Age-associated stresses induce an anti-inflammatory senescent phenotype in endothelial cells.

Age is the greatest risk factor for cardiovascular disease. In addition, inflammation and age (senescence) have been linked at both the clinical and molecular levels. In general, senescent cells have been described as pro-inflammatory based on their senescence associated secretory phenotype (SASP).

Genetically modified macrophages expressing hypoxia regulated cytochrome P450 and P450 reductase for the treatment of cancer.

This study describes a combined gene and cell therapy based on the genetic modification of primary human macrophages, as a treatment for cancer. Here, we have utilised the tumour-infiltrating properties of macrophages as vehicles to deliver a gene encoding a prodrug-activating enzyme such as human cytochrome P450 2B6 (CYP2B6) inside tumours followed by killing the tumour cells with the prodrug cyclophosphamide (CPA). Macrophages were transduced with an adenoviral vector that expresses human cytochrome CYP2B6 via a synthetic hypoxia responsive promoter (OBHRE) and with human P450 reductase (P450R), via the CMV promoter.

Stress-induced premature senescence mediated by a novel gene, SENEX, results in an anti-inflammatory phenotype in endothelial cells.

Cellular senescence is a mechanism to inhibit the growth of mammalian cells after oncogenic activation, or in response to damage or stress. We describe here the identification of a novel gene, SENEX, that regulates stress induced premature senescence pathways in endothelial cells (ECs) involving p16(INK4a) and retinoblastoma protein activation. Endogenous levels of SENEX remain unchanged during replicative senescence but are regulated by H(2)O(2)-mediated stress.

Stromal endothelin B receptor-deficiency inhibits breast cancer growth and metastasis.

The endothelin (ET) axis, often deregulated in cancers, is a promising target for anticancer strategies. Whereas previous investigations have focused mostly on ET action in malignant cells, we chose a model allowing separate assessment of the effects of ETs and their receptors ET(A)R and ET(B)R in the tumor cells and the stromal compartment, which is increasingly recognized as a key player in cancer progression. In homozygous spotting lethal rats (sl/sl), a model of constitutive ET(B)R deficiency, we showed significant reduction of growth and metastasis of MAT B III rat mammary adenocarcinoma cells overexpressing ET(A)R and ET-1 but negative for ET(B)R.

Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cells.

Introduction: The identification of potential breast cancer stem cells is of importance as the characteristics of stem cells suggest that they are resistant to conventional forms of therapy. Several techniques have been proposed to isolate or enrich for tumorigenic breast cancer stem cells, including (a) culture of cells in non-adherent non-differentiating conditions to form mammospheres and (b) sorting of the cells by their surface phenotype (expression of CD24 and CD44).

Methods: We have cultured metastatic cells found in pleural effusions from breast cancer patients in non-adherent conditions without serum to form mammospheres.

Sialyl-Lewis(x) on P-selectin glycoprotein ligand-1 is regulated during differentiation and maturation of dendritic cells: a mechanism involving the glycosyltransferases C2GnT1 and ST3Gal I.

To fulfil their function as APCs, dendritic cells (DC) and their precursors need to travel from blood to the peripheral tissues and, upon activation, migrate from tissues to draining lymph nodes. Because O-glycans play a role in T cell trafficking, we investigated the O-glycosylation profile of human monocyte-derived DC. Sialyl-Lewis(x) (sLe(x)), a glycan involved in extravasation via selectin binding, was found to be expressed exclusively on P-selectin glycoprotein ligand-1 in monocytes and immature DC.

Aberrant regulation of argininosuccinate synthetase by TNF-alpha in human epithelial ovarian cancer.

The pro-inflammatory cytokine, tumour necrosis factor-alpha, TNF-alpha, is dysregulated in malignant compared with normal ovarian surface epithelium (OSE). Several epidemiological studies have associated inflammation with ovarian tumorigenesis, with TNF-alpha playing a key role in modulating invasion, angiogenesis and metastasis. Here, we show that TNF-alpha also induces expression of arate-limiting enzyme in arginine synthesis, argininosuccinate synthetase (AS), thereby linking inflammation with several arginine-dependent metabolic pathways, implicated in accelerated carcinogenesis and tumour progression.

Endothelins induce CCR7 expression by breast tumor cells via endothelin receptor A and hypoxia-inducible factor-1.

Endothelin expression is increased in breast tumors and is associated with invasion and metastasis, whereas CCR7 expression by breast tumor cells may have a role in the organ specificity of breast cancer spread. In this article, we have analyzed whether endothelins influence breast tumor cell expression of the chemokine receptor CCR7. Stimulation of human breast tumor cell lines with endothelins increased cell surface expression of CCR7 via endothelin receptor A.

In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion.

Purpose: Malignant pleural mesothelioma (MPM) is an increasing health burden on many societies worldwide and, being generally resistant to conventional treatment, has a poor prognosis with a median survival of <1 year. Novel therapies based on the biology of this tumor seek to activate a proapoptotic cellular pathway. In this study, we investigated the expression and biological significance of argininosuccinate synthetase (AS), a rate-limiting enzyme in arginine production.

Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium.

Epidemiologic studies implicate inflammatory stimuli in the development of ovarian cancer. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) and both its receptors (TNFRI and TNFRII) are expressed in biopsies of this malignancy. Here, we tested the hypothesis that TNF-alpha is a regulator of the proinflammatory microenvironment of ovarian cancer.

Expression of endothelins and their receptors promotes an invasive phenotype of breast tumor cells but is insufficient to induce invasion in benign cells.

There is increased staining of endothelins (ET-1, -2, and -3) and receptors (ET-RA and -RB) in invasive breast tumors compared to nonneoplastic tissue, and ETs stimulate MCF-7 cell invasion in vitro. We analyzed ETstimulation of benign and transformed mammary epithelial cells, and whether expression of ETs is sufficient to induce invasiveness. In breast cancer patient serum, ET-1 was increased in those patients with lymph node metastases compared to those with no lymph node involvement; ETs, however, had no mitogenic effect on breast tumor cell lines in vitro.

Endothelins in breast tumour cell invasion.

Endothelins are a family of small, structurally related, vasoactive peptides that have a great number of physiological roles in many tissues. The 'endothelin axis' consists of three 21 amino acid peptides (ET-1, ET-2 and ET-3), two G-protein-coupled receptors (ET-RA and ET-RB), and two activating peptidases or endothelin-converting enzymes (ECE-1 and ECE-2). There is increased expression of the endothelin axis in invasive breast cancer compared to the normal breast or non-invasive neoplastic tissue.

A role for endothelin-2 and its receptors in breast tumor cell invasion.

We have studied the role of endothelins (ET-1, ET-2 and ET-3) and ET receptors (ET-RA and ET-RB) in the invasive capacity of breast tumor cells, which express ET-1 and ET-2 as well as ET-RA and ET-RB. Of five human breast tumor cell lines tested, all expressed mRNAs for ET-1, ET-2, and ET-RB. ET-RA mRNA was expressed by four of five tumor cell lines.

Endothelin-2 is a hypoxia-induced autocrine survival factor for breast tumor cells.

Endothelins (ETs) are a group of vasoactive peptides (ET-1, ET-2 and ET-3) produced by many cell types that bind to G-protein-linked transmembrane receptors, ET-A receptors (ET-RAs) and ET-B receptors (ET-RBs). These peptides are expressed in several human tumors, including carcinomas of the breast, and have a mitogenic effect in ovarian cancer cell lines. We investigated ET expression in infiltrating ductal carcinomas (IDCs) of the breast and the relationship between ET and hypoxia.

Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors.

Endothelins (ET-1, ET-2 and ET-3) are 21-amino acid vasoactive peptides that bind to G-protein-linked transmembrane receptors, ET-RA and ET-RB. As well as modulating vasoconstriction, endothelins regulate growth in several cell types and may also affect differentiation, inflammation and angiogenesis. Both macrophages and endothelins are found in areas of hypoxia in solid tumors and ET-2 expression may be modulated by hypoxia in some tumors.