RANK expression on breast cancer cells promotes skeletal metastasis

RANK ligand (RANKL), acting through its cognate receptor RANK, is a key factor for bone remodeling and metastasis by regulating the differentiation, survival and activation of osteoclasts. RANKL is also crucial for the development of mouse mammary glands during pregnancy and has been recently linked to the etiology of breast cancer via its direct activity on RANK-expressing normal or transformed breast epithelial cells, leading to increased mitogenesis, enhanced regenerative potential of mammary stem cells, and increased invasion and migration. We demonstrate that higher RANK expression in MDA-MB-231 breast cancer cells (MDA-231-RANK cells) is sufficient to confer a significantly greater metastatic growth rate in the bone compared with MDA-MB-231 cells which do not express high levels of RANK. Blockade of osteoclastic bone resorption, achieved with treatment by either RANKL inhibition or zoledronic acid, did reduce skeletal tumor progression of MDA-231-RANK cells suggesting that the vicious cycle contributes to metastatic growth. However, RANKL inhibition reduced skeletal growth of MDA-231-RANK tumors to a significantly greater extent than zoledronic acid, indicating that skeletal growth of RANK-positive tumors is also driven by direct RANKL effects. RANKL stimulated the expression of multiple genes associated with cell invasive behavior, including several matrix metalloproteinases and other genes previously defined as part of a bone metastasis gene signature. These data indicate that RANKL provokes breast cancer bone metastases via two distinct, but potentially overlapping mechanisms: stimulation of tumor-associated osteoclastogenesis and stimulation of RANK-expressing tumor cells.     

Distribution of macrophages, osteoclasts and the B-lymphocyte lineage in osteolytic metastasis of mouse mammary carcinoma

The purpose of this study was to examine the localization of macrophages, B-lymphocytes and osteoclasts in tumoral lesions of mammary carcinoma metastasized to bone of non-immunocompromised mice. Mouse mammary carcinoma cells (BALB/c-MC) were injected through the left cardiac ventricle into 5-week-old female wild-type Balb/c mice. The femora and tibiae of mice with metastasized cancer were extracted, and thereafter processed for histochemical analyses. The foci of metastasized tumor cells occupied the metaphyseal area, and the cell death zones could be identified within the tumor mass. Abundant tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts were found among the alkaline phosphatase (ALP)-reactive osteoblastic cell layer that covered the bone surface neighboring the metastatic lesion. In contrast, F4/80-positive macrophages/monocytes were localized adjacent to, or invading the metastatic tissue. In addition, some F4/80-positive cells were found in the aforementioned cell death zones. Unlike F4/80-positive cells, CD45R-positive B-lymphocytes did not accumulate at the surfaces of the tumor lesions, nor infiltrate into them, but were found scattered over bone marrow. Interestingly, some CD45R-positive cells were observed close to TRAP-positive osteoclasts in the stromal tissue surrounding the tumor lesion. Our findings suggest that, in the bone metastatic lesions of non-immunocompromised mice, F4/80-positive macrophages/monocytes accumulated on and/or infiltrated into the tumor nests, while CD45R-positive B-lymphocytes were associated with osteoclasts, rather than attacking metastatic tumor cells.     

Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis

Bone metastases cause severe skeletal morbidity including fractures and hypercalcemia. Tumor cells in bone induce activation of osteoclasts, which mediate bone resorption and release of growth factors from bone matrix, resulting in a “vicious cycle” of bone breakdown and tumor proliferation. Receptor activator of NF-κB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival, and is blocked by a soluble decoy receptor, osteoprotegerin (OPG). In human malignancies that metastasize to bone, dysregulation of the RANK/RANKL/OPG pathway can increase the RANKL:OPG ratio, a condition which favors excessive osteolysis. In a mouse model of bone metastasis, RANKL protein levels in MDA-MB-231 (MDA-231) tumor-bearing bones were significantly higher than tumor-free bones. The resulting tumor-induced osteoclastogenesis and osteolysis was dose-dependently inhibited by recombinant OPG-Fc treatment, supporting the essential role for RANKL in this process. Using bioluminescence imaging in a mouse model of metastasis, we monitored the anti-tumor efficacy of RANKL inhibition on MDA-231 human breast cancer cells in a temporal manner. Treatment with OPG-Fc in vivo inhibited growth of MDA-231 tumor cells in bony sites when given both as a preventative (dosed day 0) and as a therapeutic agent for established bone metastases (dosed day 7). One mechanism by which RANKL inhibition reduced tumor burden appears to be indirect through inhibition of the “vicious cycle” and involved an increase in tumor cell apoptosis, as measured by active caspase-3. Here, we demonstrate for the first time that OPG-Fc treatment of mice with established bone metastases resulted in an overall improvement in survival.     

Human breast adenocarcinoma (MDA-231) and human lung squamous cell carcinoma (Hara) do not have the ability to cause bone resorption by themselves during the establishment of bone metastasis

Osteolysis is an important process in the establishment of bone metastasis. The role which cancer cells play in this process is not fully understood. In this study, we first established a reproducible in vivo bone metastasis model using two types of tumor cells, human breast adenocarcinoma (MDA-231) and human lung squamous cell carcinoma (Hara cells), and examined in vitro characteristics of the tumor cells. Tumor cells injected into the left heart ventricle of nude mice preferentially metastasized to bone, 6 weeks after the inoculation. Histological observation of the bone metastatic lesion showed that tumor cells invaded the bone marrow, and osteoclasts adjacent to fibroblasts were actively resorbing the bone matrix. In vitro analysis of the tumor cells showed that MDA-231 cells express cathepsin K, matrix metalloproteinase 9 (MMP-9), and membrane type-1 matrix metalloproteinase (MT1-MMP), all of which are believed to play an important role in osteoclastic bone resorption. In contrast, Hara cells do not express cathepsin K and MT1-MMP. MMP-9 was expressed at a low level. To assess the osteolytic activity of the tumor cells, an in vitro pit assay was performed. The rabbit osteoclasts formed numerous pits on a dentin slice after 18 h of incubation, whereas tumor cells by themselves did not. Taken together, we conclude that MDA-231 and Hara cells, which metastasize to the bone in vivo, do not have enough ability to achieve bone resorption by themselves, but rather achieve it through activation of fibroblast like cells and osteoclasts.     

Expression of osteoprotegerin and RANK ligand in breast cancer bone metastasis

Bone destruction is primarily mediated by osteoclastic bone resorption, and cancer cells stimulate the formation and activation of osteoclasts next to metastatic foci. Accumulating evidences indicate that receptor activator of NF-kB ligand (RANKL) is the ultimate extracellular mediator that stimulates osteoclast differentiation into mature osteoclasts. In contrast, osteoprotegerin (OPG) inhibits osteoclast development. In order to elucidate a mechanism for cancer-induced osteoclastogenesis, cells from a human breast cancer line, MDA-MB-231, were directly co-cultured with ST2, MC3T3-E1, or with primary mouse calvarial cells. Osteoclast-like cells and tartarate resistant acid phosphatase (TRAP) activities were then quantitated. We examined these cell lines and samples from breast cancer by RT-PCR for the expressions of OPG and RANKL mRNA. Compared to controls, co-culture of MDA-MB-231 cells with stromal or osteoblastic cells induced an increase in number of osteoclasts and TRAP activities. MDA-MB-231 cells alone or breast cancer samples did not express RANKL mRNA. However, co-culture of these cancer cells with stromal or osteoblastic cells induced RANKL mRNA expression and decreased OPG mRNA expression. These experiments demonstrate that direct interactions between breast cancer and stromal or osteoblastic cells induce osteoclastogenesis in vitro through modulating RANKL expression.     

Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice

Patients with breast cancer brain metastases cannot be cured and have a poor prognosis, with a median survival time of six months after diagnosis, despite developments in diagnostic and therapeutic modalities. In large part the progress in understanding the biology of breast cancer brain metastasis has been limited by the lack of suitable cell lines and experimental models. The objective of this study was to develop a reliable experimental model to study the pathogenesis of breast cancer brain metastases, using intra-internal carotid artery injection of breast cancer cells into nude mice. Brain metastasis-selected variant cells were recovered after three cycles of injection into the internal carotid artery of nude mice and harvest of brain metastases, resulting in variants termed MDA-231 BR1, -BR2 and -BR3. The metastasis-selected cells had increased potential for experimental brain metastasis and mice injected with these cells had significantly shorter mean survival than mice injected with the original cell line. Brain metastatic lesions of the selected variants contained significantly more CD31-positive blood vessels than metastases of the non-selected cell line. The variants selected from brain metastases released significantly more VEGF-A and IL-8 into culture supernatants than the original cell line, and more VEGF-A RNA when cultured in normoxic conditions. Mice injected with MDA-231 BR3 into the carotid artery were treated with the VEGF-receptor tyrosine kinase inhibitor PTK787/Z 222584. Oral administration of the inhibitor resulted in a significant decrease in brain tumor burden, reduced CD31-positive vessels in the brain lesions and incidence of PCNA positive tumor cells, and increased apoptosis in the tumor, as measured by TUNEL labeling. We conclude that elevated VEGF expression contributes to the ability of breast cancer cells to form brain metastases. Targeting endothelial cells with a VEGF-receptor specific tyrosine kinase inhibitor reduced angiogenesis and restricted the growth of the brain metastases.     

Metastatic breast cancer cells suppress osteoblast adhesion and differentiation

Bone is a primary target for colonization of metastatic breast cancer cells. Once present, the breast cancer cells activate osteoclasts, thereby stimulating bone loss. Bone degradation is accompanied by pain and increased susceptibility to fractures. However, targeted inhibition of osteoclasts does not completely prevent lesion progression, nor does it heal the lesions. This suggests that breast cancer cells may also affect osteoblasts, cells that build bone. The focus of this study was to determine the ability of breast cancer cells to alter osteoblast function. MC3T3-E1 osteoblasts were cultured with conditioned medium from MDA-MB-231 breast cancer cells and subsequently assayed for changes in differentiation. Osteoblast differentiation was monitored by expression of osteocalcin, bone sialoprotein and alkaline phosphatase, and by mineralization. Osteoblasts cultured with MDA-MB-231 conditioned medium did not express these mature bone proteins, nor did they mineralize a matrix. Inhibition of osteoblast differentiation was found to be due to transforming growth factor β present in MDA-MB-231 conditioned medium. Interestingly, breast cancer conditioned medium also altered cell adhesion. When osteoblasts were assayed for adhesion properties using interference reflection microscopy and scanning acoustic microscopy, there was a reduction in focal adhesion plaques and sites of detachment were clearly visible. F-actin was disassembled and punctate in osteoblasts cultured with MDA-MB-231 conditioned medium rather than organized in long stress fibers. Taken together, these observations suggest that metastatic breast cancer cells alter osteoblast adhesion and prevent differentiation. These affects could account for the continued loss of bone after osteoclast inhibition in patients with bone-metastatic breast cancer.     

Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis

The mammary gland microenvironment during postlactational involution shares similarities with inflammation, including high matrix metalloproteinase activity, fibrillar collagen deposition, and release of bioactive fragments of fibronectin and laminin. Because inflammation can promote tumorigenesis, we evaluated whether the tissue microenvironment of the involuting gland is also promotional. Extracellular matrix was isolated from mammary glands of nulliparous rats or rats with mammary glands undergoing weaning-induced involution. Using these matrices as substratum, nulliparous matrix was found to promote ductal organization of normal mammary epithelial MCF-12A cells in three-dimensional culture and to suppress invasion of mammary tumor MDA-MB-231 cells in transwell filter assays. Conversely, involution matrix failed to support ductal development in normal cells and promoted invasiveness in tumor cells. To evaluate the effects of these matrices on metastasis in vivo, MDA-MB-231 cells, premixed with Matrigel, nulliparous matrix, or involution matrix, were injected into mammary fat pads of nude mice. Metastases to lung, liver, and kidney were increased in the involution matrix group, and correlated with a twofold increase in tumor vascular endothelial growth factor expression and increased angiogenesis. These data suggest that the mammary gland microenvironment becomes promotional for tumor cell dissemination during involution, thus providing a plausible mechanism to explain the high rate of metastases that occur with pregnancy-associated breast cancer.     

ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis

Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in organ-specific metastasis remain poorly defined despite their well-appreciated role in matrix degradation and tumor invasion. Here, we show a mechanism whereby two distinct metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1) and matrix metalloproteinase-1 (MMP1), orchestrate a paracrine signaling cascade to modulate the bone microenvironment in favor of osteoclastogenesis and bone metastasis. Proteolytic release of membrane-bound epidermal growth factor (EGF)-like growth factors, including Amphiregulin (AREG), heparin-binding EGF (HB-EGF), and transforming growth factor α (TGFα) from tumor cells suppress the expression of osteoprotegerin (OPG) in osteoblasts and subsequently potentiate osteoclast differentiation. EGF receptor (EGFR) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells. Furthermore, elevated MMP1 and ADAMTS1 expression is associated with increased risk of bone metastasis in breast cancer patients. This study established MMP1 and ADAMTS1 in tumor cells, as well as EGFR signaling in osteoblasts, as promising therapeutic targets for inhibiting bone metastasis of breast cancer.     

A role for leukemia inhibitory factor in melanoma-induced bone metastasis

Melanoma is commonly associated with multi-organ metastasis, and bone is a frequent metastatic site for melanoma. However, the mechanism responsible for such melanoma-induced bone metastasis is still poorly understood. In the present study, the intracardiac inoculation of leukemia inhibitory factor (LIF)-producing human melanoma-derived cells (SEKI) developed osteolytic bone destruction in male BALB/cA-nu/nu nude mice. To elucidate the role of LIF in melanoma-induced osteolysis, cells were prepared in which the expression of LIF was reduced using a siRNA technique from the parent SEKI cells. Osteoclastogenesis was induced in the co-culture of LIF and/or SEKI cells with osteoblastic stromal cells in vitro, whereas the LIF-reduced SEKI cells did not induce osteoclastogenesis. The intracardiac inoculation of LIF-reduced SEKI cells resulted in a significant reduction in the incidence and number of bone metastasis in comparison to those in the mice inoculated with the parent SEKI cells. The expression of LIF was found in seven of nine human melanoma-derived cell lines, suggesting that LIF expression is a universal event in melanoma. These findings suggest that a potential role for LIF in the melanoma-induced bone metastasis possibly through the stimulation of osteoclastogenesis. LIF might therefore be a potentially effective drug target in the treatment of bone metastasis in melanoma.     

Disaggregated osteoclasts increase in resorption activity in response to roughness of bone surface.

The roughness of the bone matrix surface affects osteoblastic differentiation. However, the effect of the roughness of the matrix surface on osteoclastic bone resorption remains to be studied. We examined the latter effect using disaggregated osteoclasts from neonatal rats. The resorption pit number and the total pit area on the rough surface were not different from those on smooth surfaces after 1 day, but they were 2 or more times higher after 3 days. The number of osteoclasts was not different on bone slices with either smooth or rough surfaces at 3 days. The alkaline phosphatase (ALP)-positive osteoblasts were relatively rare in both types of slices at first, then the number and the diameter of the enzyme-positive cells and the clusters preferentially increased on the rough bone slices. When hydroxyurea was added to the culture in order to suppress the proliferation and the subsequent differentiation of osteoblastic cells on rough surfaces, the increase in resorption on the rough surfaces was effaced; however, this agent had little affect on resorption of the smooth surfaces. The addition of ALP-positive cells to disaggregated osteoclasts increased bone resorption on the smooth surface. The results suggest that osteoblast development and subsequently bone resorption by osteoclasts is enhanced by the roughness of matrix surfaces.     

Bone sialoprotein promotes tumor cell migration in both in vitro and in vivo models

The present study was conducted to determine the effects of bone sialoprotein (BSP) in promoting vascular invasion of tumor cells in metastasis. We used a Matrigel system and the MDA-231 human breast cancer cells transfected with human BSP cDNA (MDA-231/BSP). Quantative analysis indicated an average of 1.7-fold increase in cell numbers that migrated through the endothelial cells in MDA-231/BSP cells compared with empty vector-transfected MDA-231 cells (MDA-231/EV). In an in vivo assay, the MDA-231 cells were incubated with or without BSP antibodies and were then inoculated onto the upper chorioallantoic membrane (CAM) of chicken embryos, in which the only route for the tumor cells to reach the lower CAM was to migrate through the embryonic vasculature. PCR amplification using human Alu primers and genomic DNA from harvested lower CAM showed an average reduction of 67% in the samples treated with BSP antibodies. These preliminary data suggest that, in metastasis, BSP may enhance the penetrating ability of tumor cells through endothelial cells and basement membrane into blood vessels. BSP antibodies can specifically hinder this effect in an in vivo system.     

Bone Sialoprotein Promotes Tumor Cell Migration in Both In Vitro and In Vivo Models

The present study was conducted to determine the effects of bone sialoprotein (BSP) in promoting vascular invasion of tumor cells in metastasis. We used a Matrigel system and the MDA-231 human breast cancer cells transfected with human BSP cDNA (MDA-231/BSP). Quantative analysis indicated an average of 1.7-fold increase in cell numbers that migrated through the endothelial cells in MDA-231/BSP cells compared with empty vector-transfected MDA-231 cells (MDA-231/EV). In an in vivo assay, the MDA-231 cells were incubated with or without BSP antibodies and were then inoculated onto the upper chorioallantoic membrane (CAM) of chicken embryos, in which the only route for the tumor cells to reach the lower CAM was to migrate through the embryonic vasculature. PCR amplification using human Alu primers and genomic DNA from harvested lower CAM showed an average reduction of 67% in the samples treated with BSP antibodies. These preliminary data suggest that, in metastasis, BSP may enhance the penetrating ability of tumor cells through endothelial cells and basement membrane into blood vessels. BSP antibodies can specifically hinder this effect in an in vivo system.     

Immunolocalization of matrix metalloproteinases and their inhibitors in clinical specimens of bone metastasis from breast carcinoma

Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP- 1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling. This revised version was published online in July 2006 with corrections to the Cover Date.     

Hepatocellular carcinoma with osteoclast-like giant cells: possibility of osteoclastogenesis by hepatocyte-derived cells

Giant cell tumor (GCT) of bone is a primary osteolytic tumor that is characterized by the formation of osteoclast-like giant cells. In addition to GCT of bone, extraskeletal GCT are known to be formed in several soft tissues. Giant cells in GCT of bone were suggested to be identical to osteoclasts, but the characterization of giant cells in extraskeletal GCT remains incomplete. In this study, a case of sarcomatoid hepatocellular carcinoma with osteoclast-like giant cells was analyzed. Immunohistochemistry revealed the expression of almost all markers of osteoclasts: tartrate-resistant acid phosphatase, CD68, CD51, CD54 and matrix metalloprotease-9, in osteoclast-like giant cells in the tumor. In situ hybridization revealed the expression of receptor activator of nuclear factor-kappa B (RANK) in the giant cells and receptor activator of nuclear factor-kappa B ligand (RANKL) in the tumor cells. The hepatic origin of the sarcomatoid hepatocellular carcinoma cells was confirmed by the expression of albumin. This is the first report suggesting that hepatocyte-derived cells possess the potential for osteoclastogenesis. In addition, these findings suggest that osteoclast-like cells in the hepatocellular carcinoma were formed by the same mechanism as osteoclastogenesis in bone.     

Matrix vesicles in bone tumors. Ultrastructural analysis and their significance in neoplastic bone formation.

Bone tumors were categorized into alkaline phosphatase (ALPase)-positive (2 ossifying fibromas, 1 benign osteoblastoma and 16 osteosarcomas) and negative (2 chondromas, 2 chondrosarcomas, 3 non-ossifying fibromas, 2 malignant fibrous histiocytomas and 6 giant cell tumors of bone) groups. Production and distribution of matrix vesicles (MVs) in the tumor tissues were examined to clarify their role in neoplastic bone formation. Four distinct types of MV were isolated primarily in ALPase positive bone tumors: empty, amorphous, crystalline and ruptured MVs. They were formed by budding off from the cytoplasmic projections of the osteoblastic tumor cells. The significance of differences in the production rate of MVs between ALPase-positive and negative bone tumors was investigated in view of the predominantly high production of MVs in ALPase-positive bone tumors. Many more mature MVs (crystalline and ruptured) were observed in the osteoblastic lesions of osteosarcoma than in the fibroblastic and MFH-like lesions, suggesting an intimate relationship with maturation and differentiation of the osteoblastic tumor cells. The above findings indicate that production of MVs is one of the diagnostic parameters for osteoblast-derived bone tumors, as well as ALPase activity, and that vesicle-induced mineralization is a major mineralization mechanism in neoplastic bone formation.     

Differential expression of protease-activated receptors-1 and -2 in stromal fibroblasts of normal, benign, and malignant human tissues

The serine proteases thrombin and trypsin are among many factors that malignant cells secrete into the extracellular space to mediate metastatic processes such as cellular invasion, extracellular matrix degradation, angiogenesis, and tissue remodeling. The degree of protease secretion from malignant cells has been correlated to their metastatic potential. Protease activated receptors (PAR)-1 and -2, which are activated by thrombin and trypsin respectively, have not been extensively characterized in human tumors in situ. We investigated the presence of PAR-1 and PAR-2 in human normal, benign and malignant tissues using immunohistochemistry and in situ hybridization. Our results demonstrate PAR-1 and PAR-2 expression in the tumor cells, mast cells, macrophages, endothelial cells, and vascular smooth muscle cells of the metastatic tumor microenvironment. Most notably, an up-regulation of PAR-1 and PAR-2 observed in proliferating, smooth muscle actin (SMA)-positive stromal fibroblasts surrounding the carcinoma cells was not observed in normal or benign conditions. Furthermore, in vitro studies using proliferating, SMA-positive, human dermal fibroblasts, and scrape-wounded human dermal fibroblasts demonstrated the presence of PAR-1 and PAR-2 not detected in quiescent, SMA-negative cultures. PAR-1 and PAR-2 in the cells forming the tumor microenvironment suggest that these receptors mediate the signaling of secreted thrombin and trypsin in the processes of cellular metastasis.     

The negative prognostic impact of bone metastasis with a tumor mass

OBJECTIVE:

Typically, bone metastasis causes osteolytic and osteoblastic lesions resulting from the interactions of tumor cells with osteoclasts and osteoblasts. In addition to these interactions, tumor tissues may grow inside bones and cause mass lesions. In the present study, we aimed to demonstrate the negative impact of a tumor mass in a large cohort of patients with bone metastatic cancer.

METHODS:

Data from 335 patients with bone metastases were retrospectively reviewed. For the analysis, all patients were divided into three subgroups with respect to the type of bone metastasis: osteolytic, osteoblastic, or mixed. The patients were subsequently categorized as having bone metastasis with or without a tumor mass, and statistically significant differences in median survival and 2-year overall survival were observed between these patients (the median survival and 2-year overall survival were respectively 3 months and 16% in patients with a tumor mass and 11 months and 26% in patients without a tumor mass; p<0.001).

RESULTS:

According to multivariate analysis, the presence of bone metastasis with a tumor mass was found to be an independent prognostic factor (p=0.011, hazard ratio: 1.62, 95% confidence interval: 1.11–1.76). Bone metastasis with a tumor mass was more strongly associated with osteolytic lesions, other primary diseases (except for primary breast and prostate cancers), and spinal cord compression.

CONCLUSION:

Bone metastasis with a tumor mass is a strong and independent negative prognostic factor for survival in cancer patients.     

骨转移瘤的溶骨与成骨机制研究进展

骨骼是一种动态重塑的组织,终身以骨质溶解和骨质形成的方式进行骨骼动态重塑循环。骨微环境适宜实体肿瘤定植与生长。实体肿瘤骨转移发生率高,骨转移瘤可以导致明显溶骨性和(或)成骨性骨病灶,如乳腺癌主要以溶骨性病灶为典型,前列腺癌主要以成骨性病灶为主。骨转移瘤的骨骼生理以过度溶骨和(或)成骨为中心。溶骨和成骨的主要机制相互区别独立,本质上均为溶骨与成骨的相关因子打破机体正常骨骼重塑动态循环：RANK-RANKL-OPG系统、甲状旁腺激素相关肽和转移生长因子β参与溶骨,Wnts、内皮素1、甲状旁腺激素相关肽和骨形态发生蛋白参与成骨。骨转移瘤的溶骨与成骨效应都属于正反馈性"恶性循环"。本综述在理解正常骨骼生理与骨骼重塑动态循环的基础上重点阐述骨转移瘤的溶骨和成骨生理机制。探索骨转移瘤的溶骨和成骨生理机制可以为研究者研发靶向药物提供契机。