Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cathepsin K is a novel cysteine protease previously reported to be restricted in its expression to osteoclasts. Immunolocalization of cathepsin K in breast tumor bone metastases revealed that the invading breast cancer cells expressed this protease, albeit at a lower intensity than in osteoclasts. In situ hybridization and immunolocalization studies were subsequently conducted to demonstrate cathepsin K mRNA and protein expression in samples of primary breast carcinoma. Expression of cathepsin K mRNA was confirmed by reverse transcription PCR and Southern analysis in a number of human breast cancer cell lines and in primary human breast tumors and their metastases. As this protease is known to degrade extracellular matrix, including bone matrix proteins, it is possible that cathepsin K may contribute to the invasive potential of breast cancer cells, including those that metastasize to bone. Thus, cathepsin K may be a potential target leading to the design of novel drugs for cancer therapy.
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PMID:The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. 939 64

MECHANISMS OF BONE LOSS: In patients with bone metastases, bone loss is the consequence of a dissociated process combining excessive bone resorption and inhibited bone formation. This destructive process occurs in response to soluble factors secreted by metastatic cells (PTH-rP, cytokines) which activate osteoclasts. These cells also secrete proteases (cathepsin K, metalloprotease MMP-9) which degrade the bone's collagen network. Excessive bone resorption is also favored by direct interaction between the metastatic cells and stromal cells in the bone marrow in response to the activation of membrane receptors (integrins a4 beta 1 and a4 beta 7). Finally, metastatic cells secrete non-identified soluble factors capable of inhibiting osteoblast proliferation in vitro. EFFECT OF BONE LOSS ON THE METASTASIS: Bone is a major reservoir of growth factors (mainly TGF beta and IGF-1). Positive feedback mechanism operates at the site of osteolysis where TGF beta released by bone tissue induces a paracrine stimulation of PTH-rP production by metastatic cells. IGF-1 released by the bone favors grow of metastatic cells present in the marrow. In addition, IGF-1 as well as collagen proteolytic fragments may stimulate recruitment of new metastatic cells at the site of the bone metastasis. This creates a vicious circle of mutual stimulation between bone destruction and tumor proliferation.
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PMID:[Bone hyperresorption in bone metastases]. 1074 42

Clinical disorders in which bone resorption is increased are very common and include Paget's disease of bone, osteoporosis, and the bone changes secondary to cancer, such as occur in myeloma and metastases from breast cancer. Clinical disorders of reduced bone resorption are less common and often have a genetic basis, e.g. in osteopetrosis, and in pycnodysostosis due to cathepsin K deficiency. Bone is metabolically active throughout life. After skeletal growth is complete, remodelling of both cortical and trabecular bone continues and results in an annual turnover of about 10% of the adult skeleton. The commonest disorder of bone resorption is osteoporosis, which affects one in three women over 50 years. Its pathophysiological basis includes genetic predisposition and subtle alterations in systemic and local hormones, coupled with environmental influences. Treatment depends mainly on drugs that inhibit bone resorption, either directly or indirectly. This includes bisphosphonates, oestrogens, synthetic oestrogen-related compounds (SERMs--selective oestrogen receptor modulators) and calcitonin. The most widely used drugs for all disorders of increased bone resorption, including osteoporosis, are the bisphosphonates. Recent elucidation of their mode of action, together with the rapidly increasing knowledge of regulatory mechanisms in bone biology, offers many opportunities for the development of new therapeutic agents.
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PMID:Clinical disorders of bone resorption. 1127 85

Prostate cancer (CaP) is the most commonly diagnosed malignancy in men and is often associated with bone metastases, which cause much of the morbidity associated with CaP. Lesions associated with CaP generally exhibit increased bone formation and resorption. Increased bone resorption may release factors from the extracellular matrix that contribute to tumor growth. Cathepsin K (cat K) is a cysteine protease that exhibits strong degradative activity against the extracellular matrix and is involved in osteoclast-mediated bone destruction. In this study, we analyzed the expression of cat K in CaP cell lines and patient samples. Cat K message was detected in CaP cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and in primary CaP and metastases by in situ hybridization. Immunohistochemistry revealed variable expression of cat K in primary CaP samples, as well as nonosseous metastases, whereas expression in bone metastases was significantly higher than in primary CaP, and normal prostate tissues were negative. Cat K protein was detected in CaP cell lines by Western blotting after immunoprecipitation. Cat K enzymatic activity was also detected in CaP cell lines by a fluorogenic assay and by an assay for degradation of collagen type I. Increased levels of NTx, a marker of bone matrix degradation mediated primarily by cat K, were also detected in sera of patients with CaP bone metastases. We hypothesize that CaP-expressed cat K may contribute to the invasive potential of CaP, while increased expression in bone metastases is consistent with a role in matrix degradation.
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PMID:Cathepsin K mRNA and protein expression in prostate cancer progression. 1256 99

The skeleton is the most common site of metastasis in patients with advanced prostate cancer. Despite many advances in targeting skeletal metastases, the mechanisms behind the attraction of prostate cancer cells to the bone are not known. Osteoclast cathepsin K, due to its ability to effectively degrade bone matrix collagen I, has been implicated in colonization and growth of prostate tumours in the bone. Identification of new cathepsin K substrates in the bone microenvironment and the recent findings demonstrating its involvement in obesity and inflammation suggest additional roles for this enzyme in skeletal metastases of prostate cancer.
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PMID:Cathepsin K in the bone microenvironment: link between obesity and prostate cancer? 1763 27

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

The preferential proliferation of cancer cells in the bone microenvironment is poorly characterised. Expression pattern of bone marrow and other organ microenvironment in contact with osteolytic (Walker W256) and osteoblastic (MatLyLu MLL) metastases were investigated. Fisher and Copenhagen rats received, respectively, W256 and MLL cells injection. Bone and soft tissues were analysed by immunochemistry for DKK1, cathepsin K, RANKL, MCSF or IL6 expression. Tartrate-resistant acid phosphatase (TRAcP)-positive cells were detected by a histoenzymatic technique. In bone, expressions of MCSF and DKK1 were shown in stromal cells of the bone marrow, in contact with metastatic foci of both tumours. Many stromal cells were found RANKL positive in the vicinity of the tumours. Cells expressing cathepsin K and multinucleated TRAcP+ cells were found in direct contact with trabeculae but also in bone marrow spaces near metastatic cells. In extraosseous tumours, cells in contact with malignant cells did not expressed DKK1, MCSF, cathepsin K and IL6. Some RANKL+ cells were found in the periphery of subcutaneous tumours but may represent Langerhans cells. Abnormal presence of TRAcP+ cells was never observed in the vicinity of malignant cells. Interaction between stromal and cancer cells induces the expression on the formers of characteristics leading to osteoclastogenesis only in the bone microenvironment.
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PMID:Interactions between microenvironment and cancer cells in two animal models of bone metastasis. 1825 14

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.
Clin Exp Metastasis 2008
PMID: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. 1830 92

Cathepsin K (catK) is a lysosomal cysteine protease with strong collagenolytic activity that mediates bone resorption in osteoclasts. Recently, catK expression has been reported in skin and lung fibroblasts, which suggests a role in maintaining homeostasis of the extracellular matrix outside of bone. Matrix degradation is a pivotal step in tumor invasion and metastasis. As other proteases, in particular matrix metalloproteinases and some cathepsins, but not catK, have been described to mediate melanoma invasion, we studied catK in melanoma. Immunostaining revealed strong catK expression in most primary melanomas and all cutaneous melanoma metastases. Melanocytic nevi also demonstrated catK expression, but it was less intense than in melanomas. Melanoma lines express both the pro- and the active form of catK and internalize extracellular collagen into lysosomes. Inhibition of catK greatly reduced melanoma cell invasion through Matrigel basement membrane matrix and increased detection of internalized collagen. We suggest that catK may play an important role in melanoma invasion and metastasis by mediating intracellular degradation of matrix proteins after phagocytosis. Clinical use of catK inhibitors, a class of medication currently in clinical trials for the treatment of osteoporosis, may be a promising avenue for the treatment of melanoma.
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PMID:Cathepsin K in melanoma invasion. 1836 30

Bone metastases of prostate cancer usually have an underlying osteoclastic component. Bone metastasis is incurable and contributes significantly to disease-specific morbidity and mortality. Management of bone metabolism in patients is a clinically significant issue. Several key factors have been found to be important in tumor-induced promotion of osteoclast activity. Receptor activator of nuclear factor-kappa B ligand (RANKL) is produced by bone metastasis of prostate cancer, enabling these metastasis to induce osteolysis through osteoclast activation. Matrix metalloproteinases (MMPs) are secreted by prostate cancer cells and promote osteolysis primarily through degradation of bone matrix. In this way, many factors derived from prostate cancer metastases can promote osteolysis, and these factors may serve as therapeutic targets. The new agents are targeted to osteoclasts (i.e.: zoledronic acid, anti-RANKL monoclonal antibody, cathepsin K inhibitor, and anti-PTHrP monoclonal antibody), are considered to be standard management in the care of bone metastasis patients in combination with chemotherapy and hormone therapy. In this review, we summarized the current understanding and therapy of bone metastasis in prostate cancer.
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PMID:[Bony lesion with prostate cancer]. 1837 23


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