Proteome Analysis of Pancreatic Tumors Implicates Extracellular Matrix in Patient Outcome.

Unlabelled: Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognostic, and predictive biomarkers. In-depth characterization of the disease proteome is limited. This study thus aims to define and describe protein networks underlying pancreatic cancer and identify protein centric subtypes with clinical relevance.

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma.

Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.

Differential expression of miRNAs in colorectal cancer: comparison of paired tumor tissue and adjacent normal mucosa using high-throughput sequencing.

We present the results of a global study of dysregulated miRNAs in paired samples of normal mucosa and tumor from eight patients with colorectal cancer. Although there is existing data of miRNA contribution to colorectal tumorigenesis, these studies are typically small to medium scale studies of cell lines or non-paired tumor samples. The present study is to our knowledge unique in two respects.

Predicting platinum resistance in primary advanced ovarian cancer patients with an in vitro resistance index.

Purpose: We aimed to identify primary platinum resistance in epithelial ovarian cancer (OC) patients with FIGO stage III-IV disease by an in vitro drug-response assay and to correlate the findings with clinical response. We considered whether neoadjuvant chemotherapy or anatomic sample site and tumor heterogeneity would influence the results.

Methods: We combined the ATP-based tumor-chemosensitivity and the extreme drug resistance assays for testing of 85 biopsies from 58 patients.

Wobble-enhanced ARMS method for detection of KRAS and BRAF mutations.

Monoclonal antibodies targeting the epidermal growth factor receptor have expanded the range of treatment options for patients with metastatic colorectal cancer. However, somatic mutations in the KRAS and BRAF genes have proven to be molecular predictors of resistance to treatment with anti-epidermal growth factor receptor therapy in these patients. Thus, we have developed a sensitive mutation assay, wobble-enhanced amplification refractory mutation system, for detecting the 8 most commonly reported mutations of clinical importance in the KRAS and BRAF genes; KRAS g.

The fatty acid binding protein 7 (FABP7) is involved in proliferation and invasion of melanoma cells.

Background: The molecular mechanisms underlying melanoma tumor development and progression are still not completely understood. One of the new candidates that emerged from a recent gene expression profiling study is fatty acid-binding protein 7 (FABP7), involved in lipid metabolism, gene regulation, cell growth and differentiation.

Methods: We studied the functional role of FABP7 in human melanoma cell lines and using immunohistochemistry analyzed its expression pattern and clinical role in 11 nevi, 149 primary melanomas and 68 metastases.

1,5-Disubstituted 1,2,3-triazoles as cis-restricted analogues of combretastatin A-4: Synthesis, molecular modeling and evaluation as cytotoxic agents and inhibitors of tubulin.

A series of cis-restricted 1,5-disubstituted 1,2,3-triazole analogues of combretastatin A-4 (1) have been prepared. The triazole 12f, 2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline, displayed potent cytotoxic activity against several cancer cell lines with IC(50) values in the nanomolar range. The ability of triazoles to inhibit tubulin polymerization has been evaluated, and 12f inhibited tubulin polymerization with IC(50)=4.

Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma.

The aim of this study was to analyze the expression and clinical role of DJ-1, a negative regulator of PTEN (phosphatase and tensin homolog deleted on chromosome 10), in ovarian carcinoma, and investigate the putative association between DJ-1 levels and expression of its transcriptional regulators specificity protein 1 (Sp1) and specificity protein 3 (Sp3). Effusions (n = 72) and solid tumors (n = 57, 42 primary and 15 metastases) were analyzed for DJ-1 messenger RNA (mRNA) expression using reverse transcriptase-polymerase chain reaction. Most specimens (48 effusions, 50 solid tumors) were additionally analyzed for Sp1 and Sp3 mRNA expression.

Low-molecular weight forms of cyclin E differentiate ovarian carcinoma from cells of mesothelial origin and are associated with poor survival in ovarian carcinoma.

Background: The authors recently reported on the role of cyclin E in differentiating ovarian/primary peritoneal carcinoma from malignant peritoneal mesothelioma using gene expression arrays. In the current study, they analyzed the expression of low-molecular weight (LMW) forms of cyclin E in ovarian carcinoma, malignant mesothelioma, and benign reactive effusions.

Methods: Cyclin E protein expression was analyzed in 98 effusions (72 ovarian carcinomas, 14 malignant mesotheliomas, and 12 reactive specimens) using immunoblotting.

Expression of HLA-G in malignant mesothelioma and clinically aggressive breast carcinoma.

The aim of the present study was to evaluate HLA-G expression in breast carcinoma and malignant mesothelioma (MM). Malignant breast carcinoma effusions (46) and corresponding solid tumors (39) and 104 MM (26 effusions, 78 solid tumors) were analyzed using immunohistochemistry (IHC). HLA-G protein and mRNA expression were further studied using immunoblotting (IB) and RT-PCR.

Variation in gene expression patterns in effusions and primary tumors from serous ovarian cancer patients.

Background: While numerous studies have characterized primary ovarian tumors, little information is available regarding expression patterns of metastatic sites of this cancer. To define sets of genes that distinguish primary and metastatic ovarian tumors, we used cDNA microarrays to characterize global gene expression patterns in 38 effusions (28 peritoneal, 10 pleural) and 8 corresponding primary ovarian tumors, and searched for associations between expression patterns and clinical parameters.

Results: We observed multidimensional variation in expression patterns among the cancers.

Phorbol ester phorbol-12-myristate-13-acetate promotes anchorage-independent growth and survival of melanomas through MEK-independent activation of ERK1/2.

The phorbol ester, phorbol-12-myristate-13-acetate (PMA), an activator of PKCs, is known to stimulate the in vitro growth of monolayer cultures of normal human melanocytes whereas it inhibits the growth of most malignant melanoma cell lines. We examined the effect of PMA on proliferation and survival of melanoma cells grown as multicellular aggregates in suspension (spheroids), and aimed to elucidate downstream targets of PKC signaling. In contrast to monolayer cultures, PMA increased cell proliferation as well as protected melanoma cells from suspension-mediated apoptosis (anoikis).

Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survival.

In the present study the deacetylase inhibitor trichostatin A (TSA) was used to elucidate the effect of protein acetylation on cell cycle progression and survival in seven human malignant melanoma cell lines. It was shown that TSA treatment led to a transient G(2)/M phase delay and accumulation of unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly induced protein expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in a dose-dependent manner in all cell lines including those not expressing p21(WAF1/CIP1) constitutively, whereas the levels of both wild-type and mutated p53 protein were reduced.

Expression and activation of the nerve growth factor receptor TrkA in serous ovarian carcinoma.

Purpose: The purpose is to analyze the possible correlation between expression and activation of the high-affinity nerve growth factor (NGF) receptor TrkA, cell cycle protein expression, and disease outcome in serous ovarian carcinoma. In addition, we wished to study the possible link between expression of NGF, a novel angiogenic factor and its receptor TrkA, and the expression of factors involved in angiogenesis in effusions and solid tumors.

Experimental Design: Sections from 80 malignant effusions and 65 corresponding solid tumors were evaluated for protein expression of NGF, TrkA, and phospho-TrkA (p-TrkA).