p53 null mutations are associated with a telomerase negative phenotype in ovarian carcinoma.

Telomerase activation and p53 dysfunction are important events in the development and progression of most cancers including ovarian cancer. However, many cancer cell lines and human tumors have been shown to lack telomerase, and maintain telomerase through the ALT (alternative lengthening of telomeres). It is not known whether specific types of p53 mutations are correlated with telomerase activity in human tumors.

Targeting the tumor microenvironment with chemically modified tetracyclines: inhibition of laminin 5 gamma2 chain promigratory fragments and vasculogenic mimicry.

The laminin 5 (Ln-5) gamma2 chain and matrix metalloproteinases (MMPs) MMP-2 and membrane type 1 (MT1)-MMP act cooperatively and are required for highly aggressive melanoma cells to engage in vasculogenic mimicry when cultured on a three-dimensional matrix. Furthermore, generation of Ln-5 gamma2 chain promigratory fragments by MMP-2 and MT1-MMP proteolysis is necessary for an aggressive tumor cell-preconditioned matrix to induce vasculogenic mimicry in poorly aggressive tumor cells. These observations suggest that treatment regimes that specifically target aggressive tumor cells may fail to take into account changes in the extracellular microenvironment that persist after removal or destruction of an aggressive tumor and could result in a recurrence or continuance of the tumor.

Elevated focal adhesion kinase expression facilitates oral tumor cell invasion.

Background: Understanding the molecular mechanisms of metastasis is critical with respect to oral tumorigenesis. The focal adhesion kinase (FAK) is an intracellular tyrosine kinase associated with the regulation of cell growth, migration, and survival. The purpose of the current study was to determine whether elevated FAK expression in oral malignancies was associated with increased invasiveness and oral carcinoma.

Expression of multiple molecular phenotypes by aggressive melanoma tumor cells: role in vasculogenic mimicry.

Cutaneous melanoma has been increasing at an alarming rate over the past two decades, however, there are no acceptable histopathological markers that classify various stages of melanoma progression. Recently, the molecular analysis of cancer has contributed significantly to our understanding of the cellular and molecular underpinnings of tumor progression. The data summarized in this review describe the molecular signature of aggressive cutaneous melanoma cells as that of multiple phenotypes which may be similar to a pluripotent, embryonic-like phenotype.

Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer.

Purpose: To assess the clinical relevance of serum vascular endothelial growth factor (VEGF) levels in distinguishing patients with ovarian cancer from those with benign adnexal masses.

Experimental Design: Preoperative serum VEGF levels were assessed in 101 women with invasive epithelial ovarian cancer, 16 with low malignant potential (LMP) ovarian tumors, and 34 women with benign ovarian tumors. VEGF levels were determined using an ELISA (R&D Systems, Minneapolis, MN).

Androgen receptors in human synoviocytes and androgen regulation of interleukin 1beta (IL-1beta) induced IL-6 production: a link between hypoandrogenicity and rheumatoid arthritis?

Objective: To investigate the hypothesis that synoviocytes possess androgen receptors (AR) that could be modulated by the non-aromatizable androgen, dihydrotestosterone (DHT), resulting in altered levels of inflammatory cytokines.

Methods: Using molecular analyses of AR in combination with the multiprobe ribonuclease protection assay and ELISA, we investigated the presence of AR and the effect of DHT on interleukin 1beta (IL-1beta) induced expression of the IL-6 superfamily of cytokines in synoviocytes.

Results: Our studies corroborate the presence of AR in synoviocytes.

The paradoxical expression of maspin in ovarian carcinoma.

Maspin is a noninhibitory member of the serpin family that is down-regulated in breast carcinoma but overexpressed in pancreatic carcinoma. There are no published data regarding the role of maspin in ovarian carcinoma, which is the focus of the present study. Ovarian cell lines (normal and cancer) and tumors (80 invasive, 14 benign, and 10 low malignant potential) were evaluated for maspin expression and localization.

A molecular role for lysyl oxidase in breast cancer invasion.

We identified previously an up-regulation in lysyl oxidase (LOX) expression,an extracellular matrix remodeling enzyme, in a highly invasive/metastatic human breast cancer cell line, MDA-MB-231, compared with MCF-7, a poorly invasive/nonmetastatic breast cancer cell line. In this study, we demonstrate that the mRNA expression of LOX and other LOX family members [lysyl oxidase-like (LOXL), LOXL2, LOXL3, and LOXL4] was observed only in breast cancer cells with a highly invasive/metastatic phenotype but not in poorly invasive/nonmetastatic breast cancer cells. LOX and LOXL2 showed the strongest association with invasive potential in both highly invasive/metastatic breast cancer cell lines tested (MDA-MB-231 and Hs578T).

Tyrosine phosphorylation of maspin in normal mammary epithelia and breast cancer cells.

Maspin is a 42kDa tumor suppressor protein that belongs to the serine protease inhibitor (serpin) family. It inhibits cell motility and invasion in vitro, and tumor growth and metastasis in nude mice; however, maspin's molecular mechanism of action has remained elusive. Maspin contains several tyrosine residues and we hypothesized that phosphorylation of maspin could play a role in its biological function.

Molecular determinants of human uveal melanoma invasion and metastasis.

The molecular analysis of cancer has benefited tremendously from the sequencing of the human genome integrated with the science of bioinformatics. Microarray analysis technology has the potential to classify tumors based on the differential expression of genes. In the current study, a collaborative, multidisciplinary approach was utilized to study the molecular determinants of human uveal melanoma invasion and metastasis.

Potent in vivo antiviral activity of the herpes simplex virus primase-helicase inhibitor BAY 57-1293.

BAY 57-1293 belongs to a new class of antiviral compounds and inhibits replication of herpes simplex virus (HSV) type 1 and type 2 in the nanomolar range in vitro by abrogating the enzymatic activity of the viral primase-helicase complex. In various rodent models of HSV infection the antiviral activity of BAY 57-1293 in vivo was found to be superior compared to all compounds currently used to treat HSV infections. The compound shows profound antiviral activity in murine and rat lethal challenge models of disseminated herpes, in a murine zosteriform spread model of cutaneous disease, and in a murine ocular herpes model.

The tumour suppressor gene maspin is differentially regulated in cytotrophoblasts during human placental development.

Identification of factors that play a role in regulating the highly invasive ability of human placental cells throughout gestation will contribute to a better understanding of this unique developmental process. The aims of this study were to determine whether the tumour suppressor gene maspin is present in the human placenta and plays a putative role in the regulation of cytotrophoblast invasion during placental development. The data showed that the expression of maspin mRNA was maximum in term placentae compared to the first and second trimester tissues, and absent in the HTR-SVneo (immortalized extravillous cytotrophoblast), JEG-3 and JAR (choriocarcinoma) cell lines.

New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease.

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced.

The embryonic-like properties of aggressive human tumor cells.

During embryogenesis, the formation and remodeling of primary vascular networks occur by vasculogenesis and angiogenesis. Recently, the term "vasculogenic mimicry" was introduced by our laboratory and collaborators to reflect the embryonic-like ability of aggressive, but not nonaggressive, tumor cells to form a pattern of vasculogenic-like networks in three-dimensional culture, with concomitant expression of vascular-associated cell markers. We reviewed research on the ability of invasive ovarian carcinoma cells to engage in molecular vasculogenic mimicry reflected by their plasticity.

Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination.

On the basis of the ability of aggressive melanoma cells to participate in vasculogenic mimicry, particularly their expression of endothelial-associated genes, we examined the plasticity of human metastatic cutaneous melanoma cells with respect to vascular function. Fluorescently labeled metastatic melanoma cells were challenged to an ischemic microenvironment surgically induced in the hind limbs of nude mice. The data reveal the capability of these melanoma cells to express cell-fate determination molecules, normally expressed during embryonic vasculogenesis, and to participate in the neovascularization of circulation-deficient muscle.

Prostatic tumor cell plasticity involves cooperative interactions of distinct phenotypic subpopulations: role in vasculogenic mimicry.

Background: Tumor cell plasticity represents a significant clinical challenge in that the fate and function of tumor cells can be elusive until a tumor mass is evident. A remarkable example of plasticity is tumor cell vasculogenic mimicry, recently described in aggressive uveal and cutaneous melanoma, in addition to ovarian carcinoma, whereby tumor cells express endothelial-associated genes and form de novo vasculogenic-like networks in three-dimensional (3-D) culture. In the current investigation, we examined whether there is evidence for vasculogenic mimicry in heterogeneous prostatic neoplasms.

Regulation of human cytotrophoblast morphogenesis by hepatocyte growth factor/scatter factor.

In vitro morphogenesis of epithelial cells to form tube-like structures is regulated by hepatocyte growth factor-scatter factor (HGF/SF). The placenta is a rich source of HGF/SF, and its absence in mice has been shown to lead to impaired placental growth and embryonic death. There is no information in the literature regarding in vitro morphogenesis of human cytotrophoblasts or the effect of HGF/SF on this process.

Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma.

Vasculogenic mimicry describes a process where aggressive tumor cells in three-dimensional matrices mimic embryonic vasculogenesis by forming extracellular matrix (ECM)-rich, patterned tubular networks. Microarray gene chip analyses revealed significant increases in the expression of laminin 5 (Ln-5, gamma2 chain) and matrix metalloproteinases (MMP)-1, -2, -9, and MT1-MMP (MMP-14) in aggressive compared with poorly aggressive melanoma cells. These components colocalized with developing patterned networks and antisense oligonucleotides to the Ln-5 gamma2 chain (but not sense oligonucleotides), and antibodies to MMP-2 or MT1-MMP (but not MMP-9) inhibited the formation of these networks.

Communicating science: from the laboratory bench to the breakfast table.

If we are to maintain public appreciation and support for our scientific enterprise, we need to pay more attention to translating the benefits and grandeur of science into the language of broader society. Both educators and journalists have a role to play in communicating the achievements of science, but scientists must recognize that we have a responsibility to increase the availability and salience of science to the public.

Expression and functional significance of VE-cadherin in aggressive human melanoma cells: role in vasculogenic mimicry.

We recently have introduced the term vasculogenic mimicry to describe the unique ability of aggressive melanoma tumor cells to form tubular structures and patterned networks in three-dimensional culture, which "mimics" embryonic vasculogenic networks formed by differentiating endothelial cells. In the current study, we address the biological significance of several endothelial-associated molecules (revealed by microarray analysis) with respect to expression and function in highly aggressive and poorly aggressive human cutaneous melanoma cell lines (established from the same patient). In a comparative analysis, CD31 was not expressed by any of the melanoma cell lines, whereas TIE-1 (tyrosine kinase with Ig and epidermal growth factor homology domains-1) was strongly expressed in the highly aggressive tumor cells with a low level of expression in one of the poorly aggressive cell lines.

Application of the National Cancer Institute international criteria for determination of microsatellite instability in ovarian cancer.

Recently, the National Cancer Institute (NCI) established criteria for determination of microsatellite instability (MSI) in colorectal tumors. Although the best panel of markers for ovarian tumors is not known, we evaluated epithelial ovarian cancers for MSI based on the NCI recommendations. One hundred and nine ovarian tumors were analyzed for MSI by gel analysis of paired germ-line and tumor DNA.