Bone Tumor Growth Research Articles

Abstract 1172: Targeting c-Met and VEGFR2 in the stromal compartment of prostate cancer bone metastasis

Abstract Advanced-stage prostate cancer patients commonly develop bone metastasis, accounting for significant morbidity and mortality. Metastatic prostate cancer cells characteristically induce osteoblastic reactions, for which no targeted therapies are currently available. Recent clinical and experimental data showed that dual inhibition of c-Met and VEGF receptor (VEGFR)-2 kinase activity reduced prostate cancer growth in bone with indications for suppressing osteoblastic activities, while the specific functions of c-Met and VEGFR2 in osteoblasts remain unclear. In our in vitro studies using three types of osteoblasts (MC3T3-E1 subclone 4, hFOB1.19 and murine calvarial osteoblasts), hepatocyte growth factor (HGF, a ligand for c-Met) and VEGFA increased expression of receptor activator of nuclear factor κB ligand (RANKL) and macrophage colony stimulating factor (M-CSF), two essential factors for osteoclastogenesis. In addition, siRNA-mediated knockdown of c-Met or VEGFR2 in osteoblasts suppressed HGF- or VEGFA-dependent gene expression, respectively. We demonstrate that insulin growth factor (IGF) increased RANKL and M-CSF expression in osteoblasts via c-Met transactivation. Furthermore, the conditioned media from IGF-, HGF-, or VEGFA-treated osteoblasts promoted in vitro osteoclastogenesis that was suppressed by inhibition of c-Met and VEGFR2 in osteoblasts. Subsequently, we examined whether cabozantinib, a dual kinase inhibitor of c-Met and VEGFR2 currently in clinical trials for metastatic prostate cancer, could suppress prostate cancer bone metastasis via inhibition of osteoblasts. To examine the effects of cabozantinib specifically in osteoblasts, cabozantinib-resistant PC-3 prostate cancer cells were generated and implanted in the tibiae of male nude mice. Cabozantinib (60mg/kg) or control diluent was administered via daily oral gavage for 3 weeks. In agreement with our in vitro data, cabozantinib suppressed tumor growth in bone (determined by in vivo bioluminescence) and tumor-induced osteolysis (determined by X-ray). Tumor cells were isolated and in vitro cultured to demonstrate that cabozantinib resistance was maintained during 3-week in vivo growth. Osteoblasts and osteoclasts numbers were reduced in the bones of cabozantinib-treated mice, and these histological changes were accompanied by significantly lower levels of RANKL and M-CSF levels in bone. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduces RANKL and M-CSF expression, associated with decreased osteoclastogenesis and tumor-induced osteolysis. Therefore, we conclude that c-Met and VEGFR2 are promising therapeutic targets in the stromal compartment of prostate cancer bone metastasis, suggesting hat the effects of cabozantinib on skeletal-related events of prostate cancer are, at least in part, mediated by suppression of osteoblast function. Citation Format: Changki Lee, Preston Campbell, Young Mi Whang, Jamey D. Young, Florent Elefteriou, Serk In Park. Targeting c-Met and VEGFR2 in the stromal compartment of prostate cancer bone metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1172. doi:10.1158/1538-7445.AM2014-1172

Abstract 710: The efficacy of tumor-targeting Salmonella typhimurium A1-R on bone metastasis

Abstract We have previously developed a genetically-modified bacterial strain of Salmonella typhimurium (A1-R), which expresses GFP. In this study, we measured the efficacy of A1-R on breast cancer bone metastasis. We established an early-stage bone-metastasis model in nude mice by cardiac injection and a late-stage model by injection into the intramedullary cavity of the tibia using MDA-MB-435 human breast cancer cells (Human breast cancer cell lines co-express neuronal, epithelial, and melanocytic differentiation markers in vitro and in vivo. PLoS One 5, e9712, 2010). Both mouse models of bone metastasis were treated with A1-R. Fluorescence imaging of the mice was performed to visualize the metastatic bone lesions. In a first set of experiments, we showed that A1-R invaded and replicated intracellularly in MDA-MB-435-GFP cells in vitro. A1-R dose-dependently inhibited proliferation of MDA-MB-435-GFP cells. In the early-stage bone-metastasis model, A1-R significantly improved metastasis-free survival. In the advanced-stage bone-metastasis model, A1-R significantly inhibited the growth of the metastatic lesions. These data indicated that A1-R is useful to prevent and inhibit the growth of metastatic breast cancer bone tumors. Citation Format: Shinji Miwa, Ming Zhao, Shuya Yano, Yong Zhang, Fuminari Uehara, Yasunori Matsumoto, Yukihiko Hiroshima, Mako Yamamoto, Hiroaki Kimura, Katsuhiro Hayashi, Hiroyuki Tsuchiya, Robert M. Hoffman. The efficacy of tumor-targeting Salmonella typhimurium A1-R on bone metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 710. doi:10.1158/1538-7445.AM2014-710

Targeting putative mu opioid/metabotropic glutamate receptor-5 heteromers produces potent antinociception in a chronic murine bone cancer model

The therapeutic management of chronic pain associated with many cancers is problematic due to the development of tolerance and other adverse effects during the disease progression. Recently we reported on a bivalent ligand (MMG22) containing both mu agonist and mGluR5 antagonist pharmacophores that produced potent antinociception in mice with LPS-induced acute inflammatory pain via a putative MOR-mGluR5 heteromer. In the present study we have investigated the antinociception of MMG22 in a mouse model of bone cancer pain to determine its effectiveness in reducing this type of chronic nociception. There was a 572-fold increase in the potency of MMG22 over a period of 3–21 days that correlated with the progressive increase in hyperalgesia induced by bone tumor growth following implantation of fibrosarcoma cells in mice. The enhancement of antinociception with the progression of the cancer is possibly due to inhibition of NMDA receptor-mediated hyperalgesia via antagonism of mGluR5 and concomitant activation of MOR by the MMG22-occupied heteromer. Notably, MMG22 was 3.6-million-fold more potent than morphine at PID 21. Since MMG22 exhibited a 250,000-times greater potency than that of a mixture of the mu opioid (M19) agonist and mGluR5 antagonist (MG20) monovalent ligands, the data suggest that targeting the putative MOR-mGluR5 heteromer is far superior to univalent interaction with receptors in reducing tumor-induced nociception. In view of the high potency, long duration (>24h) of action and minimal side effects, MMG22 has the potential to be a superior pharmacological agent than morphine and other opiates in the treatment of chronic cancer pain and to serve as a novel pharmacologic tool.

Zoledronic acid at the time of castration prevented castration-induced bone metastasis in mice.

Androgen deprivation therapy (ADT) is known to cause bone loss in a majority of patients with castration-resistant prostate cancer (CRPC). A study published in this issue of Endocrine-Related Cancer by Ottewell and colleagues shows that ADT increased bone resorption and triggered growth of disseminated prostate cancer (CaP) cells to form bone metastasis using an in vivo model. However, prevention of bone decay by weekly administration of zoledronic acid (ZOL) at the time of castration prevented ADT-induced tumor growth in bone. Recently, two publications from Japan have demonstrated that ZOL combined with ADT improved outcomes for patients with treatment-naïve CaP with bone metastasis. The mechanistic cause for these patients having an improved overall survival compared with those who were treated with ZOL after ADT initiation or before metastasis development was never explained. Ottewell and colleague's study now suggests that it is the bone loss caused by ADT that promoted bone metastasis, and if ZOL is administered at the time of ADT initiation, it would prevent this bone loss and prolong skeletal-related event-free survival.

Serum Factors of Angiogenesis and the Growth of Fibroblasts in Osteogenic Sarcoma

ABSTRACT Aim: The purpose of our research was to study the levels of endostatin, FFG 1, VEGF in osteogenic sarcoma patients' peripheric blood serum before conducting treatment in order to detect their possible relationship with clinical characteristic diseases and prognosis. Methods: We have studied 76 patients with osteogenic sarcoma of tubular bones. The received data showed that the levels in blood serum of patients with osteogenic sarcoma FFG-1 and endostatin composed 96±14.5pg/ml and 146.7±3.8 ng/ml, respectively, which compared with 287.8±1.9 pk/ml and 56.5±0.98 ng/ml in healthy people. Results: The expression of FFG-1 is possible and endostatin may have a connection with pathogenetic changes dealing with the growth of bone tumors. Serum concentrations of VEGF in 71.5% patients with osteogenic sarcoma were increased by 14.3 times (520±68.5 ng/ml in patients) compared with the data from the control group (36.3±0.5 ng/ml). On the basis of laboratory and clinical research the threshold concentration and connection of serum VEGF, FFG-1 and endostatin with clinical course and prognosis of disease were determined. At the level of FFG-1 less than 35.0 pg/ml 3-year survival was 94% but more than 350 pg/ml - 64%. There is also a relationship between the level of malignization of tumor and contents of VEGF in blood serum;, dependence between the concentration of VEGF, metastatic potential of osteogenic sarcoma and the term of metastasis were detected. Conclusions: Comparative research of VEGF, FFG-1 and endostatin levels in primary tumor of patients with OS can be used as criteria of prognosis of disease and introduced into the scheme of complex therapy preparations, so influencing the expression of VEGF, FFG-1 and endostatin in patients with primary neoplasms of bones with the purpose of increasing the efficacy of therapy. Disclosure: All authors have declared no conflicts of interest.

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction.

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients.

Castration-induced bone loss triggers growth of disseminated prostate cancer cells in bone

Up to 90% of patients with castrate-resistant prostate cancer develop bone metastases, and the majority of these men have received androgen deprivation therapy known to cause bone loss. Whether this treatment-induced change to the bone microenvironment affects disseminated tumour cells, potentially stimulating development of bone metastasis, remains to be determined. The objective of this study was to use an in vivo model mimicking androgen ablation to establish the effects of this intervention on disseminated prostate cancer cells in bone. We mimicked the effects of androgen deprivation on bone metastasis by castrating 12-week-old BALB/c nude mice that had disseminated, hormone-insensitive PC3 prostate cancer cells present in the long bones. Castration caused increased bone resorption and loss of bone volume, compared with sham operation. In addition, castration triggered growth of disseminated PC3 cells to form bone metastasis in 70% of animals. In contrast, only 10% of sham-operated animals had detectable long bone tumours. Weekly administration of 100 μg/kg zoledronic acid (ZOL) prevented castration-induced tumour growth in bone and increased bone volume, but did not eliminate the disseminated tumour cells. ZOL had no effect on tumour growth in the sham-operated animals, despite causing a significant increase in bone volume. This is the first demonstration that, in a model of prostate cancer bone metastasis, mimicking androgen ablation results in growth of disseminated tumour cells in bone through osteoclast-mediated mechanisms. We provide the first biological evidence supporting the administration of ZOL to prostate cancer patients at the time of androgen ablation to prevent subsequent relapse in bone.

Zoledronic Acid Has Differential Antitumor Activity in the Pre- and Postmenopausal Bone MicroenvironmentIn Vivo

Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings. Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 μg/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy. OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups. This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res; 20(11); 2922-32. ©2014 AACR.

Pharmacologic inhibition of bone resorption prevents cancer-induced osteolysis but enhances soft tissue metastasis in a mouse model of osteolytic breast cancer.

Osteoprotegerin (OPG) is a secreted member of the TNF receptor superfamily, which binds to the receptor activator of nuclear factor κB ligand (RANKL) and inhibits osteoclast activity and bone resorption. Systemic administration of recombinant OPG was previously shown to inhibit tumor growth in bone and to prevent cancer-induced osteolysis. In this study, we examined the effect of OPG, when produced locally by breast cancer cells located within bone, using a mouse model of osteolytic breast cancer. MDA-MB-231-TXSA breast cancer cells, tagged with a luciferase reporter gene construct and engineered to overexpress full-length human OPG, were transplanted directly into the tibial marrow cavity of nude mice. Overexpression of OPG by breast cancer cells protected the bone from breast cancer-induced osteolysis and diminished intra-osseous tumor growth but had no effect on extra-skeletal tumor growth. This effect was associated with a significant reduction in the number of osteoclasts that lined the bone surface, resulting in a net increase in bone volume. Despite limiting breast cancer-mediated bone loss, OPG overexpression resulted in a significant increase in the incidence of pulmonary metastasis. Our results demonstrate that inhibition of osteoclastic bone resorption by OPG when secreted locally by tumors in bone may affect the behaviour of cancer cells within the bone microenvironment and their likelihood of spreading and establishing metastasis elsewhere in the body.

Direct Crosstalk Between Cancer and Osteoblast Lineage Cells Fuels Metastatic Growth in Bone via Auto-Amplification of IL-6 and RANKL Signaling Pathways

The bone microenvironment and its modification by cancer and host cell interactions is a key driver of skeletal metastatic growth. Interleukin-6 (IL-6) stimulates receptor activator of NF-κB ligand (RANKL) expression in bone cells, and serum IL-6 levels are associated with poor clinical outcomes in cancer patients. We investigated the effects of RANKL on cancer cells and the role of tumor-derived IL-6 within the bone microenvironment. Using human breast cancer cell lines to induce tumors in the bone of immune-deficient mice, we first determined whether RANKL released by cells of the osteoblast lineage directly promotes IL-6 expression by cancer cells in vitro and in vivo. We then disrupted of IL-6 signaling in vivo either via knockdown of IL-6 in tumor cells or through treatment with specific anti-human or anti-mouse IL-6 receptor antibodies to investigate the tumor effect. Finally, we tested the effect of RANK knockdown in cancer cells on cancer growth. We demonstrate that osteoblast lineage-derived RANKL upregulates secretion of IL-6 by breast cancers in vivo and in vitro. IL-6, in turn, induces expression of RANK by cancer cells, which sensitizes the tumor to RANKL and significantly enhances cancer IL-6 release. Disruption in vivo of this auto-amplifying crosstalk by knockdown of IL-6 or RANK in cancer cells, or via treatment with anti-IL-6 receptor antibodies, significantly reduces tumor growth in bone but not in soft tissues. RANKL and IL-6 mediate direct paracrine-autocrine signaling between cells of the osteoblast lineage and cancer cells, significantly enhancing the growth of metastatic breast cancers within bone.

Zoledronic acid inhibits pulmonary metastasis dissemination in a preclinical model of Ewing’s sarcoma via inhibition of cell migration

BackgroundEwing’s sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties.MethodsInvasion assays were performed in vitro in Boyden’s chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 μg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology.ResultsZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and −9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases.ConclusionThese results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.

ALCAM/CD166 Is a TGF-β–Responsive Marker and Functional Regulator of Prostate Cancer Metastasis to Bone

The dissemination of prostate cancer to bone is a common, incurable aspect of advanced disease. Prevention and treatment of this terminal phase of prostate cancer requires improved molecular understanding of the process as well as markers indicative of molecular progression. Through biochemical analyses and loss-of-function in vivo studies, we demonstrate that the cell adhesion molecule, activated leukocyte cell adhesion molecule (ALCAM), is actively shed from metastatic prostate cancer cells by the sheddase ADAM17 in response to TGF-β. Not only is this posttranslational modification of ALCAM a marker of prostate cancer progression, the molecule is also required for effective metastasis to bone. Biochemical analysis of prostate cancer cell lines reveals that ALCAM expression and shedding is elevated in response to TGF-β signaling. Both in vitro and in vivo shedding is mediated by ADAM17. Longitudinal analysis of circulating ALCAM in tumor-bearing mice revealed that shedding of tumor, but not host-derived ALCAM is elevated during growth of the cancer. Gene-specific knockdown of ALCAM in bone-metastatic PC3 cells greatly diminished both skeletal dissemination and tumor growth in bone. The reduced growth of ALCAM knockdown cells corresponded to an increase in apoptosis (caspase-3) and decreased proliferation (Ki67). Together, these data demonstrate that the ALCAM is both a functional regulator as well as marker of prostate cancer progression.

Cabozantinib Inhibits Prostate Cancer Growth and Prevents Tumor-Induced Bone Lesions

Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both. Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2. Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively. These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy.

RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization

Prostate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model for studying the mechanisms underlying the metastatic process. Here, we report that receptor activator of NF-κB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed-forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor (TF) deletion/interference assays identified common TF complexes, c-Myc/Max, and AP4 as critical regulatory nodes. RANKL–RANK signaling activated a number of master regulator TFs that control the epithelial-to-mesenchymal transition (Twist1, Slug, Zeb1, and Zeb2), stem cell properties (Sox2, Myc, Oct3/4, and Nanog), neuroendocrine differentiation (Sox9, HIF1α, and FoxA2), and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1α, and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non metastatic LNCaP cells to express RANKL, c-Met/activated c-Met, while downregulating AR expression. These initially non-metastatic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK–RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic bystander dormant cells.

Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases.

Adipocytes are important but underappreciated components of bone marrow microenvironment, and their numbers greatly increase with age, obesity, and associated metabolic pathologies. Age and obesity are also significant risk factors for development of metastatic prostate cancer. Adipocytes are metabolically active cells that secrete adipokines, growth factors, and inflammatory mediators; influence behavior and function of neighboring cells; and have a potential to disturb local milleu and dysregulate normal bone homeostasis. Increased marrow adiposity has been linked to bone marrow inflammation and osteoporosis of the bone, but its effects on growth and progression of prostate tumors that have metastasized to the skeleton are currently not known. This review focuses on fat-bone relationship in a context of normal bone homeostasis and metastatic tumor growth in bone. We discuss effects of marrow fat cells on bone metabolism, hematopoiesis, and inflammation. Special attention is given to CCL2- and COX-2-driven pathways and their potential as therapeutic targets for bone metastatic disease.

Komplikationsmanagement nach Resektion und Defektrekonstruktion hüftgelenknaher Tumoren

Tumorous destruction of the periacetabular region and the proximal femur are a consequence of either primary malignant bone tumor manifestation or metastatic disease, which is observed much more frequently and occurs typically in these skeletal segments. Pathological fractures of the proximal femur and periacetabular regions of the pelvis have a high incidence and ultimately lead to severe pain and immobilization. Advanced resection techniques and different types of defect reconstruction, allowing for oncologically sufficient resection of extensive tumors have contributed to a marked increase in the limb salvage rate. However, these procedures are associated with an increasing rate of several, sometimes severe intraoperative and postoperative complications. Compared to elective total hip arthroplasty, the rate of postoperative deep infections, dislocations, the incidence of pathological and periprosthetic fractures and the prevalence of deep vein thrombosis are increased with high rates of postoperative mortality and local tumor recurrence, being the most serious complications. Pelvic involvement and subsequent periacetabular resection have the highest complication rate when compared to proximal femur resection with endoprosthetic treatment. In order to minimize the risk of these intraoperative and postoperative complications wide resection and advanced reconstruction as well as complicated palliative stabilization due to malignant bone tumor growth around the hip joint should be performed in musculoskeletal tumor centers with profound expertise in osteosynthetic and endoprosthetic reconstruction of the pelvis and the proximal femur. Only in specialized centers an effective, multidisciplinary emergency management of these complications and, more importantly, reliable prevention of complications can be ensured.

Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms

Incidence of skeletal metastases and death from prostate cancer greatly increases with age and obesity, conditions which increase marrow adiposity. Bone marrow adipocytes are metabolically active components of bone metastatic niche that modulate the function of neighboring cells; yet the mechanisms of their involvement in tumor behavior in bone have not been explored. In this study, using experimental models of intraosseous tumor growth and diet-induced obesity, we demonstrate the promoting effects of marrow fat on growth and progression of skeletal prostate tumors. We reveal that exposure to lipids supplied by marrow adipocytes induces expression of lipid chaperone FABP4, pro-inflammatory interleukin IL-1β, and oxidative stress protein HMOX-1 in metastatic tumor cells and stimulates their growth and invasiveness. We show that FABP4 is highly overexpressed in prostate skeletal tumors from obese mice and in bone metastasis samples from prostate cancer patients. In addition, we provide results suggestive of bi-directional interaction between FABP4 and PPARγ pathways that may be driving aggressive tumor cell behavior in bone. Together, our data provide evidence for functional relationship between bone marrow adiposity and metastatic prostate cancers and unravel the FABP4/IL-1β axis as a potential therapeutic target for this presently incurable disease.

Multifunctional Properties of RANKL/RANK in Cell Differentiation, Proliferation and Metastasis

It is known that there are close relationships between bone destruction and tumor growth in bone metastasis. RANKL is a central factor in bone metastasis, inducing osteoclastogenesis mediated by its receptor RANK. Recent reports demonstrate that RANKL has important roles in organogenesis stimulating proliferation and differentiation of epithelial and stroma cells. RANKL is induced not only by cytokines and hormones but also by UV-irradiation, inflammation and carcinogens. Expression of RANK and RANKL is found in several human cancer cell lines, and RANK signaling stimulates proliferation, migration and epithelial-mesenchymal transition of cancer cells, which may be involved in metastasis via an autocrine/paracrine mechanism. RANKL regulates the number of Tregs that produce RANKL, which may affect cancer metastasis. In this review we discuss the multifunctional roles of RANKL/RANK in osteoclastogenesis, organogenesis, and the metastasis and tumorigenesis of cancer cells.

Cellular Players in Breast Cancer Bone Metastases

The current paradigm for bone metastasis is that there is a mutual interaction between osteoclasts and cancer cells, known as the tumor/bone vicious cycle. This model is based largely on findings in immune compromised animals showing amelioration of bone metastases by targeting the osteoclasts. Thus, osteoclast inhibitors are the standard of care in breast cancer bone metastasis. However, clinical studies demonstrate only a 28 % reduction in skeletal-related events in patients with bone metastases treated with bisphosphonates, and currently, there is limited evidence supporting anti-resorptive therapies in reducing the overall incidence of bone metastasis or extending survival. These data indicate that other cells, in addition to the osteoclasts, control tumor growth in bone. This review will discuss the role of the osteoclast, and then focus on additional cellular players, thus expanding the model of bone metastasis pathophysiology to include immune and stromal components.

Solid Tumours Show Osteotropism: Mechanisms of Bone Metastases

Bone metastases are a dismal consequence of cancer, causing severe morbidity and reducing the quality of life of patients. Solid tumours such as breast, prostate, lung and kidney cancer showed a marked osteotropism dependent on the special microenvironment provided by bone. Different cellular types are involved in the formation of bone metastases, indeed bone, immune system and tumour cells interact leading to bone lesions. During the bone resorption process, there is an intense cross-talk between immune system cells and osteoclasts (OCs). In particular, T cells release factors and cytokines, which rule osteoclastogenesis, and on the other hand, OCs produce factors that act on T cells, which are mediators of the tumour growth in bone. This review will summarize the main mechanisms of action in cancer-induced bone disease with particular regard to the cross-talk among cells of bone, tumour and immune system, focusing on factors and cytokines released by osteoclast, osteoblast, tumour cells and T cells.