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)

Cells contracting connective tissue matrices generate tractional forces in tissues. Studies of fibroblast contraction, using collagen gels in an in vitro model, demonstrate that it involves the actin cytoskeleton, specific extracellular matrix receptors and requires stimulation by exogenous promoters. Fibroblast contraction is stimulated by factors released by platelets and potentially secreted within the contracting tissue. Endothelial cells secrete a potent promoter of fibroblast contraction which has been identified as endothelin 1. The pathway through which fibroblast contraction is stimulated appears to require activation of protein kinase C. Tumor cells can also secrete endothelin. These mechanisms may be relevant to tumor progression.
Cancer Metastasis Rev 1992 Mar
PMID:Extracellular matrix contraction by fibroblasts: peptide promoters and second messengers. 151 96

The aim of this study was to evaluate multimodal chemotherapy and radiotherapy in patients with Ewing's sarcoma. 142 (74 male, 68 female) patients were entered into the ET-1 study between 1978 and 1986. They were treated with vincristine, doxorubicin, actinomycin D, and cyclophosphamide with radiotherapy plus or minus surgery to the primary tumour. Of the 120 who had no metastases at diagnosis, 45 remain alive with a median follow-up of 11.2 years. Only 2 of those with metastases at diagnosis remain alive. The major prognostic factor was site of disease, but age and serum lactic dehydrogenase at diagnosis also had an influence on outcome. 45 of the 61 patients who survived 4 years or more had late effects documented. The type and extent were dependent on tumour site, type of local therapy, volume and dose of radiotherapy. 4 patients had second malignancies. Prospects for long-term survival have improved in patients treated for Ewing's sarcoma. However, late sequelae are present in the majority of patients.
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PMID:Long-term results from the first UKCCSG Ewing's Tumour Study (ET-1). United Kingdom Children's Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma Working Party. 937 88

The endothelins, a family of potent vasoconstricting peptides, have been implicated in the pathophysiology of advanced prostate cancer. Two endothelin receptors, ET-A and ET-B are found in normal prostate tissue. Malignant prostate cells are notable for the loss of ET-B receptors and increased levels of endothelin-1 [ET-1]; this distortion of the endothelin system may be a significant factor in the progression of prostate cancer. Proposed roles for endothelin in prostate cancer include growth promotion, apoptosis inhibition, bone formation, and stimulation of nociceptive receptors. ET-1 can act alone as a mitogen, but its effects are greatest as a comitogen with a variety of growth factors, including basic fibroblast growth factor, insulin-like growth factors, and platelet derived growth factor. Although their exact functions are unclear, ET-1, in conjunction with vascular endothelial growth factor, appears to play a major role in tumor angiogenesis. By a variety of methods, ET-1 alters the balance of osteoblast and osteoclasts to the favor new bone formation that is characteristic of metastatic disease. Several studies indicate that the refractory pain of metastatic cancer is related to the direct nociceptive effects ET-1. These findings suggest that ET receptors are promising therapeutic targets for pharmacologic intervention. Early clinical trials indicate that the ET-A receptor antagonist used in prostate cancer is reasonably well tolerated with mild but pervasive symptoms related to ET-1's vasoconstrictive effects. Results of ongoing clinical trials are eagerly awaited in order to see if the hypothetical promise of ET antagonism will result in clinical success.
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PMID:Endothelin-1 as a target for therapeutic intervention in prostate cancer. 1209 77

Tumours of the Ewing's sarcoma (ES) family and neuroblastoma (NBL) were examined by reverse transcriptase-PCR for expression of mRNA for endothelin (ET) receptors ET-A and ET-B, and the ligands ET-1, ET-2 and ET-3. The effect of ET-1, ET-3, an ET-1-neutralizing antibody and ET-A receptor antagonist BQ-123 on cell proliferation was examined using an ELISA. Loss of ET-B receptor mRNA occurred in 57% of ES and 42% of NBL tumours. This appeared to be associated with the presence of metastatic disease and disease progression. ET-A receptor mRNA was expressed in all ES and 85% of NBL tumours, and in all ES and NBL cell lines examined. All ET ligands were detected in NBL cell lines, but only ET-1 and ET-2 were expressed in ES cell lines. Treatment of ES and NBL cells with ET-1 increased proliferation, but ET-3 had no effect. Incubation of ES and NBL cells with an ET-1-neutralizing antibody or BQ-123 decreased proliferation. The ET-3 ligand and ET-B receptor may be associated with migration and metastasis of ES and NBL, whereas ET-1 (acting through the ET-A receptor) may regulate their proliferation.
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PMID:Endothelins may modulate invasion and proliferation of Ewing's sarcoma and neuroblastoma. 1219 14

Most evidence indicates that osteoblastic bone metastases are due to tumor-produced factors that stimulate the osteoblast. This review supports a causal role for ET-1. Based on our results, we propose a model to explain the tumor cell and bone interactions that are responsible for the osteoblastic response (Figure 2). Tumor cells housed in bone produce factors, such as ET-1, stimulate osteoblast activity. This results in the abundant and disorganized new bone formation that is characteristic of osteoblastic metastases. The effects of ET-1 to stimulate bone formation are mediated by ETA receptors on the osteoblast. ETA receptor inhibition successfully blocked osteoblastic bone metastases in a mouse model. These receptor antagonists are currently in clinical trials for advanced prostate cancer and bone metastases (Stephenson, 2001; Carducci et al., 2002; 2003). Therefore, the molecular mechanisms responsible for osteoblastic metastases are complex and involve bi-directional interactions between tumor cells and bone. Elucidation of the interactions at a molecular level can identify therapeutic targets for osteoblastic metastases. Although ET-1 and ETA receptors are potential targets for this devastating complication of cancer (Remuzzi et al., 2003), they are certainly not the only ones. The rapid pace of metastasis research, will not only expand our therapeutic armamentarium against bone metastases, but will also provide insight into achieving the ultimate goal: the prevention of cancer metastases to bone.
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PMID:Endothelins in bone cancer metastases. 1504 94

We have studied the role of endothelins (ET-1, ET-2 and ET-3) and ET receptors (ET-RA and ET-RB) in the invasive capacity of breast tumor cells, which express ET-1 and ET-2 as well as ET-RA and ET-RB. Of five human breast tumor cell lines tested, all expressed mRNAs for ET-1, ET-2, and ET-RB. ET-RA mRNA was expressed by four of five tumor cell lines. Breast tumor cells migrated toward ET-1 and ET-2 but not toward ET-3. Chemotaxis involved signaling via both receptors, and a pertussis toxin-sensitive p42/p44 mitogen-activated protein kinase (MAPK)-mediated pathway that could be inhibited by MAPK kinase (MEK)1/2 antagonists. Chemotaxis toward ETs did not involve p38 or stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) and was not inhibited by hypoxia. Incubation of tumor cells with ET-2 also increased chemotaxis toward the chemokines CXCL12 and CCL21. As well as inducing chemotaxis of tumor cells, ET-1 and ET-2 increased tumor cell invasion through Matrigel. Furthermore, stimulation of macrophage/tumor cell cocultures with ETs led to increased matrix metalloproteinase (MMP)-2 and -9 production by macrophages and a marked increase in invasion of tumor cells. Antagonism of either ET-RA or ET-RB decreased the invasion seen in ET-stimulated cocultures, as did a broad-spectrum MMP inhibitor. Immunohistochemical staining of human breast tumor sections showed increased ET and ET receptor protein expression by tumor cells in invasive ductal carcinoma compared with normal breast tissue or ductal carcinoma in situ. Furthermore, tumor cell ET and receptor expression was stronger at the invasive margin of invasive ductal carcinomas, in the lymphovascular space, and in lymph node metastases. ET expression often colocalized with ET-RB expression in all neoplastic tissue indicating a possible autocrine action of ETs. We suggest that expression of ETs and their receptors by human breast tumors, particularly in conjunction with a high macrophage infiltrate, may have a role in the progression of breast cancer and the invasion of tumor cells.
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PMID:A role for endothelin-2 and its receptors in breast tumor cell invasion. 1505 99

This paper investigates the potential for long-term survivorship for young patients diagnosed with Ewing's sarcoma. Data are examined from two successive UKCCSG Ewing's Tumour studies (ET-1 and ET-2). Patients have been followed for up to 20 years. These studies had suggested that better 5-year survival with ET-2 over the earlier ET-1 was achieved by replacing cyclophosphamide by ifosfamide and increasing the dose of doxorubicin in a four-drug chemotherapy regimen. The updated hazard ratio, stratified for metastatic status at diagnosis, of 0.39 (95% confidence interval 0.12-0.61) confirmed the advantage of the ET-2 regimen in terms of overall survival. Cure models, based on the Weibull distribution, suggested that factors for long-term survival in addition to presence of metastases were age, primary site of tumour and study. Modelling identified the proportion cured with the ET-2 protocol as best at 70% in those who are under 10 years with a nonpelvic primary site and without metastatic disease. This contrasts to only 13% cure in those with the corresponding adverse prognostic indicators. Additionally, the risk of death remains greatest but relatively constant over the first 2 years postdiagnosis, and then declines to a lower but constant value for the next 3 years before reaching the 'cure plateau' at about 5 years. This investigation suggests that 'cure' is possible for patients with Ewing's sarcoma. This is established at approximately 5 years post diagnosis and the proportion cured depends on the presence of metastases, pelvic site and age at diagnosis.
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PMID:Establishing long-term survival and cure in young patients with Ewing's sarcoma. 1521 20

Human tumor cells inoculated into the arterial circulation of immunocompromised mice can reliably cause bone metastases, reproducing many of the clinical features seen in patients. Animal models permit the identification of tumor-produced factors, which act on bone cells, and of bone-derived factors. Local interactions stimulated by these factors drive a vicious cycle between tumor and bone that perpetuates skeletal metastases. Bone metastases can be osteolytic, osteoblastic, or mixed. Parathyroid hormone-related protein, PTHrP, is a common osteolytic factor, while vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1, ET-1. Other potential osteoblastic factors include bone morphogenetic proteins, platelet-derived growth factor, connective tissue growth factor, stanniocalcin, N-terminal fragments of PTHrP, and adrenomedullin. Osteoblasts are the main regulators of osteoclasts, and stimulation of osteoblast proliferation can increase osteoclast formation and activity. Thus, combined expression of osteoblastic and osteolytic factors can lead to mixed metastases or to increased osteolysis. Prostate-specific antigen is a protease, which can cleave PTHrP and thus change the balance of osteolytic versus osteoblastic responses to metastatic tumor cells. Bone itself stimulates tumor by releasing insulin-like growth factors and transforming growth factor-beta. Secreted factors transmit the interactions between tumor and bone. They provide novel targets for therapeutic interactions to break the vicious cycle of bone metastases. Clinically approved bisphosphonate anti-resorptive drugs reduce the release of active factors stored in bone, and PTHrP-neutralizing antibody, inhibitors of the RANK ligand pathway, and ET-1 receptor antagonist are in clinical trials. These adjuvant therapies act on bone cells, rather than the tumor cells. Recent gene array experiments identify additional factors, which may in the future prove to be clinically important targets.
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PMID:Tumor-bone cellular interactions in skeletal metastases. 1561 99

Endothelins are a family of small, structurally related, vasoactive peptides that have a great number of physiological roles in many tissues. The 'endothelin axis' consists of three 21 amino acid peptides (ET-1, ET-2 and ET-3), two G-protein-coupled receptors (ET-RA and ET-RB), and two activating peptidases or endothelin-converting enzymes (ECE-1 and ECE-2). There is increased expression of the endothelin axis in invasive breast cancer compared to the normal breast or non-invasive neoplastic tissue. Endothelin expression is associated with invading regions of tumours in patient biopsies and is more common in tumours with high histological grade and lymphovascular invasion, and there is increased systemic endothelin in patients with lymph node metastases compared to those without lymph node involvement. Stimulation of breast tumour cell lines with endothelins leads to an invasive phenotype in vitro. Over-expression of the endothelins and their receptors is insufficient to induce an invasive phenotype in benign cells, yet expression by tumour cells leads to markedly increased invasive ability indicating that endothelins act in concert with other factors--both autocrine and paracrine--including cytokines, matrix metalloproteinases and the activation of tumour-associated macrophages. The association between endothelins, poor prognosis and invasion may mean that the endothelin axis is a valid therapeutic target for the treatment of invasive breast cancer. This review summarises our current knowledge of endothelins in breast cancer invasion and discusses the potential further directions of such research as well as the possibility of anti-endothelin-based therapy of breast cancer.
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PMID:Endothelins in breast tumour cell invasion. 1586 61

There is increased staining of endothelins (ET-1, -2, and -3) and receptors (ET-RA and -RB) in invasive breast tumors compared to nonneoplastic tissue, and ETs stimulate MCF-7 cell invasion in vitro. We analyzed ETstimulation of benign and transformed mammary epithelial cells, and whether expression of ETs is sufficient to induce invasiveness. In breast cancer patient serum, ET-1 was increased in those patients with lymph node metastases compared to those with no lymph node involvement; ETs, however, had no mitogenic effect on breast tumor cell lines in vitro. The benign mammary epithelial cell line, hTERT-HME1, and the poorly invasive breast tumor cell line MCF-7 secreted low levels of ET-1, while the invasive cell lines SKBR3 and MDAMB231 secreted high levels. Expression of the ETs and receptors by the cell lines broadly correlated with their in vitro invasiveness; overexpression of ETs in MCF-7 cells increased basal invasion. ET-mediated invasion involved both receptors and a calcium influx to induce a pertussis toxin-sensitive MAPK pathway. MMP-14 activity was induced via ET-RA in an autocrine manner. In contrast to transformed cells, ET stimulation or overexpression did not induce an invasive phenotype in benign cells. Benign cells do not respond to ETs, and ET expression is not sufficient to induce invasion; however, the level of ET production by tumor cells correlates with their invasiveness, and increasing expression of the ET axis promotes breast tumor cell invasion via both receptors, while MMP-14 is induced via ET-RA.
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PMID:Expression of endothelins and their receptors promotes an invasive phenotype of breast tumor cells but is insufficient to induce invasion in benign cells. 1627 97


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