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PubMed2003

The increase of voltage-gated potassium channel Kv3.4 mRNA expression in oral squamous cell carcinoma.

BACKGROUND: Potassium channels have been reported to be involved in the proliferation of many types of cells, including tumor cells. The overexpression of the K+ channel and related channel activity are involved in the neoplastic process. METHODS: We examined the expression of an A-type voltage-gated K+ channel, Kv3.4, in oral squamous cell carcinoma (OSCC) and esophageal squamous cell carcinoma (ESCC) compared with non-cancerous matched tissue (NCMT) using RT-PCR analysis. In addition, administration of an A-type K+ channel blocker, 4-aminopyridine (4-AP), and an antisense oligodeoxynucleotide (ODN) directed specifically against Kv3.4 were performed to identify the involvement of Kv3.4 in the growth of OSCC cells. RESULTS: A significantly increase in the frequency of Kv3.4 mRNA expression was identified in OSCC (64%) compared to corresponding NCMT (29%) (P = 0.05). The increase of Kv3.4 mRNA expression was also eminent in ESCC. Growth of OSCC cells was significantly inhibited by 4-AP in a dose-dependent manner at different time point of treatment. In OECM-1 OSCC cells, a significant growth inhibition was noted in antisense ODN-treated cells compared to control cells. CONCLUSION: We provide novel evidences of the increase of Kv3.4 mRNA expression in OSCC. The abrogation of Kv3.4 inhibits the growth of OSCC cells.

4-Aminopyridine↗
PubMed2004

Using gene expression profiling to differentiate benign versus malignant thyroid tumors.

DNA microarrays allow quick and complete evaluation of a cell's transcriptional activity. Expression genomics is very powerful in that it can generate expression data for a large number of genes simultaneously across multiple samples. In cancer research, an intriguing application of expression arrays includes assessing the molecular components of the neoplastic process and utilizing the data for cancer classification (Miller LD, et al. Cancer Cell 2002;2:353-61). Classification of human cancers into distinct groups based on their molecular profile rather than their histological appearance may prove to be more relevant to specific cancer diagnoses and cancer treatment regimes. Several attempts to formulate a consensus about classification and treatment of thyroid carcinoma based on standard histopathological analysis have resulted in published guidelines for diagnosis and initial disease management (Sherman SI. Lancet 2003;361:501-11). In the past few decades, no improvement has been made in the differential diagnosis of thyroid tumors by fine needle aspiration biopsy, specifically suspicious or indeterminate thyroid lesions, suggesting that a new approach to this should be explored. Therefore, in this study, we developed a gene expression approach to diagnose benign versus malignant thyroid lesions in 73 patients with thyroid tumors. We successfully built a 10 and 6 gene model able to differentiate benign versus malignant thyroid tumors. Our results support the premise that a molecular classification system for thyroid tumors is possible, and this in turn may provide a more accurate diagnostic tool for the clinician managing patients with suspicious thyroid lesions.

Diagnosis, Differential↗
PubMed2006

[Analysis of expression of LGALS3BP gene in thyroid tissues and peripheral blood lymphocytes in patients with papillary thyroid cancer].

INTRODUCTION: Galectin-3 (Gal-3), coding by LGALS3BP gene, is a protein of the lectin family that has been associated with neoplastic processes and seems to play an important role in a variety of cell biological processes. In the thyroid gland, the high expression of this protein has been described in differentiated carcinomas, especially in papillary thyroid cancer (PTC). AIM: Analysis of Gal-3 protein expression in PTC and nodular goiters; investigation of Gal-3 mRNA expression in peripheral blood lymphocytes (PBL) in patients with PTC and nodular goiter; analysis of correlation between Gal-3 protein expression in PTC and Gal-3 mRNA in PBL of the same patient. MATERIAL AND METHODS: Gal-3 protein was evaluated by immunohistochemistry in benign (27 multinodular goiters) and malignant (30 papillary carcinomas) thyroid tissues and galectin-3 mRNA expression by real-time PCR in peripheral blood lymphocytes (PBL) from 90 patients with multinodular goiter (n = 27), papillary carcinoma (n = 30) and healthy controls (n = 33). RESULTS: In PTC we observed increased expression of Gal-3 protein (all 30 cases) in cytoplasm, nucleus and cell membranes of cancer cells. 23 of 27 benign thyroid nodular goiters were negative for Gal-3 expression. In all examined blood samples we observed higher LGALS3BP gene expression than GAPDH (house keeping gene) with no difference between both groups, without relation to the Gal-3 expression in PTC. CONCLUSIONS: There is no difference in Gal-3 expression in peripheral blood lymphocytes in patients with papillary thyroid cancer in relation to nodular goiter.

Antigens, Neoplasm↗
PubMed1998

Role of hormones in mammary cancer initiation and progression.

Breast cancer, the most frequent spontaneous malignancy diagnosed in women in the Western world, is a classical model of hormone dependent malignancy. There is substantial evidence that breast cancer risk is associated with prolonged exposure to female hormones, since early onset of menarche, late menopause, hormone replacement therapy and postmenopausal obesity are associated with greater cancer incidence. Among these hormonal influences a leading role is attributed to estrogens, either of ovarian or extra-ovarian origin, as supported by the observations that breast cancer does not develop in the absence of ovaries, ovariectomy causes regression of established malignancies, and in experimental animal models estrogens can induce mammary cancer. Estrogens induce in rodents a low incidence of mammary tumors after a long latency period, and only in the presence of an intact pituitary axis, with induction of pituitary hyperplasia or adenomas and hyperprolactinemia. Chemicals, radiation, viruses and genomic alterations have all been demonstrated to have a greater tumorigenic potential in rodents. Chemical carcinogens are used to generate the most widely studied rat models; in these models hormones act as promoters or inhibitors of the neoplastic process. The incidence and type of tumors elicited, however, are strongly influenced by host factors. The tumorigenic response is maximal when the carcinogen is administered to young and virgin intact animals in which the mammary gland is undifferentiated and highly proliferating. The atrophic mammary gland of hormonally-deprived ovariectomized or hypophysectomized animals does not respond to the carcinogenic stimulus. Administration of carcinogen to pregnant, parous or hormonally treated virgin rats, on the other hand, fails to elicit a tumorigenic response, a phenomenon attributed to the higher degree of differentiation of the mammary gland induced by the hormonal stimulation of pregnancy. In women a majority of breast cancers that are initially hormone dependent are manifested during the postmenopausal period. Estradiol plays a crucial role in their development and evolution. However, it is still unclear whether estrogens are carcinogenic to the human breast. The apparent carcinogenicity of estrogens is attributed to receptor-mediated stimulation of cellular proliferation. Increased proliferation could result in turn in accumulation of genetic damage and stimulation of the synthesis of growth factors that act on the mammary epithelial cells via an autocrine or paracrine loop. Alternatively estrogens may induce cell proliferation through negative feedback by removing the effect of one or several inhibitory factors present in the serum. Multidisciplinary studies are required for the elucidation of the mechanisms responsible for the initiation of breast cancer. Understanding of such mechanisms is indispensable for developing a rational basis for its prevention and control.

Animals↗
PubMed2001

Expression of the cell cycle regulator p27(Kip1) in normal squamous epithelium, cervical intraepithelial neoplasia, and invasive squamous cell carcinoma of the uterine cervix. Immunohistochemistry and functional aspects of p27(Kip1).

BACKGROUND: Abnormality of cell cycle regulators and tumor suppressors, such as cyclin dependent kinase inhibitors (cdkIs), has been reported in malignant tumors. The current study was undertaken to examine the involvement of a cdkI, p27(Kip1) (p27), in the neoplastic process of the uterine cervical epithelium. METHODS: Immunohistochemical staining of p27 was performed in samples of normal cervical tissue (30 samples), cervical intraepithelial neoplasias (CINs; 17 samples), and invasive squamous cell carcinoma (SCC; 25 samples). The results were compared with the expression levels of Ki-67, cdk2, and cyclin E. The functional aspects of the p27 protein, such as its ability to bind to cdk2 and the phosphorylation activity of p27-bound cdk2, also were evaluated with an immunoprecipitation and histone H1 kinase assay. RESULTS: In normal cervical epithelia, the expression of p27 was strong in the intermediate and superficial cells but very weak in the parabasal cells. In CIN samples, the expression of p27 was negligible. The expression of p27 in these tissues showed an inverse topologic correlation to that of Ki-67, cdk2, and cyclin E. However, it is noteworthy that the number of p27 positive cells increased in SCC samples that also showed increased expression of Ki-67, cdk2, and cyclin E. The p27 protein in SCC samples was bound to cdk2 and cyclin E. However, cdk2 that was bound to p27 still possessed histone H1 kinase activity. CONCLUSIONS: The expression of p27 may be involved in the growth regulation of the normal squamous epithelium in the uterine cervix. However, aberrant function of p27 expression may occur in invasive SCC of the cervix.

Carcinoma, Squamous Cell↗
PubMed2005

New approaches for modelling cancer mechanisms in the mouse.

Mouse models of human cancer are vital to our understanding of the neoplastic process, and to advances in both basic and clinical research. Indeed, models of many of the major human tumours are now available and are subject to constant revision to more faithfully recapitulate human disease. Despite these advances, it is important to recognize that limitations do exist to the current range of models. The principal approach to modelling has relied upon the use of constitutive gene knockouts, which can often result in embryonic lethality, can potentially be affected by developmental compensation, and which do not mimic the sporadic development of a tumour expanding from a single cell in an otherwise normal environment. Furthermore, simple knockouts are usually designed to lead to loss of protein function, whereas a subset of cancer-causing mutations clearly results in gain of function. These drawbacks are well recognized and this review describes some of the approaches used to address these issues. Key amongst these is the development of conditional alleles that precisely mimic the mutations found in vivo, and which can be spatially and tissue-specifically controlled using 'smart' systems such as the tetracycline system and Cre-Lox technology. Examples of genes being manipulated in this way include Ki-Ras, Myc, and p53. These new developments in modelling mean that any mutant allele can potentially be turned on or off, or over- or under-expressed, in any tissue at any stage of the life-cycle of the mouse. This will no doubt lead to ever more accurate and powerful mouse models to dissect the genetic pathways that lead to cancer.

Animals↗
PubMed2006

Dominant-negative histone H3 lysine 27 mutant derepresses silenced tumor suppressor genes and reverses the drug-resistant phenotype in cancer cells.

Histone modifications and DNA methylation are epigenetic phenomena that play a critical role in many neoplastic processes, including silencing of tumor suppressor genes. One such histone modification, particularly at H3 and H4, is methylation at specific lysine (K) residues. Whereas histone methylation of H3-K9 has been linked to DNA methylation and aberrant gene silencing in cancer cells, no such studies of H3-K27 have been reported. Here, we generated a stable cell line overexpressing a dominant-negative point mutant, H3-K27R, to examine the role of that specific lysine in ovarian cancer. Expression of this construct resulted in loss of methylation at H3-K27, global reduction of DNA methylation, and increased expression of tumor suppressor genes. One of the affected genes, RASSF1, was shown to be a direct target of H3-K27 methylation-mediated silencing. By increasing DNA-platinum adduct formation, indicating increased access of the drug to target DNA sequences, removal of H3-K27 methylation resensitized drug-resistant ovarian cancer cells to the chemotherapeutic agent cisplatin. This increased platinum-DNA access was likely due to relaxation of condensed chromatin. Our results show that overexpression of mutant H3-K27 in mammalian cells represents a novel tool for studying epigenetic mechanisms and the Histone Code Hypothesis in human cancer. Such findings show the significance of H3-K27 methylation as a promising target for epigenetic-based cancer therapies.

Antineoplastic Agents↗
PubMed1995

Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma.

The distinction between malignant mesothelioma and other neoplastic processes involving the pleura is difficult, partly due to the lack of specific markers expressed on mesothelioma. Because of evidence suggesting that the Wilms' tumor susceptibility gene (WT1), unlike other tumor suppressor genes, is restricted mostly to mesenchymally derived tissues, we hypothesized that the WT1 gene products could serve as a potential marker for mesothelioma. The expression of WT1 mRNA was analyzed in 19 malignant mesothelioma cell lines and 9 tumors and compared with the expression of WT1 in 10 non-small cell lung cancer lines and 9 lung cancer specimens. WT1 mRNA was detectable by Northern analysis in 16 of 19 mesothelioma cell lines and in 5 of 8 malignant mesothelioma tumors. In contrast, WT1 mRNA was not detected by Northern analysis in non-small cell lung cancer lines or carcinomas. Immunoprecipitation with an anti-WT1 monoclonal antibody showed that a 52- to 54-kd protein was present in 4 mesothelioma cell lines. Immunostaining with this antibody localized the WT1 protein to the nucleus in two mesothelioma lines and in 20 of 21 mesothelioma tumors examined. This distinctive pattern of nuclear immunoreactivity was absent in 26 non-mesothelioma tumors involving the lung, including 20 non-small cell lung carcinomas. The detection of WT1 mRNA or protein may thus provide a specific molecular or immunohistochemical marker for differentiation of mesothelioma from other pleural tumors, in particular, adenocarcinoma.

Adult↗
PubMed2006

Comparative analysis of 99mTc-depreotide and 99mTc-EDDA/HYNIC-TOC thorax scintigrams acquired for the purpose of differential diagnosis of solitary pulmonary nodules.

BACKGROUND: Aiming at comparison of diagnostic efficacy of 2 radiopharmaceuticals: 99mTc-depreotide (Neospect, Amersham) and 99mTc-EDDA/HYNIC-Tyr3-octreotide (Tektrotyd, Polatom), in differentiation between malignant and benign etiology of solitary pulmonary nodules (SPNs), radionuclide studies with 2 radiotracers were performed in 18 patients. MATERIAL AND METHODS: For both radiopharmaceuticals the same acquisition and processing protocols were applied. Studies were acquired with SPECT technique, after administration of 740 MBq of activity. Scintigrams were assessed visually, as: positive (+), equivocal (+/-) and negative (-). Additionally, uptake intensity of both radiotracers in nodules was assessed semiquantitatively, using a tumour-to-background ratio. Verification of scintigraphic results was based in 14 cases upon a pathological examination of tumour samples (histopathology) and in the remaining 4 - on clinical observation and bacteriological studies. RESULTS: Normal scintigrams obtained with both radiopharmaceuticals differed significantly. 99mTc-depreotide was markedly accumulated in spine, sternum, ribs and lungs (mean lung/heart ratio = 2.2). This accumulation was not observed on 99mTc- -EDDA/HYNIC-TOC scintigrams (mean lung/heart ratio = 0.7). In 6 patients a malignant etiology--lung cancer--was revealed (5--adenocarcinoma, 1--squamous cell) and the other 12 cases turned out to be benign (4 hamartomas, 3 tuberculomas, a tuberculous infiltrate, an alien body with inflammatory reaction, a hyperplasia of lymphatic tissue and 2 cases of unknown etiology, from which one had a stable size and the other resolved during a 6 month observation period). In all 6 cases of lung cancer positive results were obtained with both tracers. Moreover, in 2 patients metastases in mediastinum could be observed on scintigrams obtained with both radiopharmaceuticals. From among 12 cases of benign etiology 6 99mTc-depreotide scintigrams were true negative, 1--equivocal and 5--false positive, whereas 6 99mTc-EDDA/HYNIC-TOC scintigrams were true negative, 4--equivocal and 2 false positive. Moreover, 99mTc-depreotide additionally revealed mediastinal and hilar lesions in 9 patients with benign lesions and 99mTc-EDDA/HYNIC-TOC - in 8. A visual comparison of scintigrams revealed a higher quality of 99mTc-Depreotide images in comparison with 99mTc-EDDA/HYNIC-TOC ones. 99mTc-Depreotide showed a higher than 99mTc-EDDA/HYNIC-TOC accumulation in lung tumours compared with blood pool (heart) - 4.5 (s.d. 1.05) and 1.8 (s.d. 0.29), respectively (p < 0.05). However, mean values of tumour-to-lung-background ratio were equal for both radiotracers (2.2 in malignant and 1.4 in benign lesions, respectively). A statistically significantly higher non-uniformity of counts inside lung background regions was found on 99mTc-EDDA/HYNIC-TOC scintigrams than on 99mTc-depreotide ones (16.4% vs. 11.4%; p < 0.01). CONCLUSIONS: Although both radiopharmaceuticals show similar diagnostic efficacy in differentiation of SPNs, a tendency toward a higher number of false positive results on 99mTc-depreotide scintigrams probably leads to a lower specificity. Better statistical quality of 99mTc-depreotide scintigrams facilitates their interpretation and a distinct outline of lungs simplify localization of lesions. A substantial number of false positive lesions in mediastinal and hilar regions in patients without a neoplastic process hamper the usefulness of both radiotracers for effective detection of lung cancer metastases to lymph nodes.

Adult↗
PubMed2005

Expression of delayed rectifier potassium channels and their possible roles in proliferation of human gastric cancer cells.

Voltage-gated potassium (Kv) channels have been reported to be involved in the proliferation of many types of cells, including tumor cells. The overexpression of the Kv channels and related channel activity are involved in the neoplastic process. Our previous study has shown the existence of delayed rectifier potassium (I(K)) current in gastric cancer cells SGC7901. However, the expression and function of most delayed rectifier potassium (K(D)) channel subunits in gastric cancer cells are not completely resolved. Here we examine expression of K(D) channel subunits in Kv1-Kv3 families in immortalized gastric epithelial cells GES and various gastric cancer cells (including AGS, KATOIII, MKN28, MKN45, MGC803, SGC7901, SGC7901/ADR and SGC7901/VCR), and their roles in cell proliferation. RT-PCR analysis reveals that all cell lines examined express Kv1.3, Kv1.5, Kv1.6, Kv2.1 and Kv2.2. However, Kv1.2 and Kv3.2 genes are barely detectable in any given cancer cell lines. Kv1.5 protein, high mRNA levels in all cell lines examined, is also expressed in some cancer cells lines and more frequently detected in gastric cancer tissues. Downregulation of the expression of Kv1.5 in SGC7901 with RNA interference significantly inhibited the proliferation and tumorigenicity of SGC7901 cells. Moreover, in Ca(2+)-containing rather than Ca(2+)-free medium, KCl (50mM) stimulated a rapid increase in the concentration of cytosolic calcium in empty vector transfected cells that was blocked by verapamil. Likewise, decrease the expression of Kv1.5 with short interfering RNA also blocked the depolarization-induced influx of Ca(2+). This finding suggests that more than one kind of K(D) channel subunits are expressed in various gastric cancer cell lines. Kv1.5 may be involved in tumor cells proliferation by controlling Ca(2+) entry, and the interference of K(D) channels expression and/or activity could provide a novel strategy to reverse the malignant phenotype of gastric cancer cells.

Calcium↗
PubMed2002

Neoplastic transformation of human breast epithelial cells by estrogens and chemical carcinogens.

Sporadic breast cancer, the most common cancer diagnosed in American and Northern European women, is gradually increasing in incidence in most Western countries. Prevention would be the most efficient way of eradicating this disease. This goal, however, cannot be accomplished until the specific agent(s) or mechanisms that initiate the neoplastic process are identified. Experimental studies have demonstrated that mammary cancer is a hormone-dependent multistep process that can be induced by a variety of compounds and mechanisms, that is, hormones, chemicals, radiation, and viruses, in addition to or in combination with genetic factors. Although estrogens have been shown to play a central role in breast cancer development, their carcinogenicity on human breast epithelial cells (HBECs) has not yet been clearly demonstrated. Breast cancer initiates in the undifferentiated lobules type 1, which are composed of three cell types: highly proliferating cells that are estrogen-receptor negative (ER-), nonproliferating cells that are ER positive (ER+), and very few (<1%) ER+ cells that proliferate. Interestingly, endogenous 17beta-estradiol (E(2)) is metabolized by the cytochrome P450 enzyme isoforms CYP1A1 and CYP1B1, which also activate benzo[a]pyrene (B[a]P), a carcinogen contained in cigarette smoke. We postulate that if estrogens are carcinogenic in HBECs, they should induce the same transformation phenotypes induced by chemical carcinogens and ultimately genomic changes observed in spontaneously developing primary breast cancers. To test this hypothesis we compared the transforming potential of E(2) on the HBEC MCF-10F with that of B[a]P. Both E(2) and B[a]P induced anchorage-independent growth, colony formation in agar methocel, and loss of ductulogenic capacity in collagen gel, all parameters indicative of cell transformation. In addition, the DNA of E(2)-transformed cells expressed LOH in chromosome 11 at 11q23.3, 11q24.2-q25, and LOH at 13q12-q13. B[a]P-induced cell transformation was also associated with LOH at 13q12-q13 and at 17p13.2. The relevance of these findings is highlighted by the observation that E(2)- and B[a]P-induced genomic alterations in the same loci found in ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma of the breast.

Animals↗
PubMed2002

Independent genetic events associated with the development of multiple parathyroid tumors in patients with primary hyperparathyroidism.

Multiple parathyroid tumors, as opposed to hyperplasia, have been reported in a subset of patients with sporadic primary hyperparathyroidism (PHPT). It is not clear whether these multiple tumors are representative of a neoplastic process or whether they merely represent hyperplasia that has affected the parathyroid glands differentially and resulted in asynchronous growth. The molecular genetic techniques of comparative genomic hybridization (CGH), loss of heterozygosity (LOH), and MEN1 mutation analysis were performed on a series of five patients with multiglandular PHPT, each of which had two parathyroid tumors removed. Analysis of these multiple parathyroid tumors from patients with PHPT revealed that independent genetic events were associated with the development of a subset of these tumors. The DNA sequence copy number changes, identified by CGH analyses, either involved different chromosomal regions in the paired glands of a patient (two patients), or those regions implicated in one gland were not changed in a second gland from the same patient (two patients). Each of the three patients exhibiting LOH demonstrated different changes between the paired glands. Where LOH was detected in one gland from a patient, the other gland from the same patient either exhibited no allelic loss or the loss detected was in another region. Each of the three tumors exhibiting LOH at 11q13 was found to contain a somatic MEN1 mutation in the remaining allele, however these mutations were not present in the germline or in the paired gland from the same patient. Although it is possible that a separate series of genetic changes has arisen randomly in two separate glands within the same individual, it seems more likely that the development of these multiple tumors has arisen because of the involvement of other unknown factors. These factors may be genetic [such as the involvement of one or more germline mutations in an unknown low-penetrance gene(s), germline mosaicism or alterations in calcium-sensing receptor gene(s)], epigenetic, physiological, or environmental.

Cell Transformation, Neoplastic↗
PubMed2005

Transcriptional deregulation of VEGF, FGF2, TGF-beta1, 2, 3 and cognate receptors in breast tumorigenesis.

Angiogenesis is an important event during the neoplastic process and is induced by the secretion of numerous growth factors from endothelial cells. Vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (FGF2), and transforming growth factor-beta1, beta2, beta3 (TGF-beta1, 2, 3) and cognate receptors (TGF-betaRI, II, III) mRNA expression pattern was evaluated by RT-PCR in 25 breast cancer tissue samples and adjacent normal tissues, and correlated to clinicopathological features. Western blot analysis was performed to evaluate VEGF and TGF-beta1 protein levels. TGF-beta1 and TGF-beta3 mRNA levels were significantly different in breast cancer specimens of differing histology (ductal, lobular, other) (P=0.020 and P=0.043). No statistically significant difference was observed at the mRNA level of VEGF between normal and tumor tissues while elevated VEGF protein levels in tumors were associated with patients' menopausal status. A strong hormonal influence of ER and PR on TGF-beta mRNA expression was established. FGF2 transcript levels were substantially decreased in cancer compared to adjacent normal specimens (P=0.031). A disruption of mRNA co-expression patterns was observed in malignant breast tissues compared to controls. Western blot analysis revealed differences between VEGF and TGFbeta1 mRNA and their corresponding protein levels. A substantial negative correlation of TGF-beta1 protein and TGF-beta1 mRNA levels (P=0.016) was demonstrated by breast tissue-pair analysis. Summarizing, our findings suggest that transcript levels of the examined markers in breast cancer are associated with menopausal and hormonal status, while their co-expression pattern is altered in malignant tissues compared to controls. In addition the difference between VEGF and TGF-beta1 mRNA and protein levels observed, indicates that post-transcriptional mechanisms may regulate expression of these molecules in breast cancer.

Adult↗
PubMed2003

Meningioma: is there an association with human leukocyte antigens?

The expression of human leukocyte antigen (HLA) alleles plays an important role in the development and recurrence of benign and malignant diseases. Association of single HLA alleles or haplotypes with neoplastic processes has been investigated previously, and correlation between HLA and solid tumors, such as head and neck cancers or uterine cervical squamous epithelial lesions, were reported. However, there is no published data on the influence of the HLA system on the development of symptomatic cerebral meningioma, a mostly benign intracranial tumor of mesenchymal origin in adults. The present investigation is comparing the frequency of single HLA alleles and haplotypes in 81 adult Caucasian patients with symptomatic central nervous system meningiomas to that of 157 area- and race-matched healthy controls. Both standard serological and molecular genetic (PCR) techniques were used for HLA typing. Our results suggest an association between single HLA alleles and occurrence of clinically symptomatic meningioma. Patients with HLA-A*02 had a 2.5-fold increased risk of meningioma (P = 0.02), and those with HLA-DQB1*05 had a 1.8-fold increased risk of meningioma (P = 0.05). Conversely, HLA-A*01, -B*08, and -DRB1*03 were associated with a 0.4-, 0.5-, and 0.5-fold, respectively, decreased risk of meningioma (P = 0.008, P = 0.05, and P = 0.04). Moreover, the occurrence rate of combinations and estimated haplotypes containing these HLA alleles was strikingly different in meningioma patients compared with controls: significantly increased for the haplotypes HLA-A*02:DRB1*04 (P = 0.02, relative risk = 2.5) and HLA-A*02:DRB1*04:DQB1*0302,DQB1*05 (P = 0.03, RR = 7.5), and significantly decreased for the haplotype HLA-A*01:B*08:DRB1*03 (P = 0.01, relative risk = 0.2). In conclusion, these data suggest that some single HLA alleles and haplotypes may protect from or predispose to developing symptomatic central nervous system meningioma during adult life. These associations may be indicative of the involvement of the immune system in the host antitumor surveillance, recognition, and destruction of de novo arising human tumor cells.

Adult↗
PubMed2000

Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer.

PURPOSE: NKX3.1, a member of the family of homeobox genes, exhibits prostate tissue specific expression and appears to play a role in mouse prostate development. Rapid induction of NKX3.1 gene expression in response to androgens has also been described. On the basis of the established role of androgens in prostatic growth and differentiation and studies showing an association of aberrant homeobox gene expression with the neoplastic process, we hypothesize that alterations of NKX3.1 gene expression play a role in prostate tumorigenesis. MATERIALS AND METHODS: NKX3.1 expression was analyzed in matched, microdissected normal and tumor tissues from 52 primary prostate cancer specimens from radical prostatectomy by semiquantitative RT-PCR and in situ hybridization and correlated with the clinicopathologic features. NKX3.1 expression was quantified as differential expression between matched tumor and normal tissues and was grouped as overexpression in tumor tissue, reduced expression in tumor tissue and no change between tumor and normal tissues. Androgen regulation of NKX3.1 expression was also studied in LNCaP cells. Androgen receptor (AR) expression in prostate tumor and normal tissue was correlated with NKX3.1 expression. RESULTS: Comparison of NKX3.1 expression between normal and tumor tissues revealed overexpression in 31% tumor specimens (16 of 52), decreased expression in 21% tumor specimens (11 of 52) and no change in 48% specimens (25 of 52). When these expression patterns were stratified by organ confined and non-organ-confined tumor, a higher percentage of patients exhibited NKX3.1 overexpression in non-organ confined tumor (40%) versus organ confined tumor (22%). Elevated NKX3.1 expression significantly correlated with tumor volume and serum prostate specific antigen (PSA) level in the NKX3.1 overexpression group (p<0.05). Metastatic prostate cancer cell lines did not exhibit mutations in the protein coding sequence of NKX3.1. Additionally, the NKX3.1 expression correlated with AR expression (p<0.01) in vivo in human prostate tissues. Comparison of PSA and NKX3.1 expression in response to androgen revealed a rapid androgen mediated induction of NKX3.1 expression in LNCaP cells. In situ hybridization analysis of representative specimens confirmed RT-PCR observations. CONCLUSIONS: These results suggest an association of NKX3.1 with a more aggressive phenotype of carcinoma of the prostate. Correlation of AR expression with NKX3.1 in human prostate tissues underscores the androgen regulation of NKX3.1 in the physiologic context of human prostate tissues.

Androgens↗
PubMed1998

Ornithine decarboxylase induction in transformation by H-Ras and RhoA.

The objective of these studies has been to develop a better understanding of the regulation of ornithine decarboxylase (ODC) during the neoplastic process, and to determine whether induction of ODC is a necessary component in the action of the ras oncogene. Specifically, we have studied the role of ODC overexpression in signaling pathways mediated by Raf or RhoA. Cells transformed by ras are known to have constitutively high levels of ODC activity that correlate with oncogenic transformation. To determine which pathways downstream of Ras contribute to the regulation of ODC activity, NIH-3T3 cells were transfected with plasmids coding for activated mutants of either H-Ras or RhoA, or oncogenic nu-Raf. There was a good correlation between increasing ODC specific activity and change in morphology from normal to transformed in the nu-Raf, HRas(61L), and RhoA(63L) clones. Increasing ODC activity also correlated positively with the ability to grow in soft agar in both the H-Ras- and RhoA-expressing cells. In stable transfections, coexpression of the ODC dominant negative mutant K69A/C360A with either HRas(61L) or RhoA(63L) both inhibited intracellular ODC activity and caused a reversion of the transformed phenotype, as measured by a dramatic reduction in the ability of these cells to grow in soft agar and form foci on a monolayer. These results suggest strongly that ODC induction is necessary for transformation by oncogenic Ras. In contrast, expression of K69A/ C360A had no effect on the ability of nu-Raf-transformed cells to grow in soft agar, although intracellular ODC levels were inhibited. When grown on a monolayer, these cells also maintained their transformed appearance. Furthermore, expression of the ODC dominant negative mutant did not affect the phosphorylation of mitogen-activated protein kinase in nu-Raf-transformed cells. These experiments provide strong support for the concept that transformation by activated ras is accompanied by an induction of ODC. The results using RhoA(63L) and nu-Raf suggest that this increase in ODC activity is mediated at least in part through a Raf/ mitogen-activated protein kinase independent pathway.

3T3 Cells↗
PubMedDate not supplied

Differential activity of NO synthase inhibitors as chemopreventive agents in a primary rat tracheal epithelial cell transformation system.

A model to study the effectiveness of potential chemopreventive agents that inhibit neoplastic process by different mechanisms has been used to test the efficacy of seven nitric oxide synthase (NOS) inhibitors. Five selective inducible NOS (iNOS) inhibitors: S-methyl isothiourea (S-MITU), S-2-aminoethyl isothiourea (S-2-AEITU), S-ethyl isothiourea (S-EITU), aminoguanidine (AG), 2-amino-4-methyl pyridine (2-AMP), and two non selective general NOS inhibitors: l-N(6)-(1-iminoethyl) lysine (IEL) and N(omega)-nitro-l-arginine (NNLA), were tested for efficacy against a carcinogen, benzo[a]pyrene (B[a]P)-induced primary rat tracheal epithelial (RTE) cell transformation assay. RTE cells were treated with B[a]P alone or with five nontoxic concentrations of an NOS inhibitor and the resulting foci at the end of 30 days were scored for inhibition of transformation. The results indicate that all three isothiourea compounds inhibited B[a]P-induced RTE foci in a dose-dependent manner. S-AEITU was the most effective inhibitor with an IC(50) (the molar concentration that inhibits transformation by 50%) of 9.1 microM and 100% inhibition at the highest dose tested (30 microM). However, both S-EITU and S-MITU showed a maximum percent inhibition of 81% and 100% at 1 mM with an IC(50) of 84 and 110 microM, respectively. 2-AMP did not show any dose-dependent response, but was highly effective (57% inhibition) at an intermediate dose of 30 microM and an IC(50) of 25 microM. Similar to thiourea compounds, AG exhibited good dose-dependent inhibition with a maximum inhibition of 86% at 1 mM. NNLA and IEL were negative in this assay. Based on the IC(50) values, NOS inhibitors were rated for efficacy from high to low as follows: S-2-AEITU<2-AMP<AG<S-MITU<S-EITU. The data from this study identify NOS inhibitors as a novel class of chemopreventive agents that can be developed for lung cancer prevention.

Animals↗
PubMed1980

Corneal crystalline deposits associated with dysproteinemia. Report of two cases and review of the literature.

Two patients had multiple, fine, polychromatic corneal crystals on ocular examination. Peripheral corneal biopsies and electron microscopic studies demonstrated that the crystals, which were located solely within the cytoplasm of keratocytes, exhibited an internal periodicity of 10 nm and developed within dilated cisternae of rough-surfaced endoplasmic reticulum. Histochemical studies of the corneal crystals confirmed their proteinaceous nature (immunoglobulin crystals). Serum protein analysis showed that both patients had a monoclonal gammopathy with an elevated IgG level and increased K light chains. The associated proteinopathy was unsuspected in both patients until the nature of the crystals was established. Both patients had a neoplastic process; one had a previous diagnosis of Hodgkin's disease, and multiple myeloma developed in the other on follow-up studies. Clinicians should be aware of the possibility of a malignant disorder in patients with corneal crystal-line deposits.

Adult↗