endothelin-1 and Neoplasm-Metastasis

RhoGDI2 is a guanine nucleotide dissociation inhibitor (GDI) specific for the Rho family of small GTPases that plays dual opposite roles in tumor progression, being both a promoter in tissues such as breast and a metastasis suppressor in tissues such as the bladder. Despite a clear role for this protein in modulating the invasive and metastatic process, the mechanisms through which RhoGDI2 executes these functions remain unclear. This review will highlight the current state of our knowledge regarding how RhoGDI2 functions in metastasis with a focus on bladder cancer and will also seek to highlight other potential underappreciated avenues through which this protein may affect cancer cell behavior.

Topics: Animals; Apoptosis; Endothelin-1; GTP Phosphohydrolases; Humans; Neoplasm Metastasis; Protein Kinase C-alpha; rho Guanine Nucleotide Dissociation Inhibitor beta; Urinary Bladder Neoplasms

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

Tumor metastasis is a main contributor to death in cancer patients. In the last years, a new class of molecules that reduces the metastatic propensity has been identified: metastasis suppressors. These proteins regulate multiple steps in the metastatic cascade, including cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. As a consequence, they are very important therapeutic targets. This review discusses our current understanding of metastasis suppressors and how this knowledge might be useful to improve the treatment of cancer patients.

Topics: Animals; Atrasentan; Endothelin-1; Genes, Tumor Suppressor; Humans; Neoplasm Metastasis; Pyrrolidines; Tumor Suppressor Proteins

Ovarian cancer is a highly metastatic disease and the leading cause of death from gynecologic malignancy. Hence, and understanding of the molecular changes associated with ovarian cancer metastasis could lead to the identification of targets for novel therapeutic interventions. The conversion of an epithelial cell to a mesenchymal cell plays a key role both in the embryonic development and cancer invasion and metastasis. Cells undergoing epithelial-mesenchymal transition (EMT) lose their epithelial morphology, reorganize their cytoskeleton and acquire a motile phenotype through the up- and down-regulation of several molecules including tight and adherent junctions proteins and mesenchymal markers. EMT is believed to be governed by signals from the neoplastic microenvironment including a variety of cytokines and growth factors. In ovarian cancer EMT is induced by transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and endothelin-1 (ET-1). Alterations in these cellular pathways candidate them as useful target for ovarian cancer treatment.

Topics: Bone Morphogenetic Protein 4; Cadherins; Cell Differentiation; Endothelin-1; Epidermal Growth Factor; Epithelial Cells; Female; Hepatocyte Growth Factor; Humans; Mesoderm; Neoplasm Metastasis; Ovarian Neoplasms; Transforming Growth Factor beta

Progression of hormone-refractory prostate cancer (HRPC) is associated with skeletal complications and bone pain, which contribute to deterioration in quality of life (QOL). The effects of new HRPC therapies on patients' QOL need to be studied. Patient-based assessments that help quantify the risk-benefit profile of HRPC therapies are warranted. This review summarizes the known QOL literature and estimates the potential effect of atrasentan, a novel, selective endothelin A receptor antagonist (SERA), on the QOL of HRPC patients.. Published studies were identified through a structured, detailed literature review. Clinical studies that report QOL data were reviewed, along with recent QOL data from atrasentan studies.. HRPC studies have begun to use QOL assessments as primary endpoints, but different assessments and therapies are not comparable. Very few data integrate QOL with clinical endpoints. Atrasentan clinical trials demonstrated a statistically significant difference in the prostate cancer-specific QOL in favor of atrasentan (p=.032) and an increased quality-adjusted time to progression in men with HRPC.. Atrasentan provides QOL benefits relevant to HRPC. The quality-adjusted analyses applied in the atrasentan studies have begun to lay the foundation for interpreting clinical endpoints in conjunction with QOL. These analyses will facilitate better QOL comparisons within studies and across trials. Further evaluation of atrasentan in HRPC is warranted.

Topics: Atrasentan; Drug Resistance, Neoplasm; Endothelin-1; Gonadal Steroid Hormones; Humans; Male; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms; Pyrrolidines; Quality of Life

Certain solid tumors metastasize to bone, causing an osteoblastic response. The mechanisms by which tumor cells stimulate this new bone formation are not understood completely. We identified three breast cancer lines that cause osteoblastic metastases in female nude mice and provide evidence that tumor-produced endothelin-1 (ET-1) mediates the osteoblastic response. Tumor-conditioned media and exogenous ET-1 stimulated osteoblast proliferation and new bone formation in cultures of calvarias from mice. These effects were blocked by endothelin A (ETA) but not by ETB receptor antagonists. Mice inoculated with the ZR-75-1 breast cancer line and treated with a selective ETA receptor antagonist (ABT-627) had significantly fewer osteoblastic bone metastases and less tumor burden compared with untreated mice. In contrast, there was no effect of ABT-627 on osteolytic bone metastases caused by ET-1-negative breast cancer, MDA-MB-231. ABT-627 had no effect on cell growth in vitro or at the orthotopic site (mammary fat pad) of ZR-75-1, or MDA-MB-231 cells. Collectively, the data suggest that tumor-produced ET-1 mediates osteoblastic bone metastases by stimulating osteoblast proliferation and new bone formation. Endothelin A receptor blockade may be useful for the prevention and treatment of osteoblastic bone metastases attributable to breast or prostate cancer.

Topics: Animals; Bone Neoplasms; Bone Remodeling; Disease Models, Animal; Endothelin-1; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Metastasis; Osteoblasts; Tumor Cells, Cultured

Topics: Atrasentan; Disease Progression; Double-Blind Method; Endothelin-1; Humans; Male; Neoplasm Metastasis; Pain; Prostate-Specific Antigen; Prostatic Neoplasms; Pyrrolidines; Quality of Life; Survival Analysis; Treatment Outcome

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

The expression of the transcription factor

Topics: Animals; Breast Neoplasms; Chromatin; Culture Media, Conditioned; Endothelin-1; Epigenesis, Genetic; Epithelial Cells; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; HEK293 Cells; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Promoter Regions, Genetic; RNA, Messenger; SOXC Transcription Factors; Survival Analysis; Trans-Activators; Transcription, Genetic; Xenograft Model Antitumor Assays; Zebrafish

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

Topics: Adrenal Gland Neoplasms; Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Cell Growth Processes; Cell Line, Tumor; Endothelin-1; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Idarubicin; Mice; Mice, Nude; Neoplasm Metastasis; Pheochromocytoma; Phosphoglycerate Kinase; Protein Binding; Signal Transduction; Xenograft Model Antitumor Assays

The pathogenesis of bone metastasis is unclear, and much focus in metastatic biology and therapy relays on epigenetic alterations. Since DNA-methyltransferase blockade with 5-aza-2'-deoxycytidine (dAza) counteracts tumour growth, here we utilized dAza to clarify whether molecular events undergoing epigenetic control were critical for bone metastatization. In particular, we investigated the patterns of secreted-protein acidic and rich in cysteine (SPARC) and of Endothelin 1, affected by DNA methyltransferases in tumours, with the hypothesis that in bone metastasis a coordinate function of SPARC and Endothelin 1, if any occurs, was orchestrated by DNA methylation. To this purpose, we prepared a xenograft model with the clone 1833, derived from human-MDA-MB231 cells, and dAza administration slowed-down metastasis outgrowth. This seemed consequent to the reductions of SPARC and Endothelin 1 at invasive front and in the bone marrow, mostly due to loss of Twist. In the metastasis bulk Snail, partly reduced by dAza, might sustain Endothelin 1-SPARC cooperativity. Both SPARC and Endothelin 1 underwent post-translational control by miRNAs, a molecular mechanism that might explain the in vivo data. Ectopic miR29a reduced SPARC expression also under long-term dAza exposure, while Endothelin 1 down-regulation occurred in the presence of endogenous-miR98 expression. Notably, dAza effects differed depending on in vivo and in vitro conditions. In 1833 cells exposed to 30-days dAza, SPARC-protein level was practically unaffected, while Endothelin 1 induction depended on the 3'-UTR functionality. The blockade of methyltransferases leading to SPARC reduction in vivo, might represent a promising strategy to hamper early steps of the metastatic process affecting the osteogenic niche.

Topics: Animals; Azacitidine; Bone Neoplasms; Breast Neoplasms; DNA Methylation; DNA, Neoplasm; Endothelin-1; Female; Humans; Mice; Mice, Nude; MicroRNAs; Neoplasm Metastasis; Neoplasm Proteins; Osteonectin; RNA, Neoplasm; Tumor Microenvironment

Colorectal cancer (CRC) is one of the three leading causes for cancer mortality. CRC kills over 600,000 people annually worldwide. The most common cause of death from CRC is the metastasis to distant organs. However, biomarkers for CRC metastasis remain ill-defined. We compared primary and metastatic CRC cell lines for their angiogenesis-protein profiles and intracellular signaling profiles to identify novel biomarkers for CRC metastasis. To this end, we used primary and metastatic CRC cell lines as a model system and normal human colon cell line as a control. The angiogenesis profiles two isogenic CRC cell lines, SW480 and SW620, and HT-29 and T84 revealed that VEGF was upregulated in both SW620 and T84 whereas coagulation factor III, IGFBP-3, DPP IV, PDGF AA/AB, endothelin I and CXCL16 were downregulated specifically in metastatic cell lines. Furthermore, we found that TIMP-1, amphiregulin, endostatin, angiogenin were upregulated in SW620 whereas downregulated in T84. Angiogenin was downregulated in T84 and GM-CSF was also downregulated in SW620. To induce CRC cell metastasis, we treated cells with pro-inflammatory cytokine IL-6. Upon IL-6 treatment, epithelial-mesenchymal transition was induced in CRC cells. When DLD-1 and HT-29 cells were treated with IL-6; Akt, STAT3, AMPKα and Bad phosphorylation levels were increased. Interestingly, SW620 showed the same signal activation pattern with IL-6 treatment of HT-29 and DLD-1. Our data suggest that Akt, STAT3, AMPKα and Bad activation can be biomarkers for metastatic colorectal cancer. IL-6 treatment specifically reduced phosphorylation levels of EGFR, HER2 receptor, Insulin R and IGF-1R in receptor tyrosine kinase array study with HT-29. Taken together, we have identified novel biomarkers for metastatic CRC through the angiogenesis-antibody array and intracellular signaling array studies. Present study suggests that those novel biomarkers can be used as CRC prognosis biomarkers, and as potential targets for the metastatic CRC therapy.

Topics: Antibodies; Biomarkers, Tumor; Cell Line, Tumor; Chemokine CXCL16; Chemokines, CXC; Colorectal Neoplasms; Dipeptidyl Peptidase 4; Endothelin-1; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Insulin-Like Growth Factor Binding Protein 3; Interleukin-6; Neoplasm Metastasis; Neovascularization, Pathologic; Octamer Transcription Factor-3; Platelet-Derived Growth Factor; Receptors, Scavenger; Ribonuclease, Pancreatic; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor A

The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.

Topics: Adenylyl Cyclases; Apoptosis; Arrestins; beta-Arrestins; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Endothelin-1; Enzyme Activators; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; GTP-Binding Protein alpha Subunits, Gs; Humans; Models, Biological; Neoplasm Metastasis; Neovascularization, Pathologic; Ovarian Neoplasms; Receptor, Endothelin A; Signal Transduction; Survival Analysis

To determine the mechanism of neuroblastoma (NB) bone invasion/metastasis, it is necessary to investigate the bone invasion/metastasis-related factors in the bone invasion/metastasis process. Some evidence has suggested that various proteins were involved in bone osteolytic response. The invasion/metastasis property and gene expression of NB, however, are still unknown.. Single-cell suspensions of SY5Y and KCNR cells were injected directly into the femur of nude mice. Radiological and histological analyses, immunohistochemistry analyses, and western blot assay were performed to characterize bone metastasis mechanism in these bone metastasis models.. SY5Y and KCNR NB cells result in osteolytic responses in bone metastasis model. Osteoprotegerin (OPG), receptor activator of NF-kappaB ligand (RANKL), parathyroid hormone-related peptide (PTHrP), endothelin 1 (ET-1), and CXCR4 were examined and compared among in vitro, in vivo, and normal bone, respectively. PTHrP, OPG, RANKL, and ET-1 except CXCR4 in SY5Y and KCNR NB cells xenografts were strikingly upregulated compared with normal bone and NB cells. However, significantly stronger expression of PTHrP and RANKL was presented than ET-1 and OPG; furthermore, the ratios of expression of PTHrP, RANKL to OPG, and ET-1 were also markedly increased in vivo versus in vitro.. Our study provided evidence that NB cell may enhance bone invasion through PTHrP, OPG, RANKL, and ET-1, especially PTHrP and RANKL which may display stronger effects. CXCR4 appeared not participating in bone invasion, but in tumor growth, and homing to bone. Targeting PTHrP, OPG, ET-1, and RANKL may provide a new insight and method for patient therapy by inhibiting NB bone metastasis and invasiveness.

Topics: Animals; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Endothelin-1; Femur; Humans; Immunohistochemistry; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Neuroblastoma; Osteolysis; Osteoprotegerin; Parathyroid Hormone-Related Protein; RANK Ligand; Receptors, CXCR4

Endothelin receptor B (ET(B)R) is a G-protein-coupled receptor overexpressed in melanoma, blood, and lymphatic endothelial cells. Given that aberrant signal transduction can be mediated through cross talk between receptors, here, we explore the functional relationship between ET(B)R and the vascular endothelial growth factor receptor (VEGFR)-3 system and how this cross talk might influence the aggressive behavior of melanoma cells. The expression of VEGFR-3 and its ligands, VEGF-C and VEGF-D, significantly increased after activating ET(B)R by ET-1 in primary and metastatic melanoma cell lines. These effects, similarly to those induced by hypoxia, were mediated by hypoxia-inducible factor (HIF)-1α and HIF-2α. ET-1 caused the phosphorylation of VEGFR-3, which was accompanied by the activation of the downstream signaling molecules, such as MAPK and AKT. Inhibition of c-Src activity or silencing of the scaffold protein β-arrestin-1 reduced ET-1-induced VEGFR-3 phosphorylation, demonstrating that, upon ET-1 stimulus, β-arrestin-1 is involved with c-Src in the ET(B)R-mediated VEGFR-3 transactivation. Moreover, ET-1 in combination with VEGF-C further increased VEGFR-3, MAPK, and AKT phosphorylation and markedly promoted cell migration and vasculogenic mimicry. Dual inhibition of ET(B)R and VEGFR-3 was required for the effective inhibition of these effects, as well as for VEGFR-3 phosphorylation, demonstrating that ET(B)R cross talk with VEGFR-3 enhances cell plasticity and motility. Finally, in melanoma xenografts, ET(B)R antagonist inhibited tumor growth and the activation of the VEGF-C/VEGFR-3 axis, indicating that targeting ET(B)R may improve melanoma treatment acting directly or indirectly by impairing ET(B)R cross talk with VEGFR-3.

Topics: Animals; Cell Line, Tumor; Cell Movement; Endothelin-1; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mice; Neoplasm Metastasis; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, Endothelin B; Signal Transduction; Transplantation, Heterologous; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3

Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in human breast cancers. It is known to drive tumor growth and progression and represents a prominent target in breast cancer therapy. The endothelin (ET) system, in particular ET-1 and its receptor ET(A)R, is of major relevance for breast cancer growth and invasion. Having previously demonstrated coexpression of ET(A)R and HER2 in breast tumors, this study was designed to investigate molecular interactions of HER2 (including the epidermal growth factor receptor EGFR as its major coreceptor) and ET signaling, and the potential benefit of a combined anti-HER2/ET(A)R treatment in human breast cancer cells. Dual HER2-ET(A)R targeting utilizing trastuzumab (monoclonal anti-HER2 antibody) and the ET(A)R antagonist atrasentan was superior to each agent alone in inhibiting basal and EGF-induced proliferation and invasion of HER2-overexpressing BT-474 and SK-BR-3 cells. EGF-induced invasion was partially inhibited by atrasentan alone, suggesting the involvement of ET(A)R in EGF receptor mediated invasion of breast cancer cells. Moreover, secretion of the pro-invasive ET-1 was shown to be induced by EGF via EGFR and HER2, including MAPK-dependent signaling. In turn, an ET-1/ET(A)R-dependent regulation of EGFR protein expression and phosphorylation (at Tyr845) was observed, which may contribute to the additional anti-proliferative and anti-invasive effects of atrasentan on trastuzumab treated cells; reconfirming, atrasentan failed to enhance inhibitory effects of EGFR-targeted agents. This study suggests complex interactions between HER2/EGFR and ET pathways in breast cancer and supports the hypothesis that dual HER2-ET(A)R targeting may represent a highly effective approach in breast cancer treatment.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Atrasentan; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Down-Regulation; Drug Synergism; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Genes, erbB-2; Humans; Neoplasm Metastasis; Phosphorylation; Pyrrolidines; Receptor, Endothelin A; Trastuzumab

Transcription-targeted gene delivery directed against angiogenic endothelial cells is a new approach against advanced cancer. Moreover, the herpes simplex virus-thymidine kinase (HSV-TK) gene coupled with low dose radiotherapy is an efficient and externally controlled cytotoxic system. We have previously demonstrated enhanced endothelial-specific cell expression and killing using the modified murine pre-proendothelin-1 promoter (PPE1-3x) to direct adenoviral expression of a pro-apoptotic gene. The purpose of this study was to create an externally potentiated systemic antiangiogenic gene delivery system based on an adenoviral vector expressing HSV-TK under the regulation of PPE1-3X promoter combined with radiotherapy for eradicating metastatic cancer. Ad-PPE1-3x-TK induced endothelial-specific cell killing in-vitro upon introduction of the prodrug ganciclovir (GCV). BALB/c mice bearing a primary CT-26 colon carcinoma tumor showed tumor growth suppression and diminished tumor angiogenesis when the vector was administered intravenously, activated with GCV and potentiated with a single sub-therapeutic and non-toxic radiation dose. Moreover, intravenous administration of the vector, activated with GCV and potentiated with chest aimed radiation, to C57BL/6 mice bearing Lewis lung carcinoma metastases resulted in prolongation of mice survival. PPE1-3x-regulated HSV-TK expression was detected only in lung metastases in contrast to CMV-regulated expression. This novel system may benefit patients with metastatic disease.

Topics: Adenoviridae; Animals; Antiviral Agents; Cell Line; Cell Line, Tumor; Cells, Cultured; Combined Modality Therapy; Endothelin-1; Ganciclovir; Gene Expression Regulation; Genetic Therapy; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms, Experimental; Neovascularization, Pathologic; Promoter Regions, Genetic; Protein Precursors; Radiotherapy; Simplexvirus; Survival Analysis; Thymidine Kinase; Tumor Burden

Endothelin-1[ET-1] acts as a growth factor in various malignancies. Big endothelin-1 (big ET-1) is the precursor of ET-1. The aim of this study was to determine the importance of serum big ET-1 levels as a novel marker of disease in female patients with breast cancer of various clinical stages. The study consisted of 75 female patients with breast cancer who were diagnosed and treated at the Gazi University Department of Medical Oncology and 20 controls. The patients were classified as follows: group A [n=26], patients with newly diagnosed primary breast cancer but without metastasis; group B [n=33], patients with metastatic breast cancer who had undergone treatment for their diseases and in whom metastasis was detected during follow-up; group C [n=16], off-therapy patients whose cancer had been in remission for at least 5 years; and group D [n=20] healthy controls. Serum big ET-1 level were measured with an enzyme immunoassay kit. The median serum big ET-1 levels of the 75 patients with breast cancer [10.96+/-1.36 ng/ml] were statistically significantly higher than those of controls [8.97+/-1.55 ng/ml]. The median serum big ET-1 levels of the patients with primary breast cancer patients [group A] were statistically significantly different from those in the controls, the off-therapy patients and the patients with metastatic disease [11.56+/-0.78 ng/ml, 8.97+/-1.55 ng/ml, 9.76+/-1.52 ng/ml, and 10.83+/-1.18 ng/ml respectively, P=.001]. There was no statistically significant difference in the serum big ET-1 levels of patients in group A in terms of tumor stage, hormone receptor status or lymph node status. Serum big ET-1 levels were statistically significantly higher in patients with metastatic disease than in controls or off-therapy patients (P=.001). The serum big ET-1 levels of off-therapy patients whose disease was in remission were not statistically significantly different from those in controls (P>.05). Serum big ET-1 levels seemed to represent the activation of ET-1 in female patients with breast cancer. Serum big ET- 1 levels can be an indicator of the breast cancer. Further studies are needed to demonstrate the prognostic importance of serum big ET-1 in patients with breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Endothelin-1; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging

To investigate the expressions of VEGF in prostate cancer (PCa) and benign prostatic hyperplasia (BPH), their clinical significance and their relationship with that of ET-1.. A total of 44 specimens of PCa and 36 of BPH tissues were examined by the immunohistochemical Elivision plus method for the expressions of VEGF and ET-1. The intensity of staining for VEGF and ET-1 was assessed by light microscopy on a scale from "-" to "+ + +".. The rates of positive expression of VEGF were 69.4% in BPH and 80.9% in PCa, positive staining mostly in the cytoplasm of glandular epithelia and cancer cells, and strongly positive in all the stroma vascular endothelial cells. The staining intensity of VEGF was significantly higher in the PCa than in the BPH group (P < 0.05) , in the bone metastasis (BM) than in the non-BM group (P < 0.01), and in the lowly than in the highly and moderately differentiated PCa tissues (P < 0.01). The expression of VEGF was positively correlated with that of ET-1 ( r(s) = 0.780, P < 0.01).. VEGF is involved in the development, progression and metastasis of PCa. VEGF and ET-1 may play a joint role in its development and progression.

Topics: Aged; Aged, 80 and over; Endothelin-1; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostatic Hyperplasia; Prostatic Neoplasms; Vascular Endothelial Growth Factor Receptor-1

Endothelin-1 (ET-1) is a potent vasoactive peptide and a hypoxia-inducible angiogenic growth factor associated with the development and spread of solid tumors. The clinical significance of plasma big ET-1 in patients with advanced-stage nasopharyngeal carcinoma (NPC) is not known.. Pretreatment plasma big ET-1 levels were measured in 62 patients with advanced-stage NPC using a sandwich enzyme-linked immunoassay and compared with the levels from a control group (n = 19 participants).. The median pretreatment plasma big ET-1 level in patients with advanced-stage NPC was 4.6 pg/mL (range, 1.9-15.2 pg/mL) and was significantly elevated compared with median plasma big ET-1 levels in healthy controls, 2.6 pg/mL (1.6-4.5 pg/mL) (P < .001). Using the upper limit (4.5 pg/mL) of control subjects as the cut-off value, plasma big ET-1 was < or = 4.5 pg/mL in 29 (46.8%) patients and > 4.5 pg/mL in 33 (53.2%) patients. A pretreatment plasma big ET-1 level > 4.5 pg/mL was associated with a significantly poorer 2-year distant metastasis-free survival rate (56.7% vs. 81.1%, P = .031). Multivariate analysis showed that N classification (hazard ratio [HR], 2.416; 95% confidence interval [CI], 1.071-5.447; P = .034) and pretreatment plasma big ET-1 level (HR, 3.151; 95% CI, 1.099-9.028, P = .033) were independent significant prognostic factors for posttreatment distant failure in patients with advanced-stage NPC.. Pretreatment plasma big ET-1 levels may be useful in predicting posttreatment distant failure in patients with advanced-stage NPC.

Topics: Adult; Biomarkers, Tumor; Carcinoma; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Multivariate Analysis; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Survival Analysis; Treatment Outcome

Angiogenic factors including endothelin-1 (ET-1) play a key role in the progression of breast metastases to bone. We investigated the impact of ET-1 on the development of bone metastases in an immunocompetent murine skin-fold chamber model. Murine mammary carcinoma 4T1 was injected in a skin-fold chamber implanted on CB6 mice along with bone explants. Furthermore, mice were treated with or without a dual selective antagonist of both ET-1 receptors. The progression of the vascularization within the chamber was monitored over time by intravital microscopy (IVM). The tumor growth and the development of bone metastases were assessed by cytokeratin-19 gene expression and histological studies. Results indicate that this new model associated with IVM allows for the continuous monitoring of the change in vascularization associated with the development of bone metastases. Additionally, treatment with an antagonist of both ET-1 receptors was associated with the presence of significantly less vessels near the tumor mass compared to control mice. These changes were correlated with smaller tumor masses and reduced bone invasion (P < 0.05). Thus, in an immunocompetent murine model of breast carcinoma metastases to bone, our data support the hypothesis that vascularization plays a role in tumor development and progression and that ET-1 specifically modulates the angiogenesis associated with breast metastases to the bone.

Topics: Angiogenesis Inhibitors; Animals; Bone Neoplasms; Bosentan; Breast Neoplasms; Cell Division; Endothelin-1; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Neoplasm Metastasis; RNA, Messenger; Skin; Sulfonamides

Oxygenases are a family of enzymes that dioxygenate unsaturated fatty acids, thus initiating membrane oxidation and signaling molecule synthesis. The lipoxygenases (LOs), a family of lipid-peroxidizing enzymes that induce structural and metabolic changes in the cell in a number of pathophysiological conditions, belong to the oxygenases family. This class of enzymes has several subgroups, named 5-, 8-, 12- and 15-LOs, and these LO-isoforms are capable of oxygenating arachidonic and linoleic acid. 15-LOs were reported to play an inhibitory role in tumor angiogenesis and, consequently, they slow down carcinogenesis. It has been suggested that its anti-carcinogenic effect is conferred by promoting cell differentiation and apoptosis. Using transgenic mice that over-express 15-LO-1 in endothelial cells under the regulation of the murine preproendothelin-1 promoter, we studied its effect on tumor and metastasis growth. We found that 15-LO-1 inhibited tumor and metastasis growth in the transgenic mice in two different models of cancer (mammary gland and Lewis lung carcinoma). This inhibition was concomitant with a higher number of apoptotic cells in the metastases of the transgenic mice and with a complicated network of multiple small blood vessels. This finding targets 15-LO as a new candidate in the treatment of carcinogenesis.

Topics: Animals; Apoptosis; Arachidonate 15-Lipoxygenase; Blood Vessels; Carcinoma, Lewis Lung; Cell Transformation, Neoplastic; Endothelin-1; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Metastasis; Neovascularization, Pathologic; Promoter Regions, Genetic; Up-Regulation

(1) Atrasentan (Xinlay(R)) is an anti-cancer drug from a new class of agents called selective endothelin-A receptor antagonists. The orally administered drug is being studied in a subset of patients with advanced prostate cancer. (2) Phase II and III studies evaluating time to clinical and radiographic progression failed to demonstrate a significant benefit with atrasentan versus placebo. (3) The adverse effects, observed more frequently in those treated with atrasentan than in placebo-treated patients, were peripheral edema, rhinitis, headache, infection, dyspnea, and heart failure. (4) Atrasentan's role in the various stages of advanced prostate cancer, and relative to the chemotherapeutic agent docetaxel, has not been determined.

Topics: Bone Neoplasms; Canada; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Approval; Endothelin Receptor Antagonists; Endothelin-1; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Pyrrolidines; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome; United States; United States Food and Drug Administration

Endothelin-1 (ET-1) and its receptors (ET(A)R and ET(B)R), referred to as the endothelin (ET) axis, are overexpressed in breast carcinomas, and influence tumorigenesis and tumor progression by various mechanisms, including angiogenesis. The objective of the study was to clarify if expression of the ET axis participates in angiogenesis of breast carcinoma. We analyzed expression of ET-1, ET(A)R, ET(B)R, and vascular endothelial growth factor (VEGF) immunohistochemically in 600 tissue array specimens from 200 paraffin-embedded breast carcinomas performing tissue microarray technology. Microvessel density (MVD) was determined by counting microvessels (identified by factor VIII) in each core specimen.. Moderate or strong immunostaining was observed for ET-1 in 25.4%, for ET(A)R in 43.7%, and for ET(B)R in 22.2% of breast carcinomas. Of all cases, 44.7% showed significant expression of VEGF. MVD varied between different tumor specimens (range, 0-80; median, 17). We observed a statistically significant correlation between MVD and ET expression status with higher MVD in ET-positive tumors. Moreover, expression of VEGF was found more frequently in tumors with overexpression of the ET axis (each P < 0.001). Staining of VEGF was correlated positively with MVD CONCLUSIONS: These results indicate that increased ET-1, ET(A)R, and ET(B)R expression is associated with increased VEGF expression and higher vascularity of breast carcinomas and, thus, could be involved in the regulation of angiogenesis in breast cancer. Our findings provide evidence that the expression pattern of the ET-axis and in particular of ET(A)R may have clinical relevance in future antiangiogenic targeted therapies for breast cancer.

Topics: Breast Neoplasms; Carcinoma; Cell Line, Tumor; Disease Progression; Endothelin-1; Factor VIII; Humans; Immunohistochemistry; Microcirculation; Neoplasm Metastasis; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, Endothelin A; Receptor, Endothelin B; Tissue Distribution; Vascular Endothelial Growth Factor A

Topics: Becaplermin; Bone Remodeling; Endothelin-1; Humans; Neoplasm Metastasis; Osteoblasts; Parathyroid Hormone; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis

Endothelin-1 (ET-1) is overexpressed in breast carcinomas and stimulates tumor cell growth in an autocrine and paracrine fashion via its receptors, ET(A)R and ET(B)R. In this study, we evaluated the expression of ET-1 and ET receptors in breast carcinomas and determined its clinical and prognostic significance.. We analyzed expression of ET-1, ET(A)R, and ET(B)R in 176 breast carcinomas using a semiquantitative immunohistochemical approach. Statistical analysis of clinicopathological variables such as pT stage, pN stage, hormone receptor status, Her-2/neu amplification, histological grade, and long-term follow-up data were performed.. We observed a moderate to strong cytoplasmic staining for ET-1 in 69 (43.1%), for ET(A)R in 74 (46.5%), and for ET(B)R in 86 (53.4%) cases of primary breast cancer. A correlation was found between increased ET-1 expression and its receptors with several clinicopathological parameters that characterize aggressive types of breast cancer, with the exception of increased ET(A)R and ET(B)R expression with positive estrogen receptor status. Elevated expression of ET-1, ET(A)R, and ET(B)R was more common in breast carcinomas of patients with lower disease-free survival time and overall survival. In addition, a statistically significant correlation was observed between ET(A)R expression and reduced disease-free survival time (P = 0.041). Interestingly, the prognostic impact of ET(A)R expression was shown to be more pronounced in the subgroup of patients with a putative favorable prognosis according to classic prognostic factors.. Therefore, analysis of ET(A)R expression may improve the prediction of relapse and death and facilitate an individually based risk-directed adjuvant therapy in breast cancer patients.

Topics: Breast Neoplasms; Disease-Free Survival; Endothelin-1; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Multivariate Analysis; Neoplasm Metastasis; Neoplasm Staging; Receptor, Endothelin A; Receptor, Endothelin B; Reproducibility of Results; Survival Analysis; Time Factors

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