Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The epidermal growth factor receptor (EGFR) family comprehends four different tyrosine kinases (EGFR, ErbB-2, ErbB-3, and ErbB-4) that are activated following binding to epidermal growth factor (EGF)-like growth factors. It has been long established that the EGFR system is involved in tumorigenesis. These proteins are frequently expressed in human carcinomas and support proliferation and survival of cancer cells. However, activation of the EGFR in non-malignant cell populations of the neoplastic microenvironment might also play an important role in cancer progression. EGFR signaling regulates in tumor cells the synthesis and secretion of several different angiogenic growth factors, including vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF). Overexpression of ErbB-2 also leads to increased expression of angiogenic growth factors, whereas treatment with anti-EGFR or anti-ErbB-2 agents produces a significant reduction of the synthesis of these proteins by cancer cells. EGFR expression and function in tumor-associated endothelial cells has also been described. Therefore, EGFR signaling might regulate angiogenesis both directly and indirectly. In addition, activation of EGFR is involved in the pathogenesis of bone metastases. Within the bone marrow microenvironment, cancer cells stimulate the synthesis of osteoclastogenic factors by residing stromal cells, a phenomenon that leads to bone destruction. It has been shown that EGFR signaling regulates the ability of bone marrow stromal cells to produce osteoclastogenic factors and to sustain osteoclast activation. Taken together, these findings suggest that the EGFR system is an important mediator, within the tumor microenvironment, of autocrine and paracrine circuits that result in enhanced tumor growth.
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PMID:The role of the EGFR signaling in tumor microenvironment. 1789 7

Several common cancers often metastasize to the skeleton in advanced disease. Bone metastases are incurable and cause protracted, severe symptoms. Growth of tumor in bone is driven by a vicious cycle: tumor-secreted factors stimulate bone cells, which in turn release growth factors and cytokines. The bone-derived factors fuel the vicious cycle by acting back on the tumor cells. The vicious cycle offers novel targets for the treatment of advanced cancers. Treatments can inhibit bone cells (osteoclasts and osteoblasts) that are stimulated by tumor-secreted factors. Drugs can also inhibit tumor responses to factors enriched in the bone microenvironment, such as transforming growth factor-beta. Animal models show that these approaches, especially combination treatments, can reduce tumor burden. The results suggest a novel paradigm in which tumor growth can be effectively inhibited by drugs that target cells in the bone microenvironment and not the tumor cells themselves.
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PMID:Skeletal metastases: decreasing tumor burden by targeting the bone microenvironment. 1790 52

Osteoclasts mediate bone destruction in breast cancer skeletal metastases. Cathepsin K is a proteinase that is secreted by osteoclasts and degrades bone. Here, immunohistochemistry revealed that cathepsin K was expressed not only by osteoclasts but also by breast cancer cells that metastasize to bone. Following intratibial injection with cathepsin K-expressing human BT474 breast cancer cells, tumor-bearing mice treated with a clinical dosing regimen of cathepsin K inhibitor (CKI; 50 mg/kg, twice daily) had osteolytic lesions that were 79% smaller than those of tumor-bearing mice treated with the vehicle. The effect of CKI was also studied in a mouse model in which the i.v. inoculation of human B02 breast cancer cells expressing cathepsin K leads to bone metastasis formation. Drug administration was started before (preventive protocol) or after (treatment protocol) the occurrence of osteolytic lesions. In treatment protocols, CKI (50 mg/kg, twice daily) or a single clinical dose of 100 microg/kg zoledronic acid (osteoclast inhibitor) reduced the progression of osteolytic lesions by 59% to 66%. CKI therapy also reduced skeletal tumor burden by 62% compared with vehicle, whereas zoledronic acid did not decrease the tumor burden. The efficacy of CKI at inhibiting skeletal tumor burden was similar in the treatment and preventive protocols. By contrast, CKI did not block the growth of s.c. B02 tumor xenografts in animals. Thus, CKI may render the bone a less favorable microenvironment for tumor growth by inhibiting bone resorption. These findings raise the possibility that cathepsin K could be a therapeutic target for the treatment of bone metastases.
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PMID:A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. 1794 21

Bone is a common metastatic site for many cancers. Tumor cells located in the bone marrow cavity disturb the natural balance (bone remodelling) established between new bone formation performed by osteoblasts and bone resorption carried out by osteoclasts. Tumor cells produce many factors including growth factors and cytokines (PTHrP, ET-1, BMPs, others...) that stimulate either ostoclast activity leading to osteolytic lesions or osteoblast activity generating osteosclerotic bone metastases. Growth factors released from resorbed bone matrix or throughout osteoblastic bone formation sustain tumor growth. Therefore, bone metastases are the site of vicious cycles wherein tumor growth and bone metabolism sustain each other.
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PMID:[Mechanisms of bone metastasis formation]. 1815 74

The endothelin axis, comprising endothelins and their receptors, has recently emerged as relevant player in tumor growth and metastasis by regulating mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptor receptor, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion and metastatic dissemination. Endothelin-1 participates in the growth and progression of a variety of tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, bladder, endometrial carcinomas, Kaposi's sarcoma, brain tumors, melanoma, and bone metastases. This review highlights key signaling pathways activated by endothelin-1 axis in cancer, since the understanding the full spectrum activated by endothelin-1 is critical for the optimal design of targeted therapies. Preliminary experimental and clinical data demonstrate that interfering with endothelin receptor by using endothelin-1 receptor antagonists alone and in combination with cytotoxic drugs or molecular inhibitors could represent a new mechanism-based antitumor strategy.
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PMID:The endothelin axis in cancer. 1832 24

Positron emission tomography (PET) is increasingly used to diagnose, grade, and stage different types of tumors and to assess tumor response to therapy. Metabolic data acquired by fluorine-18-fluorodeoxyglucose (18FDG)-PET may facilitate accurate grading of sarcomas and have prognostic value when combined with other grading methods and various clinical/radiological features. In addition, 18FDG-PET is currently being evaluated in several cancer types for its utility in biopsy guidance. Whole-body 18FDG-PET also appears to be superior to other imaging modalities in detecting bone metastases in certain sarcoma patients. New PET tracers currently being investigated include 18F-fluorothymidine (18F-FLT) and 18F-misonidazole. 18F-FLT can help to determine tumor growth, rather than tumor shrinkage, which could be used to evaluate treatment response in sarcomas. PET imaging offers invaluable information to help maximize the clinical benefit of patients with sarcoma. This article reviews the use of PET in sarcoma management and its potential applications in the near future.
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PMID:PET for sarcomas other than gastrointestinal stromal tumors. 1843 35

The majority of patients with advanced cancer will ultimately develop bone metastases. The bone microenvironment provides fertile soil for a cycle of tumor growth and bone destruction that increases the risk of debilitating and potentially life-limiting skeletal-related events. Therefore, developing appropriate strategies to prevent bone metastases is critical. Bisphosphonates used to treat and prevent skeletal-related events resulting from multiple myeloma and bone metastases secondary to solid tumors, may also have direct and indirect antitumor effects. Emerging evidence from in vitro and in vivo preclinical studies in several tumor types suggests that bisphosphonates can reduce tumor burden in bone and soft tissue, inhibit angiogenesis, prevent tumor cell invasion and adhesion in bone, and induce tumor cell apoptosis. The powerful antiresorptive properties of bisphosphonates appear to directly prevent tumor cell growth and angiogenesis; in addition, combining bisphosphonates with cytotoxic chemotherapy may provide further antitumor synergies. Sequential application of cytotoxic chemotherapy (e.g., doxorubicin, paclitaxel, and gemcitabine) followed by bisphosphonates has been shown to induce significantly more tumor cell apoptosis than either agent alone in vitro and effectively inhibits tumor growth in vivo. Furthermore, in vivo data suggest that optimizing the dosing schedule may significantly increase survival. Overall, preclinical data suggesting that bisphosphonates have antitumor potential are promising and have provided the impetus for several ongoing clinical studies.
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PMID:Antitumor effects of bisphosphonates: promising preclinical evidence. 1848 48

The development of osteolytic breast cancer bone metastases relies on the ability of tumor cells to stimulate the formation of bone-resorbing osteoclasts. We have studied the effects of soluble factors produced by MDA-MB-231 breast carcinoma cells on osteoclast formation from human monocytic precursors and RAW 264.7 monocytic cells. Although factors produced by breast cancer cells were ineffective in inducing osteoclast formation from monocytes, priming with RANKL for 1-3 days dramatically increased receptiveness of osteoclast precursors to cancer-derived factors, which enhanced osteoclast formation 2-3 fold in the absence of supporting cell types. Osteoclasts formed by exposure to cancer factors expressed proteases critical for bone resorption, cathepsin K and matrix metalloproteinase 9, and were capable of resorbing calcified matrices. Expression of key osteoclastogenic transcription factor NFATc1 in osteoclast precursors was dramatically increased by short treatment with RANKL. NFATc1 was localized in the nuclei of primed osteoclast precursors when RANKL was present; however removal of RANKL led to rapid nuclear export of NFATc1. Cancer-derived factors were able to substitute for RANKL in supporting nuclear localization of NFATc1. Using neutralizing antibodies against TGFbeta, and a kinase inhibitor targeting the TGFbeta type I receptor, we identified TGFbeta as a permissive factor, required for the effects of breast cancer cells on NFATc1 nuclear accumulation and osteoclast formation. Our data suggest that, during differentiation, osteoclast precursors acquire the competency to respond to factors secreted by breast cancer cells, which may serve to promote tumor growth at skeletal sites undergoing active bone turnover.
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PMID:Osteoclast precursors acquire sensitivity to breast cancer derived factors early in differentiation. 1850 14

Metastasis to bone is the leading cause of morbidity and mortality in advanced prostate cancer patients. Considering the complex reciprocal interactions between the tumor cells and the bone microenvironment, there is increasing interest in developing combination therapies targeting both the tumor growth and the bone microenvironment. In this study, we investigated the effect of simultaneous blockade of BMP pathway and RANK/RANKL axis in an osteolytic prostate cancer lesion in bone. We used a retroviral vector encoding noggin (RetroNoggin) to antagonize the effect of BMPs and RANK:Fc, which is a recombinant RANKL antagonist was used to inhibit RANK/RANKL axis. The tumor growth and bone loss were evaluated using plain radiographs, hind limb tumor measurements, micro PET/CT ((18)FDG and (18)F-fluoride tracer), and histology. Tibias implanted with PC-3 cells developed pure osteolytic lesions at 2-weeks with progressive increase in cortical bone destruction at successive time points. Tibias implanted with PC-3 cells over expressing noggin (RetroNoggin) resulted in reduced tumor size and decreased bone loss compared to the implanted tibias in untreated control animals. RANK:Fc administration inhibited the formation of osteoclasts, delayed the development of osteolytic lesions, decreased bone loss and reduced tumor size in tibias implanted with PC-3 cells. The combination therapy with RANK:Fc and noggin over expression effectively delayed the radiographic development of osteolytic lesions, and decreased the bone loss and tumor burden compared to implanted tibias treated with noggin over expression alone. Furthermore, the animals treated with the combination strategy exhibited decreased bone loss (micro CT) and lower tumor burden (FDG micro PET) compared to animals treated with RANK:Fc alone. Combined blockade of RANK/RANKL axis and BMP pathway resulted in reduced tumor burden and decreased bone loss compared to inhibition of either individual pathway alone in osteolytic prostate cancer lesion in bone. These results suggest that simultaneous targeting of tumor cells and osteoclasts may be the most effective method of inhibiting the progression of established osteolytic metastatic lesions in vivo.
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PMID:Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone. 1892 92

Src is a tyrosine kinase involved in the regulation of a range of cellular processes including proliferation, adhesion, motility and survival. In addition, it is a key regulator of bone metabolism. Src has been implicated in the pathogenesis of a number of cancers, and has been found to be overexpressed in breast, prostate, colorectal, pancreatic and nonsmall-cell lung tumors. There is also evidence that aberrant Src signaling may contribute to the increased osteoclastic activity associated with bone metastases. Bone metastases frequently occur in cancer patients with advanced disease. The metastasized cells disrupt normal bone remodeling pathways resulting in the release of growth factors that further promote tumor growth. Thus, a cycle of metastatic bone destruction is initiated, leading to compromised skeletal integrity and substantially reduced quality of life. Because of the role of Src in both cancer development and in bone metabolism, it may provide a therapeutic target for patients with bone metastases.
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PMID:Targeting Src signaling in metastatic bone disease. 1894 61


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