterizes the osteolytic stroma. In osteolytic bone metastasis, angiogenesis is denoted by vessel morphology and marker expression specific for arteries/arterioles. Interestingly, intra-tumoral neurite-like structures were in proximity to arteries. Additionally, we found that increased numbers of mesenchymal stem cells and vascular smooth muscle cells, expressing osteolytic cytokines and inhibitors of bone formation, contribute to the osteolytic bone phenotype.Osteoinductive and osteolytic cancer cells induce different types of vessels, representing functionally different hematopoietic stem cell niches. This finding suggests different growth requirements of osteolytic and osteoinductive cancer cells and the need for a differential anti-angiogenic strategy to inhibit tumor growth in osteolytic and osteoblastic bone metastasis.

Role of Tumor-Derived Chemokines in Osteolytic Bone Metastasis.

Metastasis is the primary cause of mortality and morbidity in cancer patients. The bone marrow is a common destination for many malignant cancers, including breast carcinoma (BC), prostate carcinoma, multiple myeloma, lung carcinoma, uterine cancer, thyroid cancer, bladder cancer, and neuroblastoma. The molecular mechanism by which metastatic cancer are able to recognize, infiltrate, and colonize bone are still unclear. Chemokines are small soluble proteins which under normal physiological conditions mediate chemotactic trafficking of leukocytes to specific tissues in the body. In the context of metastasis, the best characterized role for the chemokine system is in the regulation of primary tumor growth, survival, invasion, and homing to specific secondary sites. However, there is ample evidence that metastatic tumors exploit chemokines to modulate the metastatic niche within bone which ultimately results in osteolytic bone disease. In this review, we examine the role of chemokines in metastatic tumor growth within bone. In particular, the chemokines CCL2, CCL3, IL-8/CXCL8, and CXCL12 are consistently involved in promoting osteoclastogenesis and tumor growth. We will also evaluate the suitability of chemokines as targets for chemotherapy with the use of neutralizing antibodies and chemokine receptor-specific antagonists.

Bone metastases from lung cancer: A paradigm for multidisciplinary onco-rheumatology management.

Bone is the third metastatic site after liver and lungs. Bone metastases occur in one out of three lung cancers and are usually of osteolytic aspect. Osteolytic bone metastases are responsible of long bone and vertebral fractures leading to restricted mobility, surgery and medullar compression that severely alter quality of life and that have a huge medico-economic impact. In the recent years, Bone Metastatic Multidisciplinary Tumour Board (BM2TB) have been developed to optimize bone metastases management for each patient in harmony with oncology program. In this review, we will go through all the different aspects of bone metastases management including diagnosis and evaluation (CT scan, Tc 99m-MDP bone scan, 18FDG-PET scan and biopsy for molecular diagnosis), systemic bone treatments (zoledronic acid and denosumab) and local treatments (interventional radiology and radiotherapy). Surgical strategies will be discussed elsewhere. Based on the last 2017-Lung Cancer South East French Guidelines, we present a practical decision tree to help the physicians for decision making in order to reach a personalized locomotor strategy for every patient.

EP-1649: Radiotherapy for osteolytic bone metastases from breast cancer: comparison with bone-modifying agent

EP-1649: Radiotherapy for osteolytic bone metastases from breast cancer: comparison with bone-modifying agent

Antitumor Activity of Novel Bone-seeking, α-emitting 224Ra-solution in a Breast Cancer Skeletal Metastases Model.

Bone metastases are associated with increased morbidity and poor prognosis in a variety of cancers. The present study investigated the effects of targeted radionuclide therapy with α-emitting, bone-seeking radium-224 (224Ra) on osteolytic bone metastasis of MDA-MB-231(SA)-GFP human breast cancer cells injected intracardially into nude mice. Vehicle, ethylenediamine tetra (methylene phosphonic acid) (EDTMP) and 224Ra-solution (45, 91 or 179 kBq/kg) with EDTMP were intravenously administered to mice two days after cell injection. The bone-seeking EDTMP was added to the 224Ra-solution to improve bone targeting of 212Pb, which is a progeny of 224Ra. Radium-224 solution treatment decreased in a dose-dependent manner the areas of osteolytic lesions in the hind limbs and the number of tumor foci in the whole skeleton, and extended survival. Paraplegia was not observed in 179 kBq/kg 224Ra-solution group. Radium-224-solution containing chelated 212Pb is a promising candidate for the treatment of breast cancer patients with bone metastases.

Pharmacological Treatment of Bone Loss.

Bone loss is common in clinical practice, such as health assessment of postmenopausal women, treatment of tumor metastasis, side-effects of glucocorticoids, and skeletal manifestations of inflammatory diseases. The imbalance of remodeling between bone resorption and bone formation, the pathophysiological basis of bone loss, increases bone fragility. The treatment of bone loss is mainly carried out from the treatment of osteoporosis. There are various pharmacological therapies for bone loss, which will be introduced in 3 aspects, including antiresorptive agents, anabolic agents and new medications. Each kind of medication has its advantages, shortcomings and side-effects. Antiresorptive agents are widely applied in the treatment of bone loss, but can lead to overall decrease of bone turnover rate. Anabolic agents, mainly PTH, are usually combined with other anti-resorptive drugs, and PTHrP might be a promising pure anabolic agent for osteoporosis. In recent years, some novel therapies have been raised and tested in clinical trials which can be promising choices available for osteoporosis treatment. Future drug targets will mainly come from RANK-RANKL-OPG system and Wnt/β-catenin signaling pathway., and the pre-existing drugs could be explored in new patterns.

Ultrasound-guided biopsy of osteolytic metastasis - could be less than three cores enough?

The purpose of this study was to analyze the diagnostic yield and accuracy of the ultrasound (US) guided corebiopsy in a population of patients with osteolytic metastasis. We performed a retrospective analysisof 16 consecutive cases of US-guided core biopsies of osteolytic lesions performed in our Ultrasound Unit, from January 2006to May 2017. We used 18G or 16G Tru-cut needles coupled with automated biopsy guns. We procured a maximum numberof two tissue specimens per patient. We obtained a diagnostic yield and accuracy of 93.75% (15 of 16 patients) forUS-guided core biopsy of osteolytic metastasis. Most of our cases were metastasis of adenocarcinomas (8 patients), squamouscell carcinomas (3 patients) followed by multiple myelomas (2 patients). Other pathologic lesions recorded were undifferentiatedcarcinoma (1 patient) and mesenchimal undifferentiated tumor (1 patient). The pathologic result was inconclusive in onepatient. Our study supports the important diagnostic role of US-guided core biopsy for osteolytic bone metastasis.Two US-guided passages may be sufficient to procure a diagnostic tissue samples from osteolytic bone metastasis, if theirlength is at least 10 mm.

α-Tocopheryl Succinate Inhibits Osteolytic Bone Metastasis of Breast Cancer by Suppressing Migration of Cancer Cells and Receptor Activator of Nuclear Factor-κB Ligand Expression of Osteoblasts.

BackgroundBreast cancer is one of the most common cancers affecting women and has a high incidence of bone metastasis, causing osteolytic lesions. The elevated expression of receptor activator of nuclear factor-κB ligand (RANKL) in cancer activates osteoclasts, leading to bone destruction. We previously reported that α-tocopheryl succinate (αTP-suc) inhibited interleukin-1-induced RANKL expression in osteoblasts. Here, we examined the effect of αTP-suc on osteolytic bone metastasis in breast cancer.MethodsTo examine the effect of αTP-suc on the metastatic capacity of breast cancer, MDA-MB-231-FL cells were injected into the left cardiac ventricle of BALB/c nude mice along with intraperitoneal injection of αTP-suc. The mice were then analyzed by bioluminescence imaging. To investigate the effect of αTP-suc on osteolysis, 4T1 cells were directly injected into the femur of BALB/c mice along with intraperitoneal injection of αTP-suc. Microcomputed tomography analysis and histomorphometric analysis of the femora were performed.ResultsαTP-suc inhibited cell migration and cell growth of 4T1 cells. In line with these results, bone metastasis of MDA-MB-231-FL cells was reduced in mice injected with αTP-suc. In addition, αTP-suc decreased osteoclastogenesis by inhibiting 4T1-induced RANKL expression in osteoblasts. Consistent with these results, 4T1-induced bone destruction was ameliorated by αTP-suc, with in vivo analysis showing reduced tumor burden and osteoclast numbers.ConclusionsOur findings suggest that αTP-suc may be efficiently utilized to prevent and treat osteolytic bone metastasis of breast cancer with dual effects.

Paradoxical Effects of JZL184, an Inhibitor of Monoacylglycerol Lipase, on Bone Remodelling in Healthy and Cancer-Bearing Mice

Cancer associated bone disease is a serious complication in bone sarcomas and metastatic carcinomas of breast and prostate origin. Monoacylglycerol lipase (MAGL) is an enzyme of the endocannabinoid system, and is responsible for the degradation of the most abundant endocannabinoid in bone 2-arachidonoyl glycerol (2AG). Here, we report that the verified MAGL inhibitor JZL184 reduced osteolytic bone metastasis in mouse models of breast and prostate cancers, and inhibited skeletal tumour growth, metastasis and the formation of ectopic bone in models of osteosarcoma. Additionally, JZL184 suppressed cachexia and prolonged survival in mice injected with metastatic osteosarcoma and osteotropic cancer cells. Functional and histological analysis revealed that the osteoprotective action of JZL184 in cancer models is predominately due to inhibition of tumour growth and metastasis. In the absence of cancer, however, exposure to JZL184 exerts a paradoxical reduction of bone volume via an effect that is mediated by both Cnr1 and Cnr2 cannabinoid receptors. Thus, targeting MAGL is of potential therapeutic efficacy in primary bone cancer and bone metastasis, however, activation of the skeletal endocannabinoid system may limit the usefulness of MAGL inhibitors as osteoprotective agents. Funding Statement: The studies described were partly supported by funding from Cancer Research UK Development Fund (Edinburgh Cancer Research Centre, University of Edinburgh) and a programme grant from Arthritis Research UK. Declaration of Interests: A.I. Idris and S.H. Ralston are inventors on a patent concerning the use of cannabinoid receptor ligands for the treatments of bone diseases. Other authors declare no conflict of interest. Ethics Approval Statement: All procedures involving mice and their care were approved by and performed in compliance with the guidelines of Institutional Animal Care and Use Committee of Universities of Edinburgh (Scotland, UK), L’Aquila (L’Aquila, Italy) and Nantes (Nantes, France), and received institutional approval and conducted in conformity with laws and policies (UK Home Office and Italian and French authorities).

Osteolytic Breast Cancer Causes Skeletal Muscle Weakness in an Immunocompetent Syngeneic Mouse Model.

Muscle weakness and cachexia are significant paraneoplastic syndromes of many advanced cancers. Osteolytic bone metastases are common in advanced breast cancer and are a major contributor to decreased survival, performance, and quality of life for patients. Pathologic fracture caused by osteolytic cancer in bone (OCIB) leads to a significant (32%) increased risk of death compared to patients without fracture. Since muscle weakness is linked to risk of falls which are a major cause of fracture, we have investigated skeletal muscle response to OCIB. Here, we show that a syngeneic mouse model of OCIB (4T1 mammary tumor cells) leads to cachexia and skeletal muscle weakness associated with oxidation of the ryanodine receptor and calcium (Ca2+) release channel (RyR1). Muscle atrophy follows known pathways via both myostatin signaling and expression of muscle-specific ubiquitin ligases, atrogin-1 and MuRF1. We have identified a mechanism for skeletal muscle weakness due to increased oxidative stress on RyR1 via NAPDH oxidases [NADPH oxidase 2 (Nox2) and NADPH oxidase 4 (Nox4)]. In addition, SMAD3 phosphorylation is higher in muscle from tumor-bearing mice, a critical step in the intracellular signaling pathway that transmits TGFβ signaling to the nucleus. This is the first time that skeletal muscle weakness has been described in a syngeneic model of OCIB and represents a unique model system in which to study cachexia and changes in skeletal muscle.

Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy

Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast-derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis.