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Malignant Progression (malignant + progression)
Selected AbstractsMALIGNANT PROGRESSION OF ANAL INTRA-EPITHELIAL NEOPLASIAANZ JOURNAL OF SURGERY, Issue 8 2006Angus J. M. Watson Background: Anal intra-epithelial neoplasia (AIN) is believed to be a precursor to squamous cell carcinoma of the anus. The risk of developing anal cancer in patients with AIN, although known to occur, has been thought to be relatively low. This study reviews our experience with AIN, reviewing the incidence and risk factors for development of invasive malignancy and the outcome of present management strategies. Methods: This study examined a cohort of 72 patients identified from a prospective database with AIN from a single institution between January 1996 and December 2004. A single pathologist examined all pathological specimens. Results: There were 72 patients (52 women) and the median age was 49 years (range, 18,81 years). We identified progression of AIN to invasive malignancy in eight patients despite undergoing surveillance. Regression following treatment or biopsy was seen in 25 patients. Four patients required stomas for incontinence following treatment. Conclusion: This study has shown a high rate of progression to invasive malignancy (11%) with AIN despite surveillance. The patients at risk of developing squamous cell carcinoma were the immunocompromised and those with genital intra-epithelial field change. Treatment of AIN has significant complications and despite treatment, invasive cancers do occur. Decisions made for treatment of AIN can affect treatment choices if invasive malignancy develops. [source] Identification and Functional Characterization of microRNAs Involved in the Malignant Progression of GliomasBRAIN PATHOLOGY, Issue 3 2010Bastian Malzkorn Abstract Diffuse astrocytoma of World Health Organization (WHO) grade II has an inherent tendency to spontaneously progress to anaplastic astrocytoma WHO grade III or secondary glioblastoma WHO grade IV. We explored the role of microRNAs (miRNAs) in glioma progression by investigating the expression profiles of 157 miRNAs in four patients with primary WHO grade II gliomas that spontaneously progressed to WHO grade IV secondary glioblastomas. Thereby, we identified 12 miRNAs (miR-9, miR-15a, miR-16, miR-17, miR-19a, miR-20a, miR-21, miR-25, miR-28, miR-130b, miR-140 and miR-210) showing increased expression, and two miRNAs (miR-184 and miR-328) showing reduced expression upon progression. Validation experiments on independent series of primary low-grade and secondary high-grade astrocytomas confirmed miR-17 and miR-184 as promising candidates, which were selected for functional analyses. These studies revealed miRNA-specific influences on the viability, proliferation, apoptosis and invasive growth properties of A172 and T98G glioma cells in vitro. Using mRNA and protein expression profiling, we identified distinct sets of transcripts and proteins that were differentially expressed after inhibition of miR-17 or overexpression of miR-184 in glioma cells. Taken together, our results support an important role of altered miRNA expression in gliomas, and suggest miR-17 and miR-184 as interesting candidates contributing to glioma progression. [source] Protection against Malignant Progression of Spontaneously Developing Liver Tumors in Transgenic Mice Expressing O6 -Methylguanine-DNA MethyltransferaseCANCER SCIENCE, Issue 11 2000Xiusheng Qin To study the effect of O6 -methylguanine-DNA methyltransferase (MGMT) on carcinogenesis, we have previously generated MGMT transgenic mice overexpressing the bacterial MGMT gene, ada, and demonstrated that high MGMT levels in the liver suppress induction of liver tumors after treatment with an alkylating hepatocarcinogen. To examine the effects of life-long elevation of MGMT activity on mouse spontaneous liver tumor development, ada-transgenic and control nontransgenic mice were compared. We also examined mutations at codon 61 of the H-ras oncogene, reported as a hot spot in mouse liver tumors, using a direct DNA sequencing method. The results revealed no significant difference in tumor incidence or mutation spectrum, but interestingly, ada-transgenic mice were found to have fewer malignant tumors and survived longer, indicating a possible protective role of MGMT against malignant conversion. [source] Critical reappraisal of current surveillance strategies for Barrett's esophagus: analysis of a large German Barrett's databaseDISEASES OF THE ESOPHAGUS, Issue 8 2008B. H. A. Von Rahden SUMMARY Endoscopic surveillance is recommended for patients with Barrett's esophagus (BE). Based on a large database, gathered from predominantly community-based practices in Germany, we aimed to investigate the time-course of malignant progression and apply these findings to current clinical practice. Data of 1438 patients with BE from a large German BE database were analyzed. Patients with at least one follow-up endoscopy/biopsy were included. Detection of ,malignant Barrett' (either high-grade intra-epithelial neoplasia or invasive adenocarcinoma) was considered as study end-point. Of 1438 patients with BE, 57 patients had low-grade intra-epithelial neoplasia (LG-IN) on initial biopsy and 1381 exhibited non-neoplastic BE. ,Malignant Barrett' was detected in 28 cases (1.9%) during a median follow-up period of 24 months (1,255), accounting for an incidence of 0.95% per patient year of follow-up. The frequency of ,malignant Barrett' was significantly higher (P < 0.001, ,2 -test) in the LG-IN group (n = 11, 19.3%) compared with the non-neoplastic BE group (n = 17, 1.2%). In the non-neoplastic BE group, ,malignant Barrett' was predominantly found during re-endoscopy within the first year of follow-up (12 of 17; 70.6%), in contrast to the LG-IN group, in which ,malignant Barrett' was observed predominantly after a time exceeding 12 months (8 of 11, 72.7%; P = 0.05, Fisher's exact test). Initial endoscopic evaluations seem to play the most crucial role in managing BE. After 1 year of follow-up, endoscopic surveillance should be focused on patients with LG-IN. In patients with repeatedly proven non-neoplastic BE, elongation of the follow-up intervals to the upper limit of current guidelines, that is, 5 years, might be justified. [source] High-resolution comparative genomic hybridization detects extra chromosome arm 12p material in most cases of carcinoma in situ adjacent to overt germ cell tumors, but not before the invasive tumor developmentGENES, CHROMOSOMES AND CANCER, Issue 2 2003Anne Marie Ottesen High-resolution comparative genomic hybridization (HR-CGH) analysis was performed on DNA purified from laser-capture microdissected carcinoma in situ (CIS) cells from nine cases of CIS, either from tissue without any invasive tumor or from testicular parenchyma adjacent to seminoma, nonseminoma, or a combined germ cell tumor. Before CGH analysis, DNA was amplified by degenerate oligonucleotide primed PCR (DOP-PCR) and directly labeled with a mixture of FITC-dUTP and FITC-dCTP. CGH analysis revealed extra chromosome arm 12p material in six out of seven cases with CIS adjacent to overt tumors, but only a diminutive gain of 12q was noted in one of the two cases of CIS without invasive elements. In addition, gains of parts of chromosome 8 (3/7) and losses of chromosome 5 (2/7) were demonstrated in CIS adjacent to invasive tumors. Gains of parts of chromosome 7 were found in CIS adjacent to seminoma (4/4), whereas relative gains of chromosome 15 were identified in some cases of CIS adjacent to seminoma and in isolated CIS in comparison to CIS adjacent to nonseminoma. Our data seem to indicate that extra 12p material is not present in the "dormant" CIS cell before development of an invasive tumor. The gain of extra chromosome 12 material may not be an early event in the neoplastic transformation, but is most likely associated with a more malignant progression of the CIS cell. © 2003 Wiley-Liss, Inc. [source] Ceramide levels are inversely associated with malignant progression of human glial tumorsGLIA, Issue 2 2002Laura Riboni Abstract Ceramide represents an important sphingoid mediator involved in the signaling pathways that control cell proliferation, differentiation, and death. To determine whether ceramide levels correlate with the malignant progression of human astrocytomas, we investigated these levels in surgical specimens of glial tumors of low-grade and high-grade malignancy. Tumor samples obtained from 52 patients who underwent therapeutic removal of primary brain tumors were used. The tumors were classified according to standard morphologic criteria and were grouped into tumors of low-grade and high-grade malignancy. Sections of normal brain tissue adjacent to the tumor were also analyzed in 11 of the 52 patients. After extraction and partial purification, ceramide was measured by quantitative derivatization to ceramide-1-phosphate using diacylglycerol kinase and [,- 32P]ATP. Ceramide levels were significantly lower in the combined high-grade tumors compared with low-grade tumors and in both tumor groups compared with peritumoral tissue. The results indicate an inverse correlation between the amount of ceramide and tumor malignancy as assessed by both the histological grading and ganglioside pattern. Moreover, overall survival analysis of 38 patients indicates that ceramide levels are significantly associated with patient survival. The present findings indicate that ceramide is inversely associated with malignant progression of human astrocytomas and poor prognosis. The downregulation of ceramide levels in human astrocytomas emerges as a novel alteration that may contribute to glial neoplastic transformation. The low ceramide levels in high-grade tumors may provide an advantage for their rapid growth and apoptotic resistant features. This study appears to support the rationale for the potential benefits of a ceramide-based chemotherapy. GLIA 39:105,113, 2002. © 2002 Wiley-Liss, Inc. [source] Hypoxia in head and neck cancer: How much, how important?HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 7 2005H. L. Janssen MD Abstract Background. Hypoxia develops in tumors because of a less ordered, often chaotic, and leaky vascular supply compared with that in normal tissues. In preclinical models, hypoxia has been shown to be associated with treatment resistance and increased malignant potential. In the clinic, several reports show the presence and extent of tumor hypoxia as a negative prognostic indicator. This article reviews the biology and importance of hypoxia in head and neck cancer. Methods. A review of literature was carried out and combined with our own experience on hypoxia measurements using exogenous and endogenous markers. Results. Hypoxia can increase resistance to radiation and cytotoxic drugs and lead to malignant progression, affecting all treatment modalities, including surgery. Hypoxia measurements using electrodes, exogenous bioreductive markers, or endogenous markers show the presence of hypoxia in most head and neck cancers, and correlations with outcome, although limited, consistently indicate hypoxia as an important negative factor. Each hypoxia measurement method has disadvantages, and no "gold standard" yet exists. Distinctions among chronic, acute, and intermediate hypoxia need to be made, because their biology and relevance to treatment resistance differ. Reliable methods for measuring these different forms in the clinic are still lacking. Several methods to overcome hypoxia have been tested clinically, with radiosensitizers (nimorazole), hypoxic cytotoxins (tirapazamine), and carbogen showing some success. New treatments such as hypoxia-mediated gene therapy await proper clinical testing. Conclusions. The hypoxia problem in head and neck cancer needs to be addressed if improvements in current treatments are to be made. Increased knowledge of the molecular biology of intermediate, severe, and intermittent hypoxia is needed to assess their relevance and indicate strategies for overcoming their negative influence. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX,XXX, 2005 [source] Clusterin expression is associated with decreased disease-free survival of patients with colorectal carcinomasHISTOPATHOLOGY, Issue 7 2010Maximino Redondo Redondo M, Rodrigo I, Alcaide J, Tellez T, Roldan M J, Funez R, Diaz-Martin A, Rueda A & Jiménez E (2010) Histopathology,56, 932,936 Clusterin expression is associated with decreased disease-free survival of patients with colorectal carcinomas Aims:, It has been demonstrated that increased clusterin expression is involved in malignant progression and that anticlusterin treatment leads to selective apoptosis. The aim of this study was to determine the clinicopathological significance of clusterin expression in human colorectal carcinomas. Methods and results:, The expression of clusterin was examined in 31 adenomas and 103 colorectal carcinomas. Normal epithelial cells were always negative for clusterin expression, but clusterin expression was present in 16% (5/31) of adenomas and this percentage increased in colorectal carcinomas (30%, 31/103). Immunopositivity always presented an apical cytoplasmic pattern. The expression level of clusterin did not correlate with age, gender, grade or stage. However, its expression was significantly associated with a decrease in disease-free survival (P < 0.05). In a multivariate Cox proportional hazards model, clusterin expression remained a significant independent predictor. Conclusions:, Clusterin expression may have a role in colonic carcinogenesis and may help identify patients with more aggressive tumours who may benefit from targeted therapy. [source] Narrowing of the regions of allelic losses of chromosome 1p36 in meningioma tissues by an improved SSCP analysisINTERNATIONAL JOURNAL OF CANCER, Issue 8 2008Yanlei Guan Abstract Mapping loss of heterozygosity (LOH) regions in the genomes of tumor tissues is a practical approach for identifying genes whose loss is related to tumorigenesis. Conventional LOH analyses using microsatellite or single nucleotide polymorphism (SNP) markers require the simultaneous examination of tumor- and matched normal-DNA. Here, we improved the previously developed SNP-based LOH assay using single strand conformation polymorphism (SSCP) analysis, so that LOH in tumor samples heavily contaminated with normal DNA can now be precisely estimated, even when matched normal DNA is not available. We demonstrate the reliability of the improved SSCP-based LOH detection method, called the LOH estimation by quantitative SSCP analysis using averaged control (LOQUS-AC), by comparing the results with those of the previous "LOH estimated by quantitative SSCP assay" (LOQUS) method. Using the LOQUS-AC assay, LOH was detected at a high consistency (98.1%) with the previous LOQUS method. We then applied this new method to characterize LOH profiles in 130 meningiomas, using 68 SNPs (i.e., a mean inter-SNP interval of 441 kbp) that are evenly distributed throughout chromosome 1p36. Benign, atypical and anaplastic meningiomas exhibited 1p36 LOH at frequencies of 48.39, 84.62 and 100.00%, respectively, using LOQUS-AC. Subsequently, we detected a candidate common LOH region on 1p36.11 that might harbor tumor suppressor genes related to malignant progression of meningioma. © 2007 Wiley-Liss, Inc. [source] Heterogeneous expression of Wnt/,-catenin target genes within colorectal cancerINTERNATIONAL JOURNAL OF CANCER, Issue 9 2007Falk Hlubek Abstract Invasion of common colorectal adenocarcinomas is coupled with a transient loss of epithelial differentiation of tumor cells. Previously, we have shown that dedifferentiated tumor cells at the invasive front (IF) accumulate the transcriptional activator ,-catenin in the nucleus, in contrast to cells of the tumor center. To characterize the cells of these two morphogenic tumor areas, gene expression profiling was performed. Our study demonstrates that intratumorous heterogeneity in colorectal cancer correlates with differential expression of 510 genes between the central tumor region (TC) and the IF. Many genes differentially expressed at the IF are involved in cellular invasion processes like cell motility, cell adhesion and extracellular matrix interaction. This in vivo analysis shows overexpression of known Wnt/,-catenin target genes either in the entire tumor tissue (compared to normal mucosa) or specifically at the IF. Thus, even though all tumor cells overexpress ,-catenin, the existence of at least 2 groups of Wnt/,-catenin target genes selectively activated in different tumor regions is suggested. The concomitant high expression of inflammation- and tissue repair-related genes at the IF supports the hypothesis that an inflammation-activated microenvironment may trigger selective Wnt/,-catenin target gene expression and contribute to the malignant progression of colorectal cancer. © 2007 Wiley-Liss, Inc. [source] Id1 expression is transcriptionally regulated in radial growth phase melanomasINTERNATIONAL JOURNAL OF CANCER, Issue 8 2007Byungwoo Ryu Abstract Id genes have been demonstrated to be upregulated in a wide variety of human malignancies and their expression has been correlated with disease prognosis; however, little is known about the mechanisms of Id gene activation in tumors. We have previously shown that the helix-loop-helix transcription factor, Id1, is highly expressed in primary human melanomas during the radial growth phase and that Id1 is a transcriptional repressor of the familial melanoma gene CDKN2A. Here we use a series of melanoma cell lines that recapitulate the phenotypic characteristics of melanomas at varying stages of malignant progression to evaluate the expression levels of Id1 in this model system and determine the mechanism of Id1 dysregulation in these tumor cells. We find elevated protein levels of Id1 to be present consistently in radial growth phase tumor cells in accordance with our primary tumor data. Id1 transcript levels were also found to be elevated in these radial growth phase melanoma cells without any appreciable evidence of gene amplification and Id1 promoter activity was found to correlate with Id expression levels. We therefore conclude that Id1 expression is primarily regulated at the transcriptional level in radial growth phase melanomas and expect that therapies that target Id1 gene expression may be useful in the treatment of Id-associated malignancies. © 2007 Wiley-Liss, Inc. [source] Regional DNA hypermethylation and DNA methyltransferase (DNMT) 1 protein overexpression in both renal tumors and corresponding nontumorous renal tissuesINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Eri Arai Abstract To evaluate the significance of altered DNA methylation during renal tumorigenesis, tumorous tissues (T) and corresponding nontumorous renal tissues (N) from 94 patients with renal tumors, and normal renal tissues (C) from 16 patients without renal tumors were investigated. DNA methylation status on CpG islands of the p16, human MutL homologue 1 (hMLH1), von-Hippel Lindau (VHL) and thrombospondin-1 (THBS-1) genes and the methylated in tumor (MINT) -1, -2, -12, -25 and -31 clones and DNA methyltransferase (DNMT) 1 expression were examined by bisulfite modification and immunohistochemistry, respectively. The average number of methylated CpG islands was significantly higher in N than in C, and was even higher in T. The average number of methylated CpG islands in N was significantly correlated with a higher histological grade of corresponding conventional renal cell carcinomas (RCCs). The average number of methylated CpG islands in RCCs was significantly correlated with macroscopic configuration with extranodular or multinodular growth, higher histological grade, infiltrating growth pattern and vascular involvement. The recurrence-free survival rate of patients with RCCs showing accumulation of DNA methylation was significantly lower than that of patients not showing this feature. The incidence of nuclear immunoreactivity for DNMT1 tended to be higher in proximal tubules from N than in those from C, and was significantly higher in RCCs. From the viewpoint of altered DNA methylation, N is at the precancerous stage, and N showing accumulation of DNA methylation may generate more malignant RCCs. Regional DNA hypermethylation may be associated with renal tumorigenesis from a precancerous condition to malignant progression and become a predictor of patient prognosis. © 2006 Wiley-Liss, Inc. [source] Genomic analysis of Barrett's esophagus after ablative therapy: Persistence of genetic alterations at tumor suppressor lociINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Mariska Hage Abstract Barrett's esophagus (BE) is a major predisposing factor for the development of esophageal adenocarcinoma. Current strategies for treatment of BE, both dysplastic and nondysplastic, include photodynamic therapy (PDT) and argon plasma coagulation (APC). However, the effect of ablative therapy at the genetic level is unclear. We performed loss of heterozygosity (LOH) analysis of BE in baseline and follow-up biopsy specimens from 21 patients with BE (17 male, 4 female) treated with PDT and/or APC. At baseline, 14 patients had intestinal metaplasia without dysplasia (MET), 4 low-grade dysplasia (LGD) and 3 high-grade dysplasia (HGD). LOH was assessed using a panel of 9 polymorphic markers for evaluation of the P53 gene on 17p, P16 on 9p, DCC and SMAD4 on 18q and the APC gene on 5q. The tissue specimens obtained at baseline (t = 0) were analysed, as well as the first (t = 1; mean interval: 4 months) and last (t = 2; mean interval: 8 months) available biopsy with residual or recurrent BE after ablation. At t = 0, allelic loss was detected of 5q in 27%, 9p in 56%, 17p in 31% and 18q in 6% of informative cases. At t = 1 (18 patients with persistent MET and 3 with LGD) and at t = 2 (8 MET, 2 LGD), the LOH patterns were not statistically different from t = 0. Further, multiple genetic lineages before and after therapy were detected in 15 cases illustrating the multiclonal nature of BE. We conclude that recurrent and/or persistent BE after ablative therapy still contains genetic alterations associated with malignant progression to cancer. Therefore, the goal of treatment should be the complete elimination of Barrett's mucosa. © 2005 Wiley-Liss, Inc. [source] Reduction of PKC, decreases cell proliferation, migration, and invasion of human malignant hepatocellular carcinomaJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2008Trang-Tiau Wu Abstract Protein kinase C (PKC) superfamily play key regulatory roles on the development of cancer. However, the exact role of these enzymes in human hepatocellular carcinoma (HCC) has not been well established. Using the RT-PCR and Western blotting to analyze the levels of PKC isoforms mRNA and protein in the five different differentiated hepatoma cell lines, we found that PKC, was highly expressed in the poor-differentiated HCC cell lines (SK-Hep-1 and HA22T/VGH) as compared with that in the well-differentiated HCC cell lines (PLC/PRF/5, Hep3B, and HepG2). When treated with PKC, antisense oligonucleotides (ODN), both HA22T/VGH and SK-Hep-1 cells lines showed the reduction of PKC, expression, as well as a deceleration in the growth rate and in the level of cyclin D1, but the increase in the levels of p53 and p21WAF1/CIP1. Moreover, the reduction of PKC, expression also inhibited the migratory and invasive potential of both HA22T/VGH and SK-Hep-1 cells lines, and revealed a down-regulation of several migration/invasion-related genes (MMP-1, u-PA, u-PAR, and FAK). These phenomenon were also confirmed by DNA-based small interfering RNA (siRNA) PKC, and PKC,/, specific inhibitor Go6976. Thus, the results indicated that PKC, may be associated with regulation of cell proliferation/migration/invasion in human poorly differentiated HCC cells, suggesting a role for the PKC, in the malignant progression of human HCC. J. Cell. Biochem. 103: 9,20, 2008. © 2007 Wiley-Liss, Inc. [source] ErbB2 and EGFR are downmodulated during the differentiation of 3T3-L1 preadipocytes,,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2003Eleonora Pagano Abstract The expression of receptors belonging to the epidermal growth factor receptor subfamily has been largely studied these last years in epithelial cells mainly as involved in cell proliferation and malignant progression. Although much work has focused on the role of these growth factor receptors in the differentiation of a variety of tissues, there is little information in regards to normal stromal cells. We investigated erbB2 expression in the murine fibroblast cell line Swiss 3T3L1, which naturally or hormonally induced undergoes adipocyte differentiation. We found that the Swiss 3T3-L1 fibroblasts express erbB2, in addition to EGFR, and in a quantity comparable to or even greater than the breast cancer cell line T47D. Proliferating cells increased erbB2 and EGFR levels when reaching confluence up to 4- and 10-fold, respectively. This expression showed a significant decrease when growth-arrested cells were stimulated to differentiate with dexamethasone and isobutyl-methylxanthine. Differentiated cells presented a decreased expression of both erbB2 and EGFR regardless of whether the cells were hormonally or spontaneously differentiated. EGF stimulation of serum-starved cells increased erbB2 tyrosine phosphorylation and retarded erbB2 migration in SDS,PAGE, suggesting receptor association and activation. Heregulin-,1 and -,1, two EGF related factors, had no effect on erbB2 or EGFR phosphorylation. Although 3T3-L1 cells expressed heregulin, its specific receptors, erbB3 and erbB4, were not found. This is the first time in which erbB2 is reported to be expressed in an adipocytic cell line which does not depend on non EGF family growth factors (thyroid hormone, growth hormone, etc.) to accomplish adipose differentiation. Since erbB2 and EGFR expression were downmodulated as differentiation progressed it is conceivable that a mechanism of switching from a mitogenic to a differentiating signaling pathway may be involved, through regulation of the expression of these growth factor receptors. © 2003 Wiley-Liss, Inc. [source] p16INK4a -mediated suppression of telomerase in normal and malignant human breast cellsAGING CELL, Issue 5 2010Alexey V. Bazarov Summary The cyclin-dependent kinase inhibitor p16INK4a (CDKN2A) is an important tumor suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular senescence. Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression. We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells. Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes. Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal. [source] Differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in colorectal cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 6 2003TAE SOOK HWANG Abstract Background: The presence of hypoxic cells in solid tumors has been suggested to contribute to the malignant progression of various tumors. Recently, we reported an activation of heat shock transcription factor (HSF) and expression of heat shock proteins (Hsp) in murine tumor cells by hypoxia. Methods: To search for a possible role of Hsp in the malignant progression of human tumors, we analyzed the expression profiles of Hsp family proteins in weakly and highly metastatic human colorectal cancer (CRC) cell lines. We also analyzed the expression profiles of Bcl-2 family proteins because the altered expression of these proteins has been demonstrated in various solid tumors. Results: In the present paper we showed among various Hsp and Bcl-2 family proteins that the expression of Hsp70 and Hsp110 was elevated in highly metastatic CX-1 and HT-29 cells, while the expression of Bcl-2 was elevated in weakly metastatic MIP-101 and Clone A cells. Subsequent immunohistochemical analysis of 81 primary human CRC tissues demonstrated that the expression of Hsp70 and Hsp110 was highly correlated with the advanced clinical stages and positive lymph node involvement. The expression of Bcl-2, in contrast, was correlated to the early clinical stage and negative lymphovascular invasion. Conclusion: Taken together, our study demonstrated for the first time a differential, stage-dependent expression of Hsp70, Hsp110 and Bcl-2 in CRC. We suggest that the molecular mechanisms underlying the differential expression of Hsp and Bcl-2 family members deserves a more rigorous future study, the results of which might offer novel modes of rationale and strategy to predict and manipulate the malignant progression of colorectal cancers. [source] Human papillomavirus infection and cervical abnormalities in Nairobi, Kenya, an area with a high prevalence of human immunodeficiency virus infectionJOURNAL OF MEDICAL VIROLOGY, Issue 5 2008Rika Yamada Abstract Human papillomavirus (HPV) infection and cervical abnormalities, and their association with human immunodeficiency virus (HIV) infection were studied in 488 women who visited a health center in Nairobi. PCR-based HPV and cervical cytology tests were carried out on all participants, and peripheral CD4+ T cells and plasma HIV RNA were quantitated in HIV positive women. HIV were positive in 32% (155/488) of the women; 77% of these were untreated, and the others had been treated with anti-retroviral drugs within 6 months. Cervical HPV infection was detected in 17% of HIV negative and 49% of HIV positive women. Low-grade squamous intraepithelial lesions were observed in 6.9% of HIV negative and 21% of HIV positive women, while high-grade squamous intraepithelial lesions and cancer were seen in 0.6% and 5.8%, respectively. Multivariate analysis revealed that HIV and HPV infections were associated with each other. Cervical lesions were significantly associated with high-risk HPVs and with HIV infection, depending on HPV infection. HPV infection increased in accordance with lower CD4+ T cell counts and higher HIV RNA levels, and high-grade lesions were strongly associated with high-risk HPV infection and low CD4+ T cell counts. Immunosuppression as a result of HIV infection appears to be important for malignant progression in the cervix. Nationwide prevention of HIV infection and cervical cancer screening are necessary for the health of women in this area. High-risk HPV infection and low CD4+ T cell counts are the risk factors for cervical cancer. J. Med. Virol. 80:847,855, 2008. © 2008 Wiley-Liss, Inc. [source] Adverse effects of Sudanese toombak vs.JOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 2 2010Swedish snuff on human oral cells J Oral Pathol Med (2010) 39 128,140 Background:, The high incidence of oral cancer in Sudan has been associated with the use of toombak, the local type of smokeless tobacco. However, its specific effects on human oral cells are not known. We aimed to investigate the effects of toombak on primary normal human oral keratinocytes, fibroblasts, and a dysplastic oral keratinocytic cell line, and to compare them with the effects induced by Swedish snuff. Method:, Aqueous extracts were prepared from moist toombak and Swedish snuff and added in serial dilutions on in vitro monolayer cultured cells. Cell viability, morphology and growth, DNA double-strand breaks (,H2AX staining), expression of phosphatidylserine (Annexin V staining), and cell cycle were assessed after various exposure time periods. Results:, Significant decrease in cell number, occurrence of DNA double-strain breaks, morphological and biochemical signs of programmed cell death were detected in all oral cell types exposed to clinically relevant dilutions of toombak extract, although to a lesser extent in normal oral fibroblasts and dysplastic keratinocytes. G2/M-block was also detected in normal oral keratinocytes and fibroblasts exposed to clinically relevant dilutions of toombak extract. Swedish snuff extract had less adverse effects on oral cells, mainly at non-clinically relevant dilutions. Conclusion:, This study indicates a potential for toombak, higher than for Swedish snuff, to damage human oral epithelium. Dysplastic oral keratinocytes were less sensitive than their normal counterparts, suggesting that they might have acquired a partially resistant phenotype to toombak -induced cytotoxic effects while still being prone to DNA damage that could lead to further malignant progression. [source] Influence of a Self-Assembling Peptide, RADA16, Compared with Collagen I and Matrigel on the Malignant Phenotype of Human Breast-Cancer Cells in 3D Cultures and in vivoMACROMOLECULAR BIOSCIENCE, Issue 5 2009Kun Mi Abstract Cancer-cell phenotype is not only the result of malignant progression, but also dependent on the microenvironment surrounding them, including influences from the extracellular matrix and its structural properties. We have investigated the influence of the nanofiber matrix of the self-assembling peptide, RADA16, in comparison with collagen I and Matrigel on the malignant phenotype of the human breast-cancer cell, MDA-MB-231, in 3D cultures, including the morphology, survival, proliferation rate, migration potential and the effect of these matrices on the malignancy of the cancer cells in vivo. Our data indicate that these tumor cells change their morphology in response to the different 3D matrix in vitro cultures and the RADA16 self-assembling peptide scaffold mimics an extracellular matrix and could effectively reduce the malignant phenotype of the tumor cells in vitro and in vivo. [source] Acquisition of apoptotic resistance in cadmium-induced malignant transformation: Specific perturbation of JNK signal transduction pathway and associated metallothionein overexpression,MOLECULAR CARCINOGENESIS, Issue 8 2006Wei Qu Abstract Prior work has shown that chronic cadmium exposed rat liver epithelial cells (CCE-LE) become malignantly transformed after protracted low level cadmium exposure. Acquisition of apoptotic resistance is common in oncogenesis and the present work explores this possibility in CCE-LE cells. CCE-LE cells were resistant to apoptosis induced by etoposide or an acute high concentration of cadmium as assessed by flow cytometry with annexin/FITC. Three key mitogen-activated protein kinases (MAPKs), namely ERK1/2, JNK1/2, and p38, were phosphorylated in CCE-LE cells after acute cadmium exposure. However, the levels of phosphorylated JNK1/2 were markedly decreased in CCE-LE cells compared to control. JNK kinase activity was also suppressed in CCE-LE cells exposed to cadmium. Epidermal growth factor (EGF), used as a positive control for stimulating JNK phosphorylation, was much less effective in CCE-LE cells than control cells. Ro318220 (Ro), a strong activator of JNK, increased phosphorylated JNK1/2 to levels similar to the cadmium-treated control cells and also enhanced apoptosis in response to cadmium in CCE-LE cells. Metallothionein (MT), which is thought to potentially inhibit apoptosis, was strongly overexpressed in CCE-LE cells. Further, in MT knockout (MT,/,) fibroblasts, JNK1/2 phosphorylation was markedly increased after cadmium exposure compared with similarly treated wild-type (MT+/+) cells. These results indicate cadmium-transformed cells acquired apoptotic resistance, which may be linked to the specific suppression of the JNK pathway and is associated with MT overexpression, which, in turn, may impact this signal transduction pathway. The acquisition of apoptotic resistance may play an important role in cadmium carcinogenesis by contributing to both tumor initiation and malignant progression. Published 2006 Wiley-Liss, Inc. [source] J1-31 protein expression in astrocytes and astrocytomasNEUROPATHOLOGY, Issue 5 2009Shanop Shuangshoti J1-31 is one of the astrocytic proteins, the expression of which has not been evaluated in astrocytomas. In the present study, we studied the expression of J1-31 protein in astrocytes and astrocytomas in comparison with GFAP, p53 and Ki-67. Materials consisted of formalin-fixed paraffin-embedded tissue specimens that included five cases of normal brain, 17 of gliosis, 15 of pilocytic astrocytoma (WHO grade I), 26 of low-grade diffuse astrocytoma (WHO grade II), four of anaplastic astrocytoma (WHO grade III), and eight of glioblastoma (WHO grade IV). GFAP was highly expressed in all specimens examined. The anti-J1-31 antibody exhibited strong cytoplasmic staining of reactive gliosis in 17/17 (100%) cases with a higher intensity of staining than that observed in the adjacent normal astrocytes. The antibody showed reactivity with tumor cells in 12/15 (80%) cases of pilocytic astrocytoma, although intensity of staining was generally weaker and more focal than observed in reactive gliosis. J1-31-positive tumor cells were detected in only 9/26 (35%) cases of the low-grade diffuse astrocytoma and none of the cases of anaplastic astrocytoma and glioblastoma. Increasing Ki-67 indices paralleled advancing tumor grades. p53 protein was expressed more commonly in infiltrating astrocytomas compared to pilocytic astrocytoma. In conclusion, down-regulation of J1-31 expression correlates with advancing grade of astrocytomas. The result suggests this protein plays some role in astrocytes that is progressively lost in malignant progression. The anti-J1-31 antibody may help further our understanding of astrocytes in disease and may be useful as an aid in the pathologic diagnosis of astrocytic lesions. [source] Vascular endothelial growth factor expression in oligodendrogliomas: a correlative study withSainte-Anne malignancy grade, growth fractionand patient survivalNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2000P. Varlet Microangiogenesis is a delayed but crucial event in the malignant progression of oligodendrogliomas. Accord-ingly, in the new Sainte-Anne grading system of oligodendrogliomas, endothelial hyperplasia and contrast enhancement, both being indicators of microangiogenesis, are key criteria for the distinction of grade A from grade B tumours. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor: a strong correlation between VEGF expression, Sainte-Anne malignancy grade and patient outcome might thus be expected. In order to assess this hypothesis, VEGF immunostaining was performed in a series of 34 oligodendrogliomas that included 11 grade B and 23 grade A, of which nine became grade B during the study period (mean clinical and imaging follow-up: 41 months). VEGF expression correlated strongly with Sainte-Anne tumour grade (P < 0.001), and inversely with patient survival (P < 0.001) and recurrence-free survival (P = 0.002). One hundred per cent of grade B but only 17% of grade A were VEGF-positive. By contrast, the MIB-1 labelling index did not correlate with VEGF expression, total survival or recurrence-free survival. In accordance with the grading system, this study showed that, in oligodendrogliomas, VEGF expression and microangiogenesis are progression-related phenomena that confer on these tumours a growth advantage by presumably reducing hypoxia-induced apoptotic cell death. These findings might have important implications in the future for the indication and timing of anti-angiogenic therapies. [source] Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applicationsNMR IN BIOMEDICINE, Issue 5 2004Bernard Gallez Abstract This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to estimate the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacological interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed. Copyright © 2004 John Wiley & Sons, Ltd. [source] Neurofibromatosis type 1-associated unusual pleomorphic astrocytoma displaying continual malignant progressionPATHOLOGY INTERNATIONAL, Issue 7 2001Hideaki Yokoo Patients with neurofibromatosis type 1 (NF1) often have gliomas as a complication, most of which are benign pilocytic astrocytomas which have arisen in optic pathways. In the present case, a 17-year-old girl (at death) with stigmata of NF1, initially had a bulky tumor mass in the left thalamus, developing into the lateral ventricle, at 13 years of age. Partially resected tissue samples showed pleomorphic astrocytoma with abundant xanthoma cells and degenerative structures such as Rosenthal fibers (RF) and eosinophilic granular bodies. Fine eosinophilic granules identical to RF, both immunophenotypically and ultrastructurally, were also seen. The residual tumor was subtotally resected 6 months later, and the tumor histology was essentially similar as before, accompanying the regenerative structures; this was believed to be a good prognostic indicator. However, several anaplastic features such as mitosis, necrosis and vascular proliferation appeared even in areas rich in the regenerative structures. After a 2-year, disease-free interval, multiple tumor relapse occurred in June 1997. Partially resected tumor tissues were composed of monotonous small anaplastic cells with prominent proliferative activity. Surprisingly, the tumor cells had retained eosinophilic granules within the cell bodies. Postoperative chemotherapy with procarbazine, MCNU and vincristine (PCV) suppressed the residual tumor dramatically, but the regrowing tumor finally became uncontrollable, leading to the patient's death. TP53 mutation was not detected, while p27 immunopositivity was constantly high during malignant progression, suggesting acquisition of proliferative activity to overcome p53 and p27 inhibitory functions. A review of previously published reports failed to reveal any cases of this type. [source] Suppression of putative tumour suppressor gene GLTSCR2 expression in human glioblastomas,THE JOURNAL OF PATHOLOGY, Issue 2 2008Y-J Kim Abstract Glioma tumour-suppressor candidate region gene 2 (GLTSCR2/PICT-1) is localized within the well-known 1.4 Mb tumour-suppressive region of chromosome 19q, which is frequently altered in various human tumours, including diffuse gliomas. Aside from its chromosomal localization, several lines of evidence, including PTEN-phosphorylating and cell-killing activities, suggests that GLTSCR2 participates in the suppression of tumour growth and development. However, little is known about the biological functions and molecular mechanisms of GLTSCR2 as a tumour suppressor gene. We investigated the pathological significance of GLTSCR2 expression in association with the development and progression of glioblastomas, the most common malignant brain tumour. We used real-time PCR and western blot analysis to examine the expression levels of GLTSCR2 mRNA and protein in glioblastomas, normal brain tissue and in non-glial tumour tissue of different origin, and found that GLTSCR2 expression is down-regulated in glioblastomas. In addition, direct sequencing analysis and fluorescence in situ hybridization clearly demonstrates the presence of genetic alterations, such as a nonsense mutation and deletion, in the GLTSCR2 gene in glioblastomas. Finally, our immunohistochemical study demonstrates that GLTSCR2 is sequentially down-regulated according to the histological malignant progression of the astrocytic glial tumour. Taken together, our results suggest that GLTSCR2 is involved in astrocytic glioma progression. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] A comprehensive genetic profile of phyllodes tumours of the breast detects important mutations, intra-tumoral genetic heterogeneity and new genetic changes on recurrence,THE JOURNAL OF PATHOLOGY, Issue 5 2008AM Jones Abstract The aims of this study were to identify genetic changes associated with malignant progression of the fibroepithelial neoplasms, phyllodes tumours of the breast (PTs), and to ascertain whether genetic progression occurs when PTs recur locally. A further aim was to assess whether the genetic data support the classification of these tumours into three subtypes, benign, borderline and malignant. 126 PTs (37 benign, 41 borderline, 48 malignant) were analysed by either array-CGH or the Illumina Goldengate assay. The large-scale genetic changes associated with malignant/borderline phenotypes were + 1q, + 5p, + 7, + 8, , 6, , 9p, , 10p and , 13. Cluster analysis of the array-CGH data supported the division of malignant and borderline PTs into two separate groups, one comprising almost all malignant lesions and the other, benign and borderline tumours. Interstitial deletions of 9p21 that involved the p16INK4a locus were present in many malignant/borderline PTs, and some of these appeared to cause homozygous loss. Loss of expression of p16INK4a was found frequently and this was associated with 9p deletion; we also identified one p16INK4a mutation and evidence of methylation of p16INK4a in malignant PTs. Our evidence shows that inactivation of this gene is important in the development of malignant PTs. In selected PTs, multiple areas of stroma were isolated and analysed separately by array-CGH. We found considerable intra-tumoral genetic heterogeneity. Analysis of paired primary and recurrent tumours showed that recurrent tumours often acquired new genetic changes; in particular, benign tumours tended to acquire changes characteristic of the malignant/borderline phenotype. We believe it likely that unfavourable sub-clones not easily identified by histology account for the unpredictable clinical behaviour of these tumours. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Cigarette smoke condensate induces nuclear factor kappa-b activity and proangiogenic growth factors in aerodigestive cells,THE LARYNGOSCOPE, Issue 8 2010Joseph Rohrer MD Abstract Objectives/Hypothesis: Aerodigestive cancer risk of both lung and head and neck cancers has been linked to the genotoxic effects of tobacco use. These effects include upregulation of nuclear factor kappa-B (NF,B) and its downstream products associated with both lung and head and neck cancer malignant progression. Study Design: Bench Research. Methods: In the present study we examined the effects of cigarette smoke condensate on functional activation of NF,B in human papillomavirus (HPV)-transformed oral cavity cells (HOK 16B cells) and transformed bronchial epithelium (Beas2B cells) using the head and neck squamous cancer cell line, UMSCC 38, as a comparison. Luciferase reporter gene assays with two types of transiently transfected NF,B reporter genes were employed and downstream NF,B-dependent products, interleukin-6, interleukin-8, and vascular endothelial growth factor, were assayed by enzyme-linked immunosorbent assay. Results: All cell lines were able to dose dependently activate NF,B reporter genes after exposure to cigarette smoke condensate (P < .05). However, the HPV premalignant, transformed cell line had a much more robust NF,B response (3.45-fold) versus the squamous cancer cell line (1.62-fold) and SV40 transformed Beas2B (1.83). Both NF,B reporter genes had similar response curves. Conclusions: This study demonstrates cigarette smoke products might be more potent promoters of an NF,B-dependent progression from HPV+ premalignancy to cancer rather than after tumors are established. Future studies should focus on abrogating NF,B increases during malignant progression and premalignancy. This might be even more relevant in the HPV+ patient with premalignancy. Laryngoscope, 2010 [source] Outcome of endoscopy surveillance for Barrett's oesophagusANZ JOURNAL OF SURGERY, Issue 11 2009Tim Bright Abstract Background:, Endoscopic surveillance of individuals with Barrett's oesophagus is undertaken to detect early stage oesophageal malignancy. The impact of a surveillance programme on endoscopy resources and disease detection is uncertain. Methods:, In 2004, we commenced a structured Barrett's oesophagus surveillance programme. The surveillance protocol specifies surveillance interval and number of oesophageal biopsies required according to previous endoscopy and biopsy findings. The first 3 years of surveillance were reviewed to assess programme adherence, impact on endoscopy resources and the incidence of high-grade dysplasia and adenocarcinoma in patients undergoing surveillance. Results:, Four hundred five patients were enrolled in the surveillance programme, and 776 patient years of endoscopy follow-up were analysed. Four-quadrant biopsies every 2 cm throughout the Barrett's oesophagus were performed in 89.8% of endoscopies. A total of 93.7% of patients had surveillance endoscopy performed at the appropriate time interval. Formalizing surveillance was followed by a decrease in the mean time interval for endoscopy surveillance from 16 months to 15 months, although the mode endoscopy surveillance interval lengthened from 1 year to 2 years. The mean number of biopsies per endoscopy increased from 5.9 to 7. In four patients, T1 stage oesophageal adenocarcinoma was identified, and in six patients, high-grade dysplasia was identified (combined incidence of adenocarcinoma/high-grade dysplasia 1 per 77.6 endoscopy years of follow-up). Conclusions:, Structured Barrett's surveillance detects malignant progression at an early stage, which provides opportunities for curative surgical or endoscopic intervention. Formalizing surveillance resulted in a high rate of adherence to agreed guidelines and rationalized the use of endoscopy resources without significantly increasing workload. [source] Interaction of viral oncoproteins with cellular target molecules: infection with high-risk vs low-risk human papillomavirusesAPMIS, Issue 6-7 2010DAVID PIM Pim D, Banks L. Interaction of viral oncoproteins with cellular target molecules: infection with high-risk vs low-risk human papillomaviruses. APMIS 2010; 118: 471,493. Persistent infection by a subgroup of so-called high-risk human papillomaviruses (HPVs) that have a tropism for mucosal epithelia has been defined as the cause of more than 98% of cervical carcinomas as well as a high proportion of other cancers of the anogenital region. Infection of squamous epithelial tissues in the head and neck region by these same high-risk HPVs is also associated with a subset of cancers. Despite the general conservation of genetic structure amongst all HPV types, infection by the low-risk types, whether in genital or head and neck sites, carries a negligible risk of malignant progression, and infections have a markedly different pathology. In this review, we will examine and discuss the interactions that the principal viral oncoproteins of the high-risk mucosotrophic HPVs and their counterparts from the low-risk group make with cellular target proteins, with a view to explaining the differences in their respective pathology. 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