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PubMed2004

Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells.

Gemcitabine is a new standard chemotherapeutic agent used in the treatment of pancreatic cancer, but the mechanisms of gemcitabine sensitivity are still controversial. In our study to determine a mechanism that regulates gemcitabine sensitivity, we carried out molecular analysis on the susceptibility of the pancreatic cancer cells. Using a gemcitabine-sensitive pancreatic cancer cell line KLM1, we established a resistant cell line KLM1-R exhibiting a 20-fold IC50-value (the concentration of gemcitabine causing 50% growth inhibition). Microarray analysis of genes showed specific expression of selenoprotein P, one of the anti-oxidants, in the KLM1-R cell line but not in the KLM1 cell line. Administration of selenoprotein P inhibited the gemcitabine-induced cytotoxicity in the pancreatic cell lines. The levels of intracellular reactive oxygen species (ROS) were increased in the KLM1 cells by gemcitabine, but selenoprotein P suppressed the gemcitabine-induced ROS levels. Furthermore interferon-gamma suppressed the expression of selenoprotein P mRNA and increased intracellular ROS level, leading to the recovery of the gemcitabine sensitivity in KLM1-R. These results suggest a novel mechanism that selenoprotein P reduces the intracellular ROS levels, resulting in the insusceptibility to gemcitabine.

Antimetabolites, Antineoplastic↗
PubMed2005

Clinical role of tissue and serum levels of SCCA antigen in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and a common occurrence in patients with liver cirrhosis in western and North American countries. Ultrasound screening is a powerful technique for HCC diagnosis, whereas the only available serologic test, alpha-fetoprotein, has poor reliability. It has been reported that the squamous cell carcinoma antigen (SCCA) is overexpressed in HCC tissue. In our study, the expression of SCCA was investigated in tumoral and peritumoral tissues and in the serum of 52 HCC patients, as well as in the serum of 48 cirrhotic patients. The results show that SCCA expression is much stronger in the tumoral than in the peritumoral tissue of HCC. Moreover, it is also evident in metastatic nodules present in the peritumoral tissue. SCCA serum levels were significantly higher in HCC samples than in cirrhotic samples. However, no correlation was found between SCCA expression and the HCC histologic degree, nor did SCCA expression correlate with tumor size, presence of metastasis or clinical outcome. In conclusion, in HCC patients, the SCCA antigen could represent a useful marker for the detection of micro-metastasis in the tissues and for large-scale screening of serum in patients at risk.

Adult↗
PubMed2001

Molecular markers and determinants of prostate cancer metastasis.

Although intensely studied, the molecular and biochemical determinants of prostate cancer development and progression remain ill-defined. Moreover, current markers and methodologies cannot distinguish between a tumor that will remain indolent and not impinge on patient survival, versus a tumor with aggressive traits culminating in metastatic spread and death. Once prostate cancer is confirmed the most significant threat to a patient's survival and quality of life involves tumor metastasis. Radical surgery notwithstanding, prostate cancer accounts for 10% of all cancer-related deaths primarily arising through development of metastasis. Metastasis markers demonstrating an acceptable level of reliability are an obvious necessity if disproportionate and costly treatment is to be avoided and a reasonably accurate determination of clinical prognosis and measure of successful response to treatment is to be made. Therapeutic strategies that specifically inhibit metastatic spread are not presently possible and may not become available in the immediate future. This is because, while localized tumorigenesis has been relatively amenable to detection, analysis and treatment, metastasis remains a relatively undefined, complex and underexplored area of prostate cancer research. New findings in the field such subclasses of genes called metastasis suppressors and cancer progression suppressors, have opened up exciting avenues of investigation. We review current methodological approaches, model experimental systems and genes presently known or having potential involvement in human prostate cancer metastasis.

Animals↗
PubMed2004

Profiling of sulfoconjugates in urine by using precursor ion and neutral loss scans in tandem mass spectrometry. Application to the investigation of heavy metal toxicity in rats.

This paper reports a liquid chromatographic/electrospray ionization mass spectrometric (LC/ESI-MS) method for profiling a wide range of structurally different sulfoconjugated compounds in urine and its application to the characterization of biomarkers for heavy metal toxicity in rat urine. Sulfoconjugates were first isolated by solid-phase extraction and the LC separation was performed on a reversed-phase column. Sulfoconjugates were detected in a triple-quadrupole mass spectrometer by simultaneously monitoring constant losses of 80 u (or 80 Th for doubly charged ions), precursors of m/z 80 (SO(3) (-*)) and precursors of m/z 97 (HSO4-). The ESI-MS detection conditions were optimized on dehydroepiandrosterone sulfate and estradiol sulfate and tested on other sulfoconjugates. The analysis of urine samples from humans and rats by using the developed method allowed the detection of about 15 peaks in each mode of detection. It was then applied to the investigation of heavy metal toxicity in rats. Comparative analysis of the chromatographic fingerprints of urine from control and uranium- and cadmium-treated rats showed several variations in the chromatographic pattern of the sulfoconjugates. Diagnostic m/z ratios were confirmed by analyzing individual urine samples and one of the observed variations seemed to be specific to uranium toxicity. The ion responsible for this variation has been identified as 4-ethylphenol sulfate by comparison of its chromatographic retention time and collision-induced dissociation mass spectra (MS(2) and MS(3) performed on a quadrupole ion trap instrument) with those of the synthesized compound.

Animals↗
PubMed2002

Biomarkers of human skin cells identified using DermArray DNA arrays and new bioinformatics methods.

Biomarker genes of human skin-derived cells were identified by new simple bioinformatic methods and DNA microarray analysis utilizing in vitro cultures of normal neonatal human epidermal keratinocytes, melanocytes, and dermal fibroblasts. A survey of 4405 human cDNAs was performed using DermArray DNA microarrays. Biomarkers were rank ordered by "likelihood ratio" algorithms and stringent selection criteria that have general applicability for analyzing a minimum of three RNA samples. Signature biomarker genes (up-regulated in one cell type) and anti-signature biomarker genes (down-regulated in one cell type) were determined for the three major skin cell types. Many of the signature genes are known biomarkers for these cell types. In addition, 17 signature genes were identified as ESTs, and 22 anti-signature biomarkers were discovered. Quantitative RT-PCR was used to verify nine signature biomarker genes. A total of 158 biomarkers of normal human skin cells were identified, many of which may be valuable in diagnostic applications and as molecular targets for drug discovery and therapeutic intervention.

Algorithms↗
PubMedDate not supplied

Characterization of a novel hematopoietic marker expressed from early embryonic hematopoietic stem cells to adult mature lineages.

A novel membrane protein has been identified in the course of screening for differentially expressed cDNAs in human embryonic hematopoietic sites. This 37- to 38-kDa molecule, designated KLIP-1 (killer lineage protein), consisting of 350 amino acids and containing five transmembrane domains, is encoded by the 5093-bp KLIP-1 gene, composed of nine exons and located on chromosome 6 (6p21.1-6p21.2). We found the KLIP-1 protein to be expressed by nucleated hematopoietic cells, from early embryonic hematopoietic stem cells through mature adult blood lymphoid lineages, either as membrane or as cytoplasmic molecules. In day-30/32 human embryo sections, KLIP-1 protein expression is restricted to circulating hematopoietic cells at hematopoiesis sites. Membrane KLIP-1 is expressed by fetal and adult GP-A(+) erythroblasts, the fetal liver CD34(+) subset, fetal spleen, and adult bone marrow CD56(+) NK and CD19(+) B cells. Among mature blood cells, surface KLIP-1 expression is restricted to CD56(+) NK cells, indicating KLIP-1 to be a novel marker of this population. Altogether, these results indicate that membrane export of KLIP-1 antigen is developmentally and ontogenetically regulated. The high degree of conservation of the KLIP-1 protein sequence among mammals strongly suggests that it plays an important role during hematopoiesis and may exercise similar functions in human and mouse blood cells. The KLIP-1 molecule may therefore constitute a powerful tool for improving knowledge of both human hematopoiesis and NK cell ontogeny and immune functions.

Adult↗
PubMed2001

Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation.

OBJECTIVE: Endometrioid endometrial carcinoma is caused by a combination of mutational events and hormonal factors. We used large-scale messenger RNA expression analysis to discover genes that distinguish neoplastic transformation and examine the patterns of tumor expression of those genes which are normally regulated during the menstrual cycle. METHODS: Expression of approximately 6000 unique genes was quantified in 4 normal (2 proliferative, 2 secretory) and 10 malignant endometria using Affymetrix Hu6800 GeneChip probe arrays. Expression differences between normal and malignant tissue groups were measured by a test of statistical significance comparing the individual t statistic for each gene to the distribution of maximum t statistics among all genes following 1001 permutations of the tissue group assignments (Permax test). Hormonally responsive genes, selected by comparison of proliferative and secretory subsets of normal endometria using a combination of filters applied to the group means and t test rankings, were then examined in the tumors. RESULTS: Fifty genes with a Permax <0.50 provided excellent discrimination between normal and malignant groups and were predominantly characterized by diminished expression levels in the cancers. We found that 100 genes which are hormonally regulated in normal tissues are expressed in a disordered and heterogeneous fashion in cancers, with tumors resembling proliferative more than secretory endometrium. CONCLUSION: Neoplastic transformation is accompanied by predominant loss of activity of many genes constitutively expressed in normal source tissues and absence of expression profiles which characterize the antitumorigenic progestin response.

Adult↗
PubMed2001

Reverse transcriptase polymerase chain reaction (RT-PCR) detection of melanoma-related transcripts in the peripheral blood and bone marrow of patients with malignant melanoma. What have we learned?

The detection of circulating tumor cells (CTC) and bone marrow micrometastases (BMM) by reverse transcriptase polymerase chain reaction (RT-PCR) may help predict recurrence and survival in malignant melanoma (MM). Since the appearance of the original article by Smith et al. in 1991 (Lancet 338:1227), several groups have attempted the detection of CTC and BMM in MM using RT-PCR for melanocytic specific markers, mainly tyrosinase mRNA. Most studies show that tyrosinase is not present in the PB and BM of control individuals without MM. The PCR positivity rates in MM are extremely variable, ranging from 0% to 100%. There was a correlation between RT-PCR and stage in some but not all of the studies. These disparate findings could in part be explained by differences in RNA extraction and blood separation techniques, to unrecognized contamination leading to false positive results, or differences in patient selection. Despite these discrepancies, we and others have shown that RT-PCR for tyrosinase mRNA in PB is able to predict overall survival (OS) and disease-free survival (DFS) in a statistically significant manner. In AJCC stage II-IV patients rendered surgically free of disease, we found that blood tyrosinase positivity was an independent predictor of OS and DFS. We also found that BM tyrosinase positivity is an independent predictor of DFS in the same group of patients. RT-PCR may help identify subgroups of patients at high risk for early relapse for more aggressive adjuvant therapy. Large prospective studies and interlaboratory quality assurance initiatives are necessary to confirm the accuracy and prognostic value of these RT-PCR assays.

Biomarkers, Tumor↗
PubMed2002

DNA microarrays: a new diagnostic tool and its implications in colorectal cancer.

Effective treatment of colorectal cancer requires early detection and diagnostic and prognostic accuracy in characterizing patients of various risk groups. The development of DNA microarray makes it possible to analyze thousands of genes in a single tissue sample in one experiment and to characterize the biological behavior of colorectal cancer cells. Different cluster algorithms have been used to analyze large datasets on gene expression data, and initial results show significant differences between colorectal cancer and normal colon tissue. Although more than 6000 genes have been analyzed between colorectal cancer and normal tissue, different expression levels have been found in only 100-500 transcripts depending on the cluster algorithm. Most transcripts belong to genes involved in cell growth regulation, differentiation of cells, ribosomal proteins or metalloproteinase. A future goal in microarray technology will be the development of clustered gene chips which characterize each tumor type specifically and focus on gene expression that specifies cell identity.

Biomarkers, Tumor↗
PubMed2007

Serologic and immunohistochemical prognostic biomarkers of cutaneous malignancies.

Biomarkers are important tools in clinical diagnosis and prognostic classification of various cutaneous malignancies. Besides clinical and histopathological aspects (e.g. anatomic site and type of the primary tumour, tumour size and invasion depth, ulceration, vascular invasion), an increasing variety of molecular markers have been identified, providing the possibility of a more detailed diagnostic and prognostic subgrouping of tumour entities, up to even changing existing classification systems. Recently published gene expression or proteomic profiling data relate to new marker molecules involved in skin cancer pathogenesis, which may, after validation by suitable studies, represent future prognostic or predictive biomarkers in cutaneous malignancies. We, here, give an overview on currently known serologic and newer immunohistochemical biomarker molecules in the most common cutaneous malignancies, malignant melanoma, squamous cell carcinoma and cutaneous lymphoma, particularly emphasizing their prognostic and predictive significance.

Biomarkers, Tumor↗
PubMed1993

Scoparone O-demethylase assay is not useful to differentiate the effects of model inducers of cytochrome P-450 in rabbit and guinea pig liver.

Coumarin derivative, scoparone (6,7-dimethoxycoumarin), is regioselectively O-demethylated into isoscopoletin (I) and scopoletin (S). This oxidation is inversely influenced by cytochrome P-450 inducers in the rat such as 3-methylcholantrene (3-MC) and phenobarbital (PB). The I/S ratio is higher than 1.5 with 3-MC treatment whereas it is lower than 0.5 with PB treatment. With regards to this contrasting effect, it has been suggested that the I/S ratio should be useful to differentiate between the effects of these types of inducers. We studied the consequences of in vivo PB and 3-MC treatment on scoparone biotransformation in guinea pig and rabbit. In these two species, at the basal state, scoparone biotransformation was enhanced in comparison to the rat. Moreover, in these untreated animals, two other metabolites were formed. After 3-MC or PB treatment, scoparone metabolism is, in contrast to the rat, inappropriate to differentiate between the P-450 profile of other animals.

Animals↗
PubMed2006

Polo-like kinase and survivin are esophageal tumor-specific promoters.

For developing successful cancer gene therapy strategies, tumor-specific gene delivery is essential. In this study, we used esophageal cancer (EC) cells to identify and evaluate esophageal tumor-specific gene promoters. Four genes (polo-like kinase-1/PLK, survivin/BIRC5, karyopherin alpha 2/KPNA2, and pituitary tumor transforming gene protein 1/PTTG1) were identified by a microarray analysis as highly expressed in EC cell lines vs. five normal organ tissues (liver, lung, kidney, brain, and heart). By quantitative RT-PCR, the average mRNA expression levels of these four genes in 20 primary ECs were 2.7-fold (PLK), 6.1-fold (survivin), 2.6-fold (KPNA2), and 2.4-fold (PTTG1) higher than that of each gene in 24 different normal organs. By dual luciferase assay, the promoter activity of PLK and survivin in EC cell lines was 18.9-fold and 28.5-fold higher, respectively, than in normal lung and renal cells. The promoters of PLK and survivin could be useful tools for developing EC-specific gene therapy vectors.

Biomarkers, Tumor↗
PubMed2004

Microarray analysis of proliferative and hypertrophic growth plate zones identifies differentiation markers and signal pathways.

Longitudinal bone growth results from coordination of proliferation and hypertrophy of chondrocytes, calcification of the matrix, vascular invasion, and completion of endochondral bone formation in the growth plate. Although proliferative and hypertrophic chondrocytes are well characterized histomorphologically, the understanding of factors governing this transition is not fully explained. Our hypothesis was that significant differential gene expression exists between proliferative and hypertrophic chondrocytes that may provide clues to the regulation of this transition at the transcriptional level. Normal Sprague-Dawley rat growth plate chondrocytes from the proliferative zone (PZ) and hypertrophic zone (HZ) were isolated by laser capture microdissection and then subjected to microarray analysis. Confirmation of the differential expression of selected genes was done by in situ hybridization and quantitative reverse transcription (RT) polymerase chain reaction (PCR). A total of 40 transcripts showed at least twofold greater expression in the PZ compared to HZ at both 6 and 7 weeks of age, while 52 transcripts showed twofold greater expression in the HZ compared to PZ at these time points. Many of the differentially expressed genes in each zone had very high levels of expression and thus were classified as "enriched transcripts" for that zone. The PZ-enriched transcripts included fibromodulin, proline arginine-rich end leucine-rich repeat protein, lactate dehydrogenase, and enolase 1 alpha. In contrast, HZ-enriched transcripts included collagen I, protein kinase (lysine deficient 4), proteasome (prosome, macropain) activator subunit 4, prostaglandin I2 synthase, and integrin-binding sialoprotein, matrix metalloproteinase 13 (MMP13), and collagen X. Other genes were highly expressed in cells from both zones, including collagen II, aggrecan, cartilage oligomeric protein, cartilage link protein, laminin receptor, and eukaryotic translocation elongation factor. Functional classification of the PZ-enriched transcripts showed an increased percentage of genes expressed in nuclear cell cycle and transcription functions. In contrast, the HZ-enriched transcripts were more involved in extracellular structure and membrane receptor and transporter functions. Pathway analysis indicated that transforming growth factor beta and parathyroid hormone-related protein (PTHrP) pathways were important in both zones, and bone morphogenic protein pathway played a role in the HZ. It is likely that these differentially expressed genes are involved in regulation of the transition from proliferation to differentiation functions in the growth plate.

Animals↗
PubMed2004

Coexpression of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor cMET predict recurrence of meningiomas.

Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the cMET tyrosine kinase participate in cancer invasion, angiogenesis and metastasis in a wide variety of neoplastic cells. Meningioma is a bening tumour, however, it has a high rate of recurrence after surgery; the most important factor to predict relapse is the extent of surgical resection, several other potentially predictive factors have been studied with poor results. We examined by immunohistochemistry the expression of HGF/SF and its cMET receptor in a group of patients with benign meningioma with or without recurrence (n = 17 and n = 25, respectively), after a minimal follow-up of least 6 years. Expression and coexpression of HGF/SF and cMET were compared with cell proliferation index, vascular density and clinical outcome. Coexpression of HGF/SF and cMET in meningiomas had a significant association with cell proliferation index and with recurrence (P < 0.037). Determination of HGF and cMET coexpression in meningiomas could be used as a predictor of recurrence.

Adult↗
PubMed2004

Survivin expression in chronic myeloid leukemia.

In this study, we investigated the expression of survivin (SVV) in 44 patients with typical Ph-positive chronic myeloid leukemia (CML) in different phases of the disease as well as in 20 matched healthy donors. We found a very high SVV expression in a predominant percentage of CML patients. We also observed a significantly increased SVV expression in patients in accelerated/blastic phase of the disease compared to patients in chronic phase. Moreover, SVV expression levels correlated in all CML patients with % of Ph-chromosome positive cells, with Bcr-Abl expression levels and with WBC-count. Based on this finding we suggest that SVV detection and monitoring in CML could represent both a useful biomarker and attractive candidate for devising new targeted and combined therapies in CML.

Adolescent↗
PubMed2005

Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer.

OBJECTIVE: Our objective was to estimate the pharmacokinetic parameters of CCI-779 and its metabolite, sirolimus, and evaluate associations of exposure parameters with safety and clinical activity. Exposure parameters were also correlated with pharmacogenomic responses in peripheral blood mononuclear cells (PBMCs). METHODS: In this randomized, double-blind, multicenter trial, once-weekly intravenous doses of 25, 75, or 250 mg CCI-779 were administered to patients with advanced renal cancer. Whole blood for CCI-779 and sirolimus concentrations was drawn. Population pharmacokinetic analyses yielded Bayesian-predicted exposure metrics that were correlated with severity and duration of adverse events and survival. PBMC samples taken before and after treatment were examined for pharmacogenomic responses. Ribonucleic acid samples were converted to labeled probes and hybridized to oligonucleotide arrays containing more than 12,600 human sequences. RESULTS: The final population pharmacokinetic models of CCI-779 and sirolimus included 235 and 305 observations, respectively, from 50 patients. For CCI-779, dose, single versus multiple dose, and body surface area were significant pharmacokinetic covariates. For sirolimus, dose and hematocrit were significant covariates. Age, sex, or race did not influence drug disposition. CCI-779 area under the curve correlated with adverse event severity for thrombocytopenia (P = .007), pruritus (P = .011), and hyperlipemia (P = .040). Exposure (CCI-779 cumulative area under the curve) correlated with a specific subset of gene transcripts in PBMCs following 16 weeks after therapy (P < .001, Spearman correlation). CONCLUSIONS: Concentrations of CCI-779 and sirolimus were adequately described with a population model incorporating factors for dose, attenuated exposure of multiple doses, body surface area, and hematocrit. Correlations with adverse event severity and duration profiles were provided to aid in the detection of treatment-emergent effects. Pharmacogenomic profiling of PBMCs identified altered ribonucleic acid transcript expression levels that correlate with exposure. These transcripts represent potential biomarkers of CCI-779 exposure in peripheral blood.

Adult↗
PubMed2004

SELDI-TOF-based serum proteomic pattern diagnostics for early detection of cancer.

Proteomics is more than just generating lists of proteins that increase or decrease in expression as a cause or consequence of pathology. The goal should be to characterize the information flow through the intercellular protein circuitry that communicates with the extracellular microenvironment and then ultimately to the serum/plasma macroenvironment. The nature of this information can be a cause, or a consequence, of disease and toxicity-based processes. Serum proteomic pattern diagnostics is a new type of proteomic platform in which patterns of proteomic signatures from high dimensional mass spectrometry data are used as a diagnostic classifier. This approach has recently shown tremendous promise in the detection of early-stage cancers. The biomarkers found by SELDI-TOF-based pattern recognition analysis are mostly low molecular weight fragments produced at the specific tumor microenvironment.

Algorithms↗