endothelin-1 and Neoplasms

The association between obstructive sleep apnea (OSA) and cancer is still debated and data are scarce regarding the link between OSA and breast cancer progression. Since conclusive epidemiological studies require large sample sizes and sufficient duration of exposure before incident cancer occurrence, basic science studies represent the most promising approach to appropriately address the topic. Here we assessed the impact of intermittent hypoxia (IH), the major hallmark of OSA, on the development of breast cancer and explored the specific involvement of the endothelin signaling pathway. Original in vitro and in vivo models were used where 3D-spheroids or cultures of murine 4T1 breast cancer cells were submitted to IH cycles, and nude NMRI mice, orthotopically implanted with 4T1 cells, were submitted to chronic IH exposure before and after implantation. The role of the endothelin-1 in promoting cancer cell development was investigated using the dual endothelin receptor antagonist, macitentan. In vitro exposure to IH significantly increased 4T1 cell proliferation and migration. Meta-analysis of 4 independent in vivo experiments showed that chronic IH exposure promoted tumor growth, assessed by caliper measurement (overall standardized mean difference: 1.00 [0.45-1.55], p < 0.001), bioluminescence imaging (1.65 [0.59-2.71]; p < 0.01) and tumor weight (0.86 [0.31-1.41], p < 0.01), and enhanced metastatic pulmonary expansion (0.77 [0.12-1.42]; p = 0.01). Both in vitro and in vivo tumor-promoting effects of IH were reversed by macitentan. Overall, these findings demonstrate that chronic intermittent hypoxia exposure promotes breast cancer growth and malignancy and that dual endothelin receptor blockade prevents intermittent hypoxia-induced tumor development.

Topics: Animals; Endothelin-1; Hypoxia; Mice; Neoplasms; Receptor, Endothelin A; Sleep Apnea, Obstructive

Topics: Cell Cycle Proteins; Endothelin-1; Female; Humans; Neoplasms; Transcription Factors

In human cancers, the autocrine and paracrine loop mediated by the aberrantly activation of endothelin-1 (ET-1) receptor (ET-1R) elicits pleiotropic effects, preferentially mediated by the scaffold protein β-arrestin 1 (β-arr1), on tumor cells and on the host microenvironment, providing a strong rationale for targeting ET-1 receptors. This review describes the most up-to-date preclinical and clinical results obtained by using ET-1 therapeutics. The previous negative clinical results of ET-1 therapeutics should not prevent us from setting the standard of this class of drugs for future well-designed clinical trials. The preclinical data obtained with the dual ETAR and ETBR antagonist macitentan indicate that this molecule, which targets cancer cells and tumor-associated microenvironmental elements, could be a cancer therapeutic option. The field of ET-1 therapeutics will be improved in the next decade, facilitated by the new knowledge on the genomic landscape of the human stroma and tumor, and by the low invasive approaches based on liquid biopsies for the discovery of predictive biomarkers. The information obtained from preclinical studies in patient-derived models and from the Cancer Genome Atlas will set the scene of precision medicine for cancer. Results from these studies are expected to open the possibility that ET-1R antagonists might be more efficacious as molecular cancer therapeutics, able to hamper the functional β-arr1-dependent signaling complexes, either alone or coupled with new targeted approaches.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Endothelin-1; Humans; Neoplasms; Receptor, Endothelin A; Receptor, Endothelin B

The advent of targeted therapeutics in human cancer has begun to find novel druggable targets and, in this context, the endothelin-1 receptor (ET-1R), namely ETA receptor (ETAR) and ETB receptor, among the GPCR family represents a class of highly druggable molecules in cancer. ET-1R are aberrantly expressed in human malignancies, potentially representing prognostic factors. Their activation by ligand stimulation initiate signaling cascades activating different downstream effectors, allowing precise control over multiple signaling pathways. ET-1R regulates cell proliferation, survival, motility, cytoskeletal changes, angiogenesis, metastasis as well as drug resistance. The molecular events underlying these responses are the activation of transcriptional factors and coactivators, and downstream genes, acting as key players in tumor growth and progression. ET-1R represent crucial cancer targets that have been exploited for ET-1R therapeutics. Importantly, efforts to explore new information of ETAR in cancer have uncovered that their functions are crucially regulated by multifunctional scaffold protein β-arrestins (β-arrs) which orchestrate the multidimensionality of ETAR signaling into highly regulated and distinct signaling complexes, a property that is highly advantageous for tumor signaling. Moreover, the role of β-arr1 in ET-1 signaling in cancer highlights why the pleiotropic effects of ET-1 and its dynamic signaling are more complex than previously recognized. In order to improve therapeutic strategies that interfere with the widespread effects of ET-1R, it is important to consider antagonists able to turn the receptors "off" selectively controlling β-arr1-dependent signaling, highlighting the possibility that targeting ETAR/β-arr1 may display a large therapeutic window in cancer.

Topics: beta-Arrestin 1; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Endothelin-1; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Invasiveness; Neoplasms; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction

Inflammation is one of the most important causes of the majority of cancer symptoms, including pain, fatigue, cachexia, and anorexia. Cancer pain affects 17 million people worldwide and can be caused by different mediators which act in primary efferent neurons directly or indirectly. Cytokines can be aberrantly produced by cancer and immune system cells and are of particular relevance in pain. Currently, there are very few strategies to control the release of cytokines that seems to be related to cancer pain. Nevertheless, in some cases, targeted drugs are available and in use for other diseases. In this paper, we aim to review the importance of cytokines in cancer pain and targeted strategies that can have an impact on controlling this symptom.

Topics: Adrenal Cortex Hormones; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemokines; Cyclooxygenase 2; Cytokines; Endothelin-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interferon-gamma; Interleukin-6; Neoplasms; Neurons, Efferent; Pain Management; Quality of Life

Since the discovery of endothelin (ET)-1 in 1988, the main components of the signalling pathway have become established, comprising three structurally similar endogenous 21-amino acid peptides, ET-1, ET-2 and ET-3, that activate two GPCRs, ETA and ETB . Our aim in this review is to highlight the recent progress in ET research. The ET-like domain peptide, corresponding to prepro-ET-193-166 , has been proposed to be co-synthesized and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long-lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ETA receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET-converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ETB receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally, we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research.

Topics: Antineoplastic Agents; Aspartic Acid Endopeptidases; Benzazepines; Bosentan; Endothelin A Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelin-Converting Enzymes; Endothelins; Epigenesis, Genetic; Humans; Hypertension, Pulmonary; Metalloendopeptidases; Neoplasms; Peptide Fragments; Phenylpropionates; Pyridazines; Pyrimidines; Receptor, Endothelin B; Sulfonamides; Vasodilator Agents

Activation of autocrine and paracrine signalling by endothelin 1 (ET1) binding to its receptors elicits pleiotropic effects on tumour cells and on the host microenvironment. This activation modulates cell proliferation, apoptosis, migration, epithelial-to-mesenchymal transition, chemoresistance and neovascularization, thus providing a strong rationale for targeting ET1 receptors in cancer. In this Review, we discuss the advances in our understanding of the diverse biological roles of ET1 in cancer and describe the latest preclinical and clinical progress that has been made using small-molecule antagonists of ET1 receptors that inhibit ET1-driven signalling.

Topics: Autocrine Communication; Cell Proliferation; Cell Survival; Endothelin-1; Humans; Lymphangiogenesis; Neoplasms; Neovascularization, Pathologic; Paracrine Communication; Receptors, Endothelin; Signal Transduction; Tumor Microenvironment

To assure their growth advantage cancer cells require the appropriation of key pathways, such as those controlled by G-protein coupled receptor (GPCR), that influence cell growth, migration, and death, as well as the expansion of vascular networks. Accumulating molecular and in vivo evidences demonstrate that the activation of the endothelin-1 (ET-1) axis elicites pleiotropic effects on tumour cells and on the tumour microenvironment as well, modulating epithelial to mesenchymal transition, chemoresistance, and other tumourassociated processes. As ET-1 axis blockade has been shown to reduce tumor growth in preclinical models, several small molecule antagonists of ET-1 receptors are currently undergoing clinical trial as novel agents in cancer therapy. To fully appreciate the potential hegemony of the ET-1 axis in cancer, here we review emerging preclinical and clinical data outlining the spectrum of cellular activities triggered by ET-1 signaling and the challenges facing molecular targeted therapy. Because scaffold proteins, such as β-arrestin, create signalling platforms that drive cellular transformation upon GPCR activation, mechanisms mediated by β-arrestin in ET-1 signalling are discussed. Deeper understanding of molecular mechanisms activated by ET-1 receptor, as well as of how pathway crosstalk can influence ET-1 signalling outcome in cancer, is of paramount translational relevance in the study of ET-1 receptor-targeted therapy. The improved knowledge of the interconnected molecular mechanism promoted by ET-1 axis in cancer will certainly result in more effective and durable mechanism-guided combinations of ET-1 receptor antagonists with cytotoxic drugs or other targeted agents in the clinical management of ET-1 axis-dependent malignancies.

Topics: Disease Progression; Drug Resistance, Neoplasm; Endothelin-1; Humans; Neoplasms; Receptors, G-Protein-Coupled

Endothelin Converting Enzyme-1 (ECE-1) plays a significant role in the regulation of vascular tone and hence blood pressure. It has also been implicated in the pathogenesis of cardiovascular diseases, female malignancies and Alzheimer's disease. Four different isoforms of ECE-1 exist and have varying degrees of distribution throughout the cell. Production of ET-1 by ECE-1 occurs at the cell surface and the expression and localisation of ECE-1 is the rate limiting step in the production of ET-1. This review looks at the current knowledge on ECE-1 phosphorylation and other stimuli which act induce trafficking of ECE-1 to the cell surface.

Topics: Alzheimer Disease; Amino Acid Sequence; Animals; Aspartic Acid Endopeptidases; Biological Transport; Cell Membrane; CHO Cells; Cricetinae; Cricetulus; Endothelin-1; Endothelin-Converting Enzymes; Female; Humans; Metalloendopeptidases; Models, Biological; Molecular Sequence Data; Neoplasms; Phosphorylation; Protein Isoforms

Understanding molecular mechanisms of tumourigenesis underlies new therapeutic strategies that specifically target tumours. This has led to the evolution of personalised therapy that was first used in breast cancer when hormone receptor status was determined. More recently in colorectal cancer treatment the Epidermal Growth Factor receptor and its tumourigenic role has led to its targeting by using Cetuximab and Panitumumab. Addition of these drugs to existing drug regimes (FOLFOX and FOLFIRI) showed improved respectability rates in patients with liver metastasis. Most recently the Endothelin receptor has been implicated in multiple tumourigenic processes. Interest has grown in using Endothelin A receptor antagonists as adjuvant or combination therapy as suggested by the FOLFERA and FOLFIRI trials currently on-going.

Topics: Animals; Antineoplastic Agents; Biological Products; Endothelin Receptor Antagonists; Endothelin-1; ErbB Receptors; Humans; Neoplasms; Precision Medicine; Receptors, Endothelin

Metastasis remains the major driver of mortality in patients with cancer. The multistep metastatic process requires the concerted actions of several genes and involves tumor cell invasion, epithelial mesenchymal transition (EMT), shedding from primary tumor, intravasation, arrest, extravasation and colonization at a preferential site. Understanding this complex process would provide the basis for the development of molecularly targeted therapeutics aimed at the tumor cell or its interaction with the host microenvironment. The neuropeptide hormones endothelins (specially, ET-1) have been correlated with invasiveness and metastasis of several cancers and high ET-1 levels are associated with decreased disease-specific survival. The mechanism(s) by which ET-1 promotes metastasis are being gradually unraveled. Through preferential binding to cognate receptors (ET(A)R or ET(B)R), ET-1 triggers autocrine and paracrine signaling cascades in tumor, immune and stromal cells, at both primary and distant sites, supporting cancer progression and metastasis. In this review, we will summarize the role of the ET axis in metastasis of different cancers and potential targeting of ET receptors in the therapeutic setting.

Topics: Drug Design; Endothelin-1; Humans; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

The endothelins (ET) are a group of proteins that act through G-protein coupled receptors. Endothelin-1 (ET-1) was initially identified as a potent vasoconstrictor and dysregulation of the ET axis contributes to pathological processes responsible for cardiovascular disease states. More recently, the ET axis, in particular ET-1 acting through the endothelin A receptor (ET(A) ), has been implicated in the development of several cancers through activation of pathways involved in cell proliferation, migration, invasion, epithelial-mesenchymal transition, osteogenesis and angiogenesis. The endothelin B receptor (ET(B) ) may counter tumour progression by promoting apoptosis and clearing ET-1; however, it has recently been implicated in the development of some tumour types including melanomas and oligodendrogliomas. Here, we review emerging preclinical and clinical data outlining the role of the ET axis in cancer, and its antagonism as an attractive and challenging approach to improve clinical cancer management. Clinical data of ET(A) antagonists in patients with prostate cancer are encouraging and provide promise for new ET(A) antagonist-based treatment strategies. Given the unexpected opportunities to affect pleiotrophic tumorigenic signals by targeting ET(A)-mediated pathways in a number of cancers, the evaluation of ET-targeted therapy in cancer warrants further investigation.

Topics: Animals; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Humans; Molecular Targeted Therapy; Neoplasms; Receptor, Endothelin A; Receptor, Endothelin B

Antibody, small molecule and protein inhibitors of angiogenesis are used in the management of several cancers. These do not specifically target tumor vascularity, and resistance can be problematic. VB-111 is a vascular-targeting agent consisting of a non-replicating adenovirus vector with a pre-proendothelin-1 promoter that encodes an apoptotic receptor.. The rationale and design of VB-111, its mechanism of action, and preclinical studies examining antitumor activity, toxicology and pharmacodynamics are reviewed. Phase I and Phase II clinical trials are also reviewed.. VB-111 is a vascular-targeting gene therapeutic that is both tissue- and condition-specific, with effects limited to endothelial cells undergoing angiogenesis. Systemic administration produces selective destruction of tumor vascularity. Synergistic antitumor activity can be observed when combined with chemotherapy. VB-111 has been found to be safe and well tolerated in a Phase I clinical trial in patients with advanced solid tumors. Phase II clinical trials are in progress. VB-111 is novel agent for cancer that may have application as monotherapy and in combination with other therapies.

Topics: Adenoviridae; Animals; Apoptosis; Endothelin-1; fas Receptor; Genetic Therapy; Genetic Vectors; Humans; Neoplasms; Neovascularization, Pathologic; Promoter Regions, Genetic; Receptors, Tumor Necrosis Factor, Type I; Treatment Outcome

The endogenous peptide endothelin-1 (ET-1), originally identified as a potent vasoconstrictor, plays a role in a number of painful conditions. In this review article we discuss the mechanisms that are essential for local sensitization by subcutaneously administered ET-1, and report evidence of ET-1's ability to sensitize distant regions of the body, through the central nervous system and, likely, coupling through the spinal cord. In addition, we will review the latest information on the role of ET-1 in cancerous and non-cancerous conditions. Cancer pain has indeed been shown to be attenuated by antagonists of endothelin receptors, and ET-1 is known to be secreted by cancer cells of many different histologic types. Furthermore, a growing body of evidence links increased expression and secretion of ET-1 to the occurrence of non-cancer related pain syndromes, such as inflammatory and neuropathic pain syndromes.

Topics: Animals; Central Nervous System; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Humans; Inflammation Mediators; Neoplasms; Nociceptors; Pain; Receptors, Endothelin; Receptors, G-Protein-Coupled; Sensory Receptor Cells

The endothelin peptides have an important role in the cancer-stromal interactions that promote tumour growth. Endothelin-1 (ET-1), clinically the most investigated endothelin, is a vital agent in the growth and progression of several tumours including prostate, ovarian, colorectal, bladder, breast and lung carcinomas. ET-1 exerts its effects through the activation of two distinct receptors, ET(A) and ET(B). Once activated, these receptors transmit signals via numerous intracellular signalling pathways. The effects of ET receptor stimulation in cancer cells or cancer-associated cells include proliferation, resistance to apoptosis, angiogenesis, migration and subsequent invasion. At present, the manipulation of the endothelin axis within the pre-clinical setting is the subject of intense investigation. Recent studies into ET receptor antagonism have produced interesting results highlighting the fact that these receptors may provide novel targets for a new generation of chemotherapeutic agents in a variety of cancers.

Topics: Antineoplastic Agents; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Male; Neoplasm Proteins; Neoplasms; Receptors, Endothelin; Signal Transduction

The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and 2 G protein-coupled receptor subtypes, ET AR and ET BR, promotes growth and progression of a variety of tumors, such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, lung, bladder, endometrial carcinoma, Kaposi's sarcoma, brain tumors, and melanoma. Acting on selective receptors, ET-1 regulates mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptors, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion, and metastatic dissemination. At the molecular level, endothelin receptor antagonists, besides providing ideal tools for dissecting the ET axis, have demonstrated their potential in developing novel therapeutic strategies. Emerging experimental and clinical data demonstrate that interfering with endothelin receptors provides an opportunity for the development of rational combinatorial approaches using endothelin receptor antagonists in combination with chemotherapy or molecularly targeted therapy.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Endothelin-1; Endothelins; Humans; Neoplasms; Neovascularization, Pathologic; Receptors, Endothelin; Signal Transduction

The endothelin axis (ET axis), comprising the three peptides endothelin (ET)-1, -2, -3 and their receptors ET(A)R and ET(B)R, is expressed in various cells and tissues. The biologically active ET-1 is formed by endothelin-converting enzyme (ECE) from inactive big-ET-1. ET-1 has emerged as an important peptide in a host of biological functions, including development, cellular proliferation, apoptosis and angiogenesis, thereby playing an important physiological and pathophysiological role. As these effects are mediated by ET(A)R, activation of ET(B)R prevents apoptosis, inhibits ECE expression and mediates the clearance of ET-1. Emerging data indicate that the ET axis is involved in tumourigenesis and tumour progression of various cancers. Expression of the ET axis has been demonstrated in a wide range of human tumours. Since most data have been reported for female malignancies, this review will focus on the role of the ET axis in cancers of the ovary, the cervix and the breast. In ovarian cancer, activation of ET(A)R by ET-1 is a key mechanism in the cellular signalling network promoting cancer growth and progression. Similar effects have been shown for cervical and endometrial cancer. In breast cancer, ET-1 via ET(A)R promotes proliferation and invasion, mediates bone metastases and predicts unfavourable response to chemotherapy. The outstanding role of ET-1 and ET(A)R in carcinogenesis and tumour progression has led to an extensive search for interfering agents, resulting in the development of selective ET(A)R antagonists on the one hand and inhibitors of the endothelin-converting enzyme (ECE) on the other. Targeting the ET axis via ET(A)R or ECE blockade seems to be a promising approach in the treatment of female malignancies.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Aspartic Acid Endopeptidases; Breast Neoplasms; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelin-Converting Enzymes; Enzyme Inhibitors; Female; Humans; Metalloendopeptidases; Molecular Sequence Data; Neoplasms; Ovarian Neoplasms; Receptor, Endothelin A; Receptor, Endothelin B; Uterine Cervical Neoplasms

Endothelins are a family of peptide compounds which exert regulatory control over cellular processes important for growth, survival, invasion, and angiogenesis. In particular, endothelin-1, acting primarily through the endothelin-A receptor, is implicated in the neoplastic growth of multiple tumor types. In preclinical models, endothelin antagonism inhibits tumor cell proliferation, invasiveness, and new vessel formation, as well as attenuates osteoblastic and pain-related responses to tumor. Clinical testing of an orally bioavailable endothelin antagonist has demonstrated benefit in PSA progression, markers of bone turnover, and pain in men with prostate cancer, but has not demonstrated significant improvement in survival or time to cancer progression. Although this class of drugs is promising for targeted anti-cancer therapy, their role in treatment remains to be defined by completion of future clinical trials.

Topics: Atrasentan; Bosentan; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Male; Neoplasms; Ovarian Neoplasms; Prostatic Neoplasms; Pyrimidines; Pyrrolidines; Receptors, Endothelin; Signal Transduction; Sulfonamides

Endothelin-1 (ET-1) and angiotensin II (AngII), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (ETA-R and ETB-R for ET-1, AT1R and AT2R for AngII) that all belong to the superfamily of G-protein coupled receptors. There is increasing evidence that ETA-R, ETB-R and AT1R are expressed in a variety of cancer cells and tissues, and may play a role on tumor growth, angiogenesis and invasion in vivo. This review summarizes the similarities and differences between the ET-1 and AngII systems with regard to their reported effects on various aspects of cancer. In addition to being expressed on vascular endothelium, ET-1 and AngII receptors participate in tumor angiogenesis through the production of the angiogenic factor VEGF. Furthermore, recent clinical studies indicate that a selective ETA-R antagonist has beneficial effects in prostate cancer, suggesting that a similar approach using ETB-R and AT1R blockers might be envisioned. Experimental data presented here suggest that a combined therapy targeting both ET-1 and AngII systems may prove valuable for future treatments of highly angiogenic tumors.

Topics: Angiogenesis Inhibitors; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Antineoplastic Agents; Benzimidazoles; Biphenyl Compounds; Clinical Trials as Topic; Endothelin-1; Humans; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Receptors, Angiotensin; Receptors, Endothelin; Tetrazoles

Tumours require oxygenation, nutrition and a route for dissemination. This necessitates the development of new vessels or angiogenesis. High levels of new vessel development are indicators of poor prognosis in cancer; they also provide new avenues of anti-tumour therapy. Angiogenesis in cancer produces structurally different vessels from angiogenesis in wound healing and inflammation. This article reviews the differences between vessels in tumour angiogenesis and normal angiogenesis. The main focus of the article is the role of the vasoactive peptide endothelin-1 (ET-1) in tumour angiogenesis. The role of ET-1 in tumour development is reviewed, before the direct and indirect effects of ET-1 in angiogenesis are examined. ET-1 has a direct angiogenic effect on endothelial and peri-vascular cells. It also has an indirect action through the increased release of the potent pro-angiogenic substance vascular endothelial growth factor (VEGF), via hypoxia inducible factor-1. ET-1 also indirectly stimulates angiogenesis by stimulating fibroblasts and cancer cells to produce pro-angiogenic proteases. ET-1 is a novel stimulator of tumour angiogenesis and warrants further examination as an anti-angiogenic treatment target.

Topics: Animals; Endothelin-1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Neovascularization, Pathologic; Transcription Factors; Vascular Endothelial Growth Factor A

Topics: Animals; Breast Neoplasms; Endothelin-1; Humans; Linoleic Acid; Melatonin; Neoplasms; Telomerase

Tumor vessels express distinct molecular markers that are functionally relevant in the angiogenic process. Although tyrosine kinase receptor agonists are the major mediators of angiogenesis, several G-protein-coupled receptor agonists have also been shown to have a role. Among these, endothelin-1 (ET-1), by acting directly on endothelial cells via the ET(B) receptor, modulates different stages of neovascularization, including proliferation, migration, invasion, protease production and morphogenesis, and also stimulates neovascularization in vivo. ET-1 can also modulate tumor angiogenesis indirectly through the induction of vascular endothelial growth factor (VEGF). Engagement of the ET(A) receptor by ET-1 induces VEGF production by increasing levels of hypoxia-inducible factor 1 alpha. Moreover, tumor cells themselves, predominantly expressing the ET(A) receptor, might form vessel-like channels within the tumors. The role of ET-1 and its signaling network in tumor angiogenesis suggests that new therapeutic strategies using specific ET(A)-receptor antagonists could improve antitumor treatment by inhibiting both neovascularization and tumor cell growth.

Topics: Animals; DNA-Binding Proteins; Endothelial Growth Factors; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Signaling Peptides and Proteins; Lymphokines; Neoplasms; Neovascularization, Pathologic; Nuclear Proteins; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Signal Transduction; Transcription Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Endothelin-1 is a small vasoconstrictor peptide that was first identified in 1988. Here we review the evidence implicating ET-1 in tumorigenesis. In particular, we concentrate on the role of ET-1 in mitogenesis, apoptosis, angiogenesis, tumour invasion and metastasis, and discuss the potential for endothelin-system modulation as an adjuvant therapeutic strategy.

Topics: Apoptosis; Disease Progression; Endothelin-1; Humans; Neoplasms; Neovascularization, Pathologic; Receptors, Endothelin

Chemotherapy is an established approach for several malignancies, but its utility may be hampered by induced cardiac toxicity possibly leading to heart failure, with a negative impact on the patient's quality of life and ultimately survival. Prospective left ventricular systolic function monitoring has demonstrated that cardiotoxicity could be subclinically present for many months or years before its overt manifestation. Although considered irreversible, some reports suggested recovery or delayed progression of cardiac dysfunction by preventive cardioactive therapies. Thus, the identification of earlier instrumental or biochemical markers of cardiac injury able to predict heart failure remains a major task. Diastolic indexes as a primary expression of hemodynamic dysfunction after cardiac damage, analyzed by means of conventional or newer Doppler technologies (tissue Doppler, color M-mode, etc.) are discussed. Moreover, brain natriuretic peptides, troponins and endothelin-1, as possible sensitive/specific markers/predictors of subclinical cardiotoxicity are reviewed in order to update and possibly improve the strategy for the detection and clinical management of chemotherapy-related cardiotoxic effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Cardiac Output, Low; Endothelin-1; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Neoplasms; Predictive Value of Tests; Primary Prevention; Prognosis; Quality of Life; Sensitivity and Specificity; Severity of Illness Index; Troponin; Ventricular Dysfunction, Left

Topics: Aged; Endothelin-1; Female; Hemangiosarcoma; Hormones, Ectopic; Humans; Neoplasms; Paraneoplastic Endocrine Syndromes; Vascular Neoplasms

This review summarises the process of angiogenesis, its role in tumourigenesis and suggests a mechanism by which endothelin-1 may influence these processes.

Topics: Endothelin-1; Humans; Neoplasms; Neovascularization, Pathologic

There has been a growing conviction amongst oncologists that cancer is a disease characterized by changes in specific molecules. These changes include alteration in the structure, regulation or quantity of growth factors and their receptors, signal transducers and the proteins encoded by dominant or suppressor/recessive oncogenes. The role of endothelin (vasoactive peptide) in tumour cell signal transduction and mitogenesis and induction of endothelial cell growth and angiogenesis in tumour growth is discussed in this article.

Topics: Endothelin-1; Humans; Mitogens; Neoplasms; Neovascularization, Pathologic; Receptors, Endothelin; Signal Transduction

Suboptimal drug distribution and hypoxia, which can contribute to treatment failure, are a direct consequence of the spatial and temporal heterogeneity in perfusion that occurs in solid tumors. Therefore, improvements in tumor blood flow have wide-ranging therapeutic importance. Paradoxically, controlled decreases in tumor blood flow can also be exploited and, if permanent, induce extensive tumor cell death on their own. We review the current knowledge of the factors controlling tumor blood flow with emphasis on the roles of the endogeneous vasodilator nitric oxide and the endogenous vasoconstrictor endothelin-1. The potential importance and application of approaches that irreversibly damage vascular function, so-called vascular targeting, are also discussed. Emphasis is given to the drug-based approaches to vascular targeting that are now entering clinical evaluation. There is no doubt that increased understanding of the processes that determine blood flow in tumors, coupled with the availability of techniques to monitor blood flow noninvasively in the clinic, will enable strategies for selectively modifying tumor blood flow to be transferred from the laboratory to the clinical setting.

Topics: Antineoplastic Agents; Blood Vessels; Cell Death; Cell Hypoxia; Endothelin-1; Humans; Neoplasms; Nitric Oxide; Regional Blood Flow; Tissue Distribution; Treatment Failure; Vasoconstrictor Agents; Vasodilator Agents

Although pain is a frequent feature in patients with cancer, its etiology is still poorly understood. In recent years, endothelin-1 (ET-1) has become a major target molecule in the etiology of cancer pain. In this randomised, double-blind study the effects of intradermal injection of ET-1 on spontaneous pain, temperature perception and sensation of punctate stimulation were evaluated. Thirty-five subjects were randomised to receive either placebo or one of four concentrations of ET-1 (ranging from 10(-10) to 10(-6)M). Besides assessment of spontaneous pain, three neurosensory testings were performed: (1) cold and warm sensation, (2) cold and heat pain, and (3) punctate stimulation using a von Frey monofilament. ET-1 produced a dose-dependent flare zone that was absent after placebo injection. Subjects reported a short-lasting spontaneous pain upon administration of the highest concentrations of ET-1. Injection of ET-1 induced a long-lasting and dose-dependent punctate hyperalgesia in an area around the injection site (secondary hyperalgesia). Thermal testing revealed a short period of hypoesthesia to non-noxious warm and cold stimuli after some doses of ET-1. In addition to the mechanical hyperalgesia, intradermal injection of ET-1 almost instantaneously induced a state of cold hyperalgesia outlasting the study period (120 min). No development of heat hyperalgesia was observed. The observed psychophysical characteristics of this new model of ET-1 induced nociception indicate its potential as a human experimental model for cancer pain.

Topics: Adult; Behavior; Biophysics; Dose-Response Relationship, Drug; Double-Blind Method; Endothelin-1; Humans; Hyperalgesia; Injections, Intradermal; Male; Models, Neurological; Neoplasms; Nociceptors; Pain; Receptor, Endothelin A; Sensory Receptor Cells; Thermosensing

Recent reports suggest that complex interactions exist between the neuroendocrine and immune systems. It has been shown for example that cytokines are able to stimulate the hypothalamo-pituitary-adrenal axis. In addition, some studies present evidence that endothelin is able to modulate the activity of several hypothalamic-pituitary axes, e.g. by inducing the ACTH production.. We investigated the effects of interleukin-2 on endothelin levels and the hypothalamo-pituitary-adrenal axis. We determined the interleukin-6, big-endothelin, endothelin-1, ACTH, cortisol and AVP responses to intravenously and subcutaneously administered interleukin-2 in 8 cancer patients in a randomized placebo controlled trial.. 8 Patients (2 female and 6 male), age 44 +/- 4.8 years, were enrolled. All patients had a World Health Organization performance status of 1 or less and a Karnofsky Index of at least 80%.. Blood-samples were taken before and 15, 30, 45, 60, 120, 180, 240, 300 and 360 min after interleukin-2 injection. Cytokine serum levels and the plasma levels of big-endothelin, endothelin, ACTH and AVP were analysed using radioimmuno-assays. Cortisol was assayed by an enzyme-linked immunosorbent assay.. Interleukin-2 treatment significantly increased plasma big-endothelin levels (P < 0.01 vs basal) and endothelin-1 levels (P < 0.05 vs basal) within two hours and this was followed by an increase in ACTH (P < 0.01 vs basal) and cortisol (P < 0.05 vs basal) within three hours. Interleukin-6 levels increased two hours after interleukin-2 administration (P < 0.01 vs basal). Interleukin-2 had no detectable effect on AVP, blood pressure or heart rate.. Our data demonstrate that cytokines are able to activate the human hypothalamo-pituitary-adrenal axis in vivo. On the basis of the observed time kinetics and in connection with previous findings from in vitro and animal models, we conclude that endothelin may be a link between cytokines and corticotrophin-releasing hormone, most probably functioning as a cytokine-induced neuromodulator controlling pituitary functions.

Topics: Adrenocorticotropic Hormone; Adult; Arginine Vasopressin; Endothelin-1; Endothelins; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Interleukin-2; Interleukin-6; Kidney Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Pituitary-Adrenal System; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Precursors; Stimulation, Chemical

Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti-angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic-related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient-derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET-1), an important regulator of angiogenesis and the hypoxia-related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET-1-induced hypoxia-inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy.

Topics: Animals; Cell Line, Tumor; Endothelin-1; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Metformin; Mice; Neoplasms; Neovascularization, Pathologic; Simvastatin

GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients.. We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint.. GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease.. Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

Topics: Adrenomedullin; Aged; Breast Neoplasms; C-Reactive Protein; Cause of Death; Endothelin-1; Female; Gastrointestinal Neoplasms; Glycopeptides; Growth Differentiation Factor 15; Humans; Interleukin-6; Lung Neoplasms; Male; Middle Aged; Mortality; Myelodysplastic Syndromes; Myeloproliferative Disorders; Natriuretic Peptide, Brain; Neoplasm Metastasis; Neoplasms; Peptide Fragments; Prognosis; Proportional Hazards Models; Prospective Studies; Protein Precursors; Serum Amyloid A Protein; Troponin T

Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO- levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Cardiotoxicity; Cell Communication; Cell-Derived Microparticles; Cells, Cultured; Endothelial Cells; Endothelin-1; Female; Humans; Male; Middle Aged; Neoplasms; Nitric Oxide; Reactive Oxygen Species; Signal Transduction; Tyrosine; Vascular Endothelial Growth Factor A

The overexpression of endothelin (ET)-1 or ET receptors (ETRs) is related to initiation and progression of tumor. In cancer cells, ET-1 activates various signaling pathways, including mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase C through ETRs, although the mechanisms by which ET-1 activates these signaling pathways remain uncertain. Here, we found that ETRs interacted with annexin A2, which is overexpressed in various cancers. Annexin A2 bound to ET type A receptor and ET type B receptor. Upon ET-1 stimulation, serine phosphorylation of annexin A2 increased, while there is no change in tyrosine phosphorylation of annexin A2. On the other hand, annexin A2 silencing suppressed activation of ERK upon ET-1 stimulation. These results suggest that interaction of ETRs and annexin A2 may play important roles in activation of extracellular signal-regulated kinase upon ET-1 stimulation.

Topics: Annexin A2; Cell Line, Tumor; Endothelin-1; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; HeLa Cells; Humans; MAP Kinase Signaling System; Neoplasms; Phosphorylation

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor involved in many diseases, including certain cardiovascular disorders and cancer. As previous studies have shown that the G protein estrogen receptor (GPER) may regulate ET-1 dependent effects on the vascular system, we evaluated whether GPER could contribute to the effects elicited by ET-1 in breast cancer and hepatocarcinoma cells. Here, we demonstrate that ET-1 increases GPER expression through endothelin receptor A (ETAR) and endothelin receptor B (ETBR) along with the activation of PI3K/ERK/c-Fos/AP1 transduction pathway. In addition, we show that GPER is involved in important biological responses observed upon ET-1 exposure, as the migration of the aforementioned tumor cells and the formation of tube-like structures in human umbilical vein endothelial cells (HUVECs). Our data suggest that GPER may contribute to ET-1 action toward the progression of some types of tumor.

Topics: Cell Line, Tumor; Cell Movement; Cells, Cultured; Endothelin-1; Hep G2 Cells; Humans; Neoplasms; Neovascularization, Physiologic; Receptors, Estrogen; Receptors, G-Protein-Coupled; Signal Transduction; Transcription Factor AP-1; Transcriptional Activation; Up-Regulation

Cancer patients with bone metastases often suffer breakthrough pain. However, little progress has been made in the treatment of breakthrough pain and its associated mechanism(s) in the patient with cancer due to lacking of resembling and predictive animal models. We previously have demonstrated that endothelin-1 plays an important role in breakthrough cancer pain. In the present study, we have established an animal model of breakthrough cancer pain induced by endothelin-1. The animal model of breakthrough cancer pain is strictly followed the definition and meets the characteristics of breakthrough pain. The model is reliable, reproducible and easy to be produced. To our knowledge, this is the first report for establishing such an animal model. In addition, we also found that a selective ETA receptor antagonist BQ-123 could reverse endothelin-1 induced breakthrough pain. We further studied the characteristics of pain behaviors such as hind limb use score and voluntary wheel running as well as the electrophysiology of sciatic nerve fibers with the model. The murine model shows high resemblance compared to the breakthrough cancer pain in the patients with cancer clinically. It provides a platform for further study of the pathogenesis of breakthrough cancer pain and targeted intervention.

Topics: Action Potentials; Analgesics, Opioid; Animals; Breakthrough Pain; Cell Line, Tumor; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Hindlimb; Male; Mice, Inbred C57BL; Morphine; Motor Activity; Neoplasm Transplantation; Neoplasms; Nerve Fibers; Peptides, Cyclic; Sciatic Nerve

The endothelins ET-1, ET-2 and ET-3 are a family of peptides, which exert their actions via two G protein-coupled receptor subtypes, ETA and ETB. ET-1 is a potent vasoconstrictor and is involved in the development of different cardiovascular and renal disorders. Additionally, ET-1 and the ETA receptor have been shown to be important mediators of cancer growth and metastasis. We have extensively characterized the novel monoclonal rabbit anti-ETA antibody UMB-8 using transfected cells as well as mouse, rat and human tissues. UMB-8 was then tested in a large series of formalin-fixed and paraffin-embedded human normal and neoplastic tissue specimens. Specificity of UMB-8 was demonstrated by detection of a broad band migrating at 70-80kDa in Western blot analyses of ETA-transfected HEK-293 cells and of different mouse tissues and by agonist-dependent translocation of the immunosignal from the surface of ETA-transfected cells into the cytosol. In tissue samples, UMB-8 yielded an efficient immunostaining of distinct cell populations with a predominance of plasma membrane staining, which was abolished after preadsorption of the antibody with its immunizing peptide. In normal tissue, ETA was present in the heart, blood vessels, gut and kidneys. ETA was also detected with a hitherto unappreciated high prevalence in all types of sarcomas and in glioblastomas, but also in various epithelial tumor entities and in tumor stroma. All in all, UMB-8 may prove of great value in the identification of ETA-expressing tumors during routine histopathological examinations.

Topics: Antibodies, Monoclonal; Endothelin-1; HEK293 Cells; Humans; Immunohistochemistry; In Vitro Techniques; Neoplasms; Receptor, Endothelin A; Receptor, Endothelin B

Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer.. We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint.. During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP.. Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Topics: Adrenomedullin; Aged; Asymptomatic Diseases; Atrial Natriuretic Factor; Austria; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Endothelin-1; Female; Glycopeptides; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Neoplasm Staging; Neoplasms; Peptide Fragments; Prospective Studies; Protein Precursors; Troponin T

Many studies of human subjects have demonstrated the utility of assessing serum levels of endothelin-1 (ET-1) and big ET-1 as clinical biomarkers in cardiopulmonary and neoplastic diseases. In this study we explored the feasibility of using serum big ET-1 as a reliable veterinary marker in dogs with various cardiopulmonary and neoplastic diseases.. Serum big ET-1 levels were measured by ELISA in dogs with cardiopulmonary (n=21) and neoplastic diseases (n=57). Dogs exhibiting cardiopulmonary disease were divided into two groups based on the velocity of tricuspid valve regurgitation (3.0>m/s) measured by ultrasound: without and with pulmonary hypertension. Big ET-1 levels for the dogs with the diseases were compared with levels in normal healthy dogs (n=17).. Dogs with cardiopulmonary disease (4.6±4.6 pmol/l) showed a significantly (P<0.01) higher level of big ET-1 than healthy control dogs (1.1±0.53 pmol/l). Serum levels in the dogs with pulmonary hypertension (6.2±5.3 pmol/l) were significantly (P<0.01) higher than those without pulmonary hypertension (2.0±0.6 pmol/l). Dogs with hemangiosarcoma (5.6±2.2 pmol/l), adenocarcinoma (2.0±1.8 pmol/l), histiocytic sarcoma (3.3±1.9 pmol/l), chondrosarcoma or osteosarcoma (3.0±1.6 pmol/l) and hepatocellular carcinoma (2.7±1.8 pmol/l) showed significantly (P<0.05) higher levels than healthy control dogs.. These findings point to the potential of serum big ET-1 as a clinical marker for cardiopulmonary and neoplastic diseases in dogs.

Topics: Animals; Biomarkers; Cardiovascular Diseases; Dogs; Endothelin-1; Female; Humans; Lung Diseases; Male; Natriuretic Peptide, Brain; Neoplasms; Peptide Fragments

Endothelin-1 (ET-1) is a potent vasoconstrictor and an elevated plasma level is a prognostic marker in patients with cardiovascular diseases and/or malignancies. We hypothesized that an elevated plasma level might be a prognostic marker even in subjects without apparent cardiovascular disease or malignancy at baseline.. We measured plasma ET-1 levels in 1,440 healthy subjects over 40 years of age (580 men, 860 women) who were periodically followed for 10 years. The follow-up rate was 96.8%. Baseline plasma ET-1 levels were categorized into quartiles. Baseline plasma ET-1 levels were significantly associated with age, blood pressure, high-density lipoprotein-cholesterol, renal function, uric acid and all-cause death, but not with cardiovascular or cancer death. Kaplan-Meier curves demonstrated that all-cause mortality was significantly higher in the highest quartile of ET-1 than in the lowest quartile. Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause death [hazard ratio: 1.11, 95% confidence interval (CI) 1.01-1.23 per 1 pg/ml difference]. The hazard ratio of all-cause death in the highest quartile of plasma ET-1 (≥5.9 pg/ml) vs. the lowest quartile after adjusting for confounding factors was 1.54 (95% CI 1.09-2.20).. The plasma ET-1 level may be a predictor of all-cause death in a healthy population.

Topics: Aged; Asian People; Biomarkers; Cardiovascular Diseases; Cause of Death; Chi-Square Distribution; Confounding Factors, Epidemiologic; Endothelin-1; Female; Follow-Up Studies; Health Surveys; Humans; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Neoplasms; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment.

Topics: Animals; beta-Endorphin; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Endothelin-1; Endothelins; Humans; Mice; Mice, Nude; Narcotic Antagonists; Neoplasm Transplantation; Neoplasms; Nociceptors; Oligopeptides; Opioid Peptides; Pain; Peptide Fragments; Piperidines; Receptor, Endothelin B; Receptors, Opioid; Sensory Receptor Cells; Up-Regulation

The membrane glycoprotein podoplanin is expressed by several types of human cancers and might be associated with their malignant progression. Its exact biological function and molecular targets are unclear, however. Here, we assessed the relevance of tumor cell expression of podoplanin in cancer metastasis to lymph nodes, using a human MCF7 breast carcinoma xenograft model. We found that podoplanin expression promoted tumor cell motility in vitro and, unexpectedly, increased tumor lymphangiogenesis and metastasis to regional lymph nodes in vivo, without promoting primary tumor growth. Importantly, high cancer cell expression levels of podoplanin correlated with lymph node metastasis and reduced survival times in a large cohort of 252 oral squamous cell carcinoma patients. Based on comparative transcriptional profiling of tumor xenografts, we identified endothelin-1, villin-1, and tenascin-C as potential mediators of podoplanin-induced tumor lymphangiogenesis and metastasis. These unexpected findings identify a novel mechanism of tumor lymphangiogenesis and metastasis induced by cancer cell expression of podoplanin, suggesting that reagents designed to interfere with podoplanin function might be developed as therapeutics for patients with advanced cancer.

Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cytoskeletal Proteins; Endothelin-1; Extracellular Matrix Proteins; Gene Expression Profiling; Humans; Lymphangiogenesis; Lymphatic Metastasis; Membrane Glycoproteins; Mice; Mice, Nude; Microarray Analysis; Middle Aged; Neoplasm Transplantation; Neoplasms; Survival Rate; Transplantation, Heterologous

Endothelin-1 is a powerful mitogen for various tumor and non-tumor cells. Its signaling cascade induces the inflammatory NF-kappaB complex, leading to expression of a number of target genes. In this context, MAPK p38 has been regarded as a potential phosphate donor for the p65 subunit of NF-kappaB. In the present study in HeLa cells, we have found that ET-1 induced signalling activates the NF-kappaB transcription complex (TC) in the nucleus at 6 h specifically via ET-A - but not ET-B receptor. The TC contains p65, p38 (alpha and beta) - binding to the NLS of p65 in the cytoplasm - as well as p50, but no IkappaBalpha. Specific p38 inhibition by SB203580 or by siRNA interferes markedly with gene expression of several target genes. Complex formation occurs in the cytoplasm, and both transcription factors transmigrate as a complex in the nucleus. Overexpression of p38, treatment with Chrysin, MG132, or dimethylformamide shows dependence of TC on p38 as partner. In other tumor cells lines studied, ET-1 activates TC, with p38 as an important complex partner of p65. TC-induction by ET-1 contains about twice the amount of p38 than by TNFalpha. Thus, p38 may be an additional therapeutic target to control inflammatory gene expression in tumor cells.

Topics: Cell Line, Tumor; Cytoplasm; Electrophoretic Mobility Shift Assay; Endothelin-1; HeLa Cells; Humans; Neoplasms; Nuclear Localization Signals; p38 Mitogen-Activated Protein Kinases; Receptor, Endothelin A; RNA Interference; Signal Transduction; Transcription Factor RelA; Transcription, Genetic; Tumor Necrosis Factor-alpha

To study the changes and significance of prethrombotic state indexes in patients with malignant cancer.. The expression of CD62p on platelets, level of plasma tissue plasminogen activator (t-PA), level of serum endothelin (ET-1), activated partial thromboplastin time (APTT), fibrinogen ( FIB), prothrombin time (PT), and thrombin time (TT) were examined by flow cytometer, enzyme-linked immunosorbent assay, radioimmunoassay method, and auto coagulometer.. The average expression of CD62P, level of plasma FIB and serum ET-1 in the tumor group increased compared with those in the control group (P<0.05); the level of t-PA in the tumor group decreased compared with that in the control group (P<0.05). APTT and PT were significantly shortened in the tumor group (P<0.05). There was no significant changes of TT in 2 groups (P>0.05).. The platelet is activated, the thrombin activity increases, and the fibrinolytic function declines in patients with malignant cancer; there is an obvious prethrombotic state in patients with malignant cancer.

Topics: Adult; Aged; Blood Coagulation; Blood Platelets; Case-Control Studies; Endothelin-1; Female; Fibrinogen; Humans; Male; Middle Aged; Neoplasms; P-Selectin; Partial Thromboplastin Time; Plasminogen Activator Inhibitor 1; Prothrombin Time; Thrombin Time; Tissue Plasminogen Activator

The endothelins (ETs), which include ET-1, ET-2, ET-3, and their receptors ET-A and ET-B, play a major role in tumor growth, proliferation, apoptosis, angiogenesis, and bone metastasis. Atrasentan is a novel and selective inhibitor of ET-1 and ET-A. In vitro and in vivo data show that this oral agent is capable of inhibiting tumor cells in vitro. More recently, this agent was studied in several phase I trials with refractory carcinoma patients. Subsequently, phase II and III clinical trials evaluating atrasentan in patients with hormone-refractory prostate carcinoma have suggested that targeting this pathway may be a new therapeutic strategy in the treatment of solid malignancies, specifically, prostate cancer.

Topics: Antineoplastic Agents; Atrasentan; Clinical Trials as Topic; Disease Progression; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Male; Neoplasms; Prostatic Neoplasms; Pyrrolidines; Receptor, Endothelin A; Receptors, Endothelin

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ET(A) receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ET(A) receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ET(A) antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ET(A) antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Arterioles; Blood Flow Velocity; Blood Pressure; Blood Vessels; Cyclophosphamide; Drug Delivery Systems; Endothelin A Receptor Antagonists; Endothelin-1; In Situ Nick-End Labeling; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Muscle Relaxation; Neoplasms; Neovascularization, Pathologic

Aldosterone is produced not only in the adrenal gland but also in the extra-adrenal tissues, including failing human heart. This study examined the production of dehydroepiandrosterone (DHEA) in human heart and elucidated the possible physiological significance. Method and Results- Using left ventricular tissues obtained at autopsy, reverse transcription-polymerase chain reaction followed by Southern blot analysis revealed the gene expressions of CYP17. By measuring plasma aldosterone and DHEA levels at the coronary sinuses and aortic roots during cardiac catheterization, we found that DHEA but not aldosterone was secreted from control subjects (P<0.0001 and P=0.74, respectively), whereas aldosterone but not DHEA was secreted from patients with heart failure (P=0.0017 and P=0.67, respectively). To examine the significance of DHEA, we measured myocyte cell sizes and the gene expression of B-type natriuretic peptide (BNP), using a neonatal rat cardiocyte culture system. We found that DHEA (10(-8) mol/L) significantly inhibited the increase in myocyte cell sizes and BNP mRNA levels upregulated by endothelin-1 (P=0.031 and P<0.0001, respectively).. CYP17 gene expression and production of DHEA were demonstrated in human control heart. Also, we found that cardiac production of DHEA was suppressed in failing heart. We postulated that DHEA and/or its metabolites exert a cardioprotective action through antihypertrophic effects.

Topics: Adult; Aged; Aldosterone; Animals; Blotting, Southern; Cardiac Catheterization; Cell Size; Cells, Cultured; Dehydroepiandrosterone; Endothelin-1; Female; Heart Failure; Heart Ventricles; Humans; Hypertrophy; Male; Middle Aged; Myocytes, Cardiac; Natriuretic Peptide, Brain; Neoplasms; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Steroid 11-beta-Hydroxylase; Steroid 17-alpha-Hydroxylase

Angiogenesis is necessary for the growth of primary tumors and the formation of metastases. It is well known that vascular endothelial growth factor (VEGF) and its receptors play a major role in this process. To date, the formation of bone metastases has been poorly understood. Tumor cells must interact with the microenvironment of the bone and new blood vessels must spread. The ET/ET(A) (endothelin) receptor system seems to play an important role in this process. Specimens from metastatic bone lesions and non-malignant bone tissue were analyzed by histological and immunohistochemical staining. Sections were stained with antibodies against CD31, Flt-1, KDR, endothelin-1 (ET-1) and endothelin receptor A (ET(A)). Our studies show that there is an increased microvessel density (MVD) in metastatic bone lesions from different primary tumors in contrast to normal bone tissue. In nearly all tumor formations of the bone, ET-1 and its receptor ET(A) was found by immunohistochemistry. We also performed immunohistochemical staining for the VEGF-receptors Flt-1 and KDR. In conclusion, there is an increased vessel density in metastatic bone lesions in contrast to normal bone tissue. The ET/ET(A) system can be detected in nearly all bone specimens and is upregulated in metastatic bone lesions in contrast to healthy bone tissue.

Topics: Bone Neoplasms; Case-Control Studies; Endothelin-1; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Neoplasms; Neovascularization, Pathologic; Receptor, Endothelin A; Up-Regulation; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

The characteristics of specific binding of human [125I]Tyr(13)-endothelin-(1-21), [125I]-Tyr(13)-Suc-[Glu(9),Ala(11, 15)]-endothelin-(8-21), ([125I]IRL-1620) and endothelin ET(A) receptor antagonist [125I]Tyr(3)-(N-[(hexahydro-1H-azepin-1-yl)carbonyl]-L-Leu]-1Me )-D-Trp ([125I]PD151242) (number of sites and their affinity) and proliferation responses to exogenous endothelin receptor agonists (endothelin-1 and the endothelin ET(B) receptor-selective, truncated N-acetyl-[Ala(11,15)]-endothelin-(6-21) analogue BQ3020) were determined in cultured human fibroblasts and in tumorigenic HeLa cells. The cells were pre-incubated with equimolar concentrations of human endothelin-1 or its truncated analogue BQ3020. After pre-incubation (2 h), both peptides induced down-regulation of surface-membrane endothelin-1 receptors. This process was specific for endothelin ET(B) receptors and was much more intensive in tumorigenic cells. BQ3020, acting mostly through its C-terminus, induced nearly maximal endothelin ET(B) receptor down-regulation in HeLa cells. Staurosporine, a wide spectrum protein kinase inhibitor, significantly reduced, and N-[N-[N-[2, 6-dimethyl-1piperidinyl)carbonyl]-4-Me-L-Leu]-1-(methoxycarbonyl)- D-t ryptophanyl]-D-norleucine (BQ788), an endothelin ET(B) receptor antagonist, attenuated the down-regulation of endothelin receptors induced by endothelin receptor agonists. The down-regulation of endothelin ET(B) receptors was prevented by pre-incubation of the cells with the lysosomal enzyme blocker chloroquine. The endothelin-1-induced cell proliferation was attenuated by pre-incubation of the cells with the non-selective endothelin receptor antagonist Ac-D-10,11-dihydro-5H-dibenzo[a,d] cycloheptene-glycine-3,3-D-diphenyl-Ala-Leu-Asp-Ile-Ile-Trp (PD142893) and it was only partially reduced by the endothelin ET(A) receptor-selective endothelin antagonist PD151242.

Topics: Cells, Cultured; Down-Regulation; Endothelin-1; Endothelins; Fibroblasts; HeLa Cells; Humans; Kinetics; Ligands; Membranes; Neoplasms; Peptide Fragments; Receptor, Endothelin B; Receptors, Endothelin

Topics: Endothelin-1; Humans; Neoplasms; Neovascularization, Pathologic; Nitric Oxide

Plasma concentrations of the vasoconstrictor endothelin-1 (ET-1) increase during acute physiologic stress, but the role of ET-1 in the pathophysiology of stress remains largely undefined. Whether ET-1 mediates thermoregulatory changes in vasomotor tone is unknown. ET-1 and its more stable precursor, Big ET-1, were measured in plasma obtained at several perioperative time points from 95 consecutive elderly patients (mean age 70 +/- 1 yr) randomized to receive either normothermic or hypothermic perioperative care while undergoing major surgical procedures. In the postoperative period, there were no significant changes in plasma ET-1 concentrations, but Big ET-1 concentrations increased considerably (P < 0.0001). There were no significant differences in mean ET-1 or Big ET-1 levels in normothermic and hypothermic patients. Preoperative and postoperative ET-1 concentrations were significantly higher in patients with a history of hypertension (P < 0.002) and in those requiring treatment for postoperative hypertension (P < 0.003). Patients with cancer and those undergoing abdominal surgery had significantly higher Big ET-1 concentrations (P < 0.0001 and P < 0.003, respectively). These data support the hypothesis that Big ET-1 is a more sensitive measure of endothelin system activation after major surgery. Premorbid conditions and location and type of surgery influence perioperative ET-1/Big ET-1 concentrations.. The endothelin response seems to be significantly associated with perioperative hemodynamic aberrations. The endothelin-1 (ET-1) precursor Big ET-1 is a more sensitive measure of the endothelin system activation in response to surgical stress than ET-1 alone. Thermoregulatory vasoconstriction in response to mild perioperative hypothermia occurs independently of the endothelin system.

Topics: Abdomen; Age Factors; Aged; Elective Surgical Procedures; Endothelin-1; Endothelins; Hemodynamics; Humans; Neoplasms; Postoperative Period; Protein Precursors; Sex Factors

Ectopic hormone secretion in tumor cells is here described as an amplification of hormone production already present in normal, nonendocrine tumor-originated tissue. This idea is tested on the available data regarding endothelin-1 (ET-1) secreting tumors. The endothelins are ubiquitous regulatory peptides produced by various tissues. The precursor cells of many tumor types secrete endothelins. ET-1 protein expression was detected in situ in all tested prostate cancers as well as in normal prostate tissue. The majority of hepatocellular carcinomas produce ET-1, while ET-1 is secreted by the normal hepatic stellate cells. Human breast cancer cells produce immunoreactive ET-1. Similar data exist for pancreatic tissue, the thyroid and large bowel. We can conclude that tumor cells might sustain endothelin secretions already present in the normal tumor-originated tissue. The model that is presented of the pseudoectopic hormone secretion consists of relations between a few parameters. The proportion of hormone-secreting tumors (Th) among all tumors (T) of that organ depends on the amount of the hormone-secreting cells (Ch) among all cells (C) susceptible to malignant transformation. The corrective factor (k) was introduced in the expression Th/T=Ch/C*k, to represent specific conditions altering the malignant transformation probability for a certain normal hormone-secreting cell. In prostate, breast and colon, the kvalue is predicted to be approximately 1, suggesting that ET-1-secreting normal cells are not more prone to the malignant transformation than their neighbours. In liver and pancreas, the incidence of ET-1-secreting tumors outnumbers the proportions of normal ET-1-secreting cells (k values >1). In these organs, normal ET-1-secreting cells seem more likely to turn malignant in comparison to their neighbours, perhaps due to their function, position and exposition to oncogenic factors, or even due to their ET-1 secretion. There are similar data for thyroid and adrenal glands. No ET-1 secretion was reported in kidney neoplasms. Normal renal ET-1 secreting cells might be less prone to turn malignant than other renal cells. Unlse the normal lung tissue, small cell lung cancers often secrete adrenocorticotrophic hormone (ACTH). The pancreatic islet cells do not secrete gastrin, but their tumors often do. Constant k would exceed 1 in both cases. We speculate that these tumors might originate from a small subset of cells with the described feature. Tumor cells s

Topics: Animals; Breast Neoplasms; Endothelin-1; Female; Hormones; Humans; Kidney Neoplasms; Male; Models, Biological; Neoplasms

Treatment with intravenous recombinant human interleukin-2 (rh IL-2) is frequently accompanied by the capillary leak syndrome and disturbances of the coagulation system. Although the exact mechanisms are still not fully understood, the involvement of the endothelium is proven. This investigation aimed to elucidate more precisely the role of the endothelium in the generation of IL-2-based side-effects. In nine tumour patients receiving intravenous rh IL-2, parameters characterizing endothelial cell activation as well as activation of the coagulation system were evaluated. A significant increase of the circulating endothelial leucocyte adhesion molecule-1 (cELAM-1) and the vasoconstrictor peptide endothelin-1 (ET-1) was observed (P<0.05), indicating activation of endothelial cells. The simultaneous increase of tissue-plasminogen activator and plasminogen activator inhibitor type-1 during therapy (P<0.05) corroborated this observation. A decrease in platelet count parallelled by an increase of fibrin degradation products, the prolongation of partial thromboplastin time, and the decrease of fibrinogen (P<0.05) suggested the development of disseminated intravascular coagulation (DIC), induced by activated endothelium and intensified by transient hepatic failure. We concluded that activation of the endothelium mediated by IL-2 was accompanied by a loss of endothelial integrity and capillary leak. The activated endothelium can trigger DIC via activation of the coagulation cascade. The increased ET-1 might act as an endogenous counter-regulator of the disadvantageous haemodynamic side-effects induced by IL-2.

Topics: Blood Coagulation; Capillaries; Cell Adhesion Molecules; Cytokines; E-Selectin; Endothelin-1; Endothelium, Vascular; Fibrinolysis; Humans; Intercellular Adhesion Molecule-1; Interleukin-2; Neoplasms; Syndrome; Vascular Diseases

Vascular endothelial damage may play an important role in the pathophysiology of disseminated intravascular coagulation (DIC), a frequent complication of malignant neoplasms. It may mediate a variety of triggering events to initiate DIC and platelet aggregation, which in turn leads to additional endothelial destruction. If so, endothelin-1 (ET-1), the most potent vasoconstrictor of naturally occurring pressor substances known, may leak from injured endothelial cells and aggravate the disease process.. The study included 36 patients with various malignant neoplasms in whom DIC developed. The authors measured plasma levels of ET-1 and big ET-1, a precursor peptide of ET-1, in these patients and compared them with other laboratory abnormalities during the course of DIC.. Plasma ET-1 and big ET-1 levels were elevated in most patients with DIC. When compared with the results of other diagnostic tests, elevated plasma big ET-1 was the most frequently found abnormality associated with DIC. Elevation of plasma ET-1 and big ET-1 levels was closely related to the initiation and progression of DIC and provided a higher degree of sensitivity and specificity than did other indicators in assessing patients with cancer and DIC.. Vascular endothelial damage with the resultant increases in plasma ET-1 and big ET-1 levels is universally associated with DIC caused by malignancy. Excessive secretion or leakage of ET-1 and big ET-1 from injured endothelial cells may cause vasospasm and aggravate the DIC process by facilitating the formation of intravascular microthrombi, ultimately leading to ischemic end-organ dysfunction. Plasma ET-1 and big ET-1 are sensitive and specific markers for vascular endothelial injury in DIC.

Topics: Adult; Aged; Aged, 80 and over; Antithrombin III; Disseminated Intravascular Coagulation; Endothelin-1; Endothelins; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Lymphoma; Male; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Neoplasms; Platelet Count; Protein Precursors; Prothrombin Time