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Human Malignancies (human + malignancy)
Kinds of Human Malignancies Selected AbstractsProteasome inhibitor-induced apoptosis in human monocyte-derived dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006Alessio Nencioni Dr. Abstract Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen-presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte-derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up-regulation and intracellular redistribution of Bcl-2-associated X,protein (Bax), a pro-apoptotic Bcl-2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen-presenting cell level. [source] Hypomethylation of PRAME is responsible for its aberrant overexpression in human malignanciesGENES, CHROMOSOMES AND CANCER, Issue 9 2007Tino Schenk The preferentially expressed antigen of melanoma (PRAME) is expressed at high levels in large fractions of human malignancies, e.g., acute myeloid leukemia. Therefore, PRAME is an important marker for diagnosis of various malignant diseases and a relevant parameter for monitoring minimal residual disease. It is supposed to be involved in tumorigenic processes. Because of these important aspects we investigated its transcriptional regulation in detail. Most relevant was a detailed DNA methylation analysis of the PRAME 5, region by genomic sequencing in correlation with PRAME expression in various human patient samples and cell lines. In combination with DNA-truncation/transfection experiments with respect to DNA methylation, we show that changes in the methylation pattern in defined parts of the regulatory regions of PRAME are sufficient for its upregulation in cells usually not expressing the gene. © 2007 Wiley-Liss, Inc. [source] Prognostic significance of Bcl-2 and p53 expression in advanced laryngeal squamous cell carcinomaHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 4 2001Michael Friedman MD Abstract Background Proteins regulating the cell cycle and cell death are frequently abnormally expressed in cancer. Several of these, particularly p53 and Bcl-2, have been widely suggested as possible prognostic markers in diverse human malignancies. Their role in predicting outcome in squamous cell carcinomas of the head and neck is unclear and may depend on the location, stage, and treatment of the tumor. Methods To assess this question specifically for advanced squamous cell carcinoma of the larynx, we studied 69 patients with stage III or IV tumors, all but 6 of whom were treated with surgery plus postoperative irradiation by a single physician. We studied the patients retrospectively to test the association between expression of Bcl-2 and p53, as assessed by immunohistochemistry, with treatment outcome and survival. Results Twenty of the 69 patients died from their tumor (poor outcome); the rest were alive and tumor free at the last follow-up or died of unrelated causes without clinical tumor recurrence (good outcome). Fourteen tumors had detectable Bcl-2 expression, including 8 scored as overexpressors. Thirty-nine tumors overexpressed p53. Expression of neither Bcl-2 nor p53 was associated with outcome, overall survival, or disease-free survival. Only tumor stage was significantly associated with outcome and disease-free survival. Conclusion These data indicate that assessing expression of p53 or Bcl-2 is unlikely to be prognostically useful for surgically treated advanced laryngeal carcinoma. © 2001 John Wiley & Sons, Inc. Head Neck 23: 280,285, 2001. [source] Presence of nanobacteria in psammoma bodies of ovarian cancer: evidence for pathogenetic role in intratumoral biomineralizationHISTOPATHOLOGY, Issue 6 2004G Hudelist Aims:, The presence of laminated, calcified extracellular debris known as psammoma bodies is a well-known histomorphological feature of ovarian adenocarcinomas and other human malignancies. Biomineralization has recently been found to be associated with a group of extremely small Gram-negative bacteria capable of precipitating calcium salts. The aim of the present study was to evaluate a possible pathogenic link between the development of psammoma bodies and nanobacteria infection. Material and results:, Immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to analyse nanobacterial protein and gene expression in eight psammona body-containing adenocarcinomas and in 10 malignant ovarian tumours without signs of biomineralization. Nanobacterial proteins were detected in eight out of eight (100%) psammoma-positive tumour samples. Conversely, none of the 10 psammoma-negative tissues (0%) was positive for nanobacterial antigens. Furthermore, nanobacterial mRNA was detectable in all of the four tissues (100%) that contained psammoma bodies, but was absent in all 10 ovarian cystadenocarcinomas (0%) that were psammoma negative. Conclusions:, We found a 100% concordance between the expression of nanobacteria and the presence of psammoma bodies in malignant ovarian tumours. Several lines of evidence suggest the involvement of these organisms in the process of biomineralization. We therefore conclude that nanobacterial infection of malignant ovarian tissue contributes to mechanisms leading to the formation of calcified deposits known as psammoma bodies. [source] Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherinINTERNATIONAL JOURNAL OF CANCER, Issue 6 2010Akiko Hayashi Abstract Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examined the immunohistochemical expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathological parameters. In addition, we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related molecules and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochemical expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examined, only HDAC1 was associated with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in association with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes. [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] In vitro and in vivo evaluation and a case report of intense nanosecond pulsed electric field as a local therapy for human malignanciesINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Edward B. Garon Abstract When delivered to cells, very short duration, high electric field pulses (nanoelectropulses) induce primarily intracellular events. We present evidence that this emerging modality may have a role as a local cancer therapy. Five hematologic and 16 solid tumor cell lines were pulsed in vitro. Hematologic cells proved particularly sensitive to nanoelectropulses, with more than a 60% decrease in viable cells measured by MTT assay 96 hr after pulsing in 4 of 5 cell lines. In solid tumor cell lines, 10 out of 16 cell lines had more than a 10% decrease in viable cells. AsPC-1, a pancreatic cancer cell line, demonstrated the greatest in vitro sensitivity among solid tumor cell lines, with a 64% decrease in viable cells. When nanoelectropulse therapy was applied to AsPC-1 tumors in athymic nude mice, responses were seen in 4 of 6 tumors, including clinical complete responses in 3 of 6 animals. A single human subject applied nanoelectropulse therapy to his own basal cell carcinoma and had a complete pathologic response. In summary, we demonstrate that electric pulses 20 ns or less kill a wide variety of human cancer cells in vitro, induce tumor regression in vivo, and show efficacy in a single human patient. Therefore, nanoelectropulse therapy deserves further study as a potentially effective cancer therapy. © 2007 Wiley-Liss, Inc. [source] Analysis of chromosome 10 aberrations in rat endometrial cancer,evidence for a tumor suppressor locus distal to Tp53INTERNATIONAL JOURNAL OF CANCER, Issue 7 2007Carola Nordlander Abstract We have recently shown in the BDII rat model of human endometrial adenocarcinoma (EAC), rat chromosome 10 (RNO10) is frequently involved in chromosomal aberrations. In the present study, we investigated the association between RNO10 deletions, allelic imbalance (AI) at RNO10q24 and Tp53 mutation in 27 rat EAC tumors. We detected chromosomal breakage accompanied by loss of proximal and/or gain of distal parts of RNO10 in approximately 2/3 of the tumors. This finding is suggestive of a tumor suppressor activity encoded from the proximal RNO10. Given the fact that Tp53 is located at RNO10q24-q25, we then performed Tp53 mutation analysis. However, we could not find a strong correlation between AI/deletions at RNO10q24 and Tp53 mutation. Instead, the observed patterns for AI, chromosomal breaks and deletions suggest that major selection was directed against a region located close to, but distal of Tp53. In different human malignancies a similar situation of AI at chromosome band 17p13.3 (HSA17p13.3) unassociated with TP53 mutation has been observed. Although RNO10 is largely homologous to HSA17, the conservation with respect to gene order among them is not extensive. We utilized publicly available draft DNA sequences to study intrachromosomal rearrangement during the divergence between HSA17 and RNO10. By using reciprocal comparison of rat and human genome data, we could substantially narrow down the candidate tumor suppressor region in rat from 3 Mb to a chromosomal segment of about 0.5 Mb in size. These results provide scientific groundwork for identification of the putative tumor suppressor gene(s) at 17p13.3 in human tumors. © 2006 Wiley-Liss, Inc. [source] Alteration of subcellular and cellular expression patterns of cyclin B1 in renal cell carcinoma is significantly related to clinical progression and survival of patientsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2006Stephen O. Ikuerowo Abstract Cyclin B1, identified as a regulator of late cell cycle, is involved in the development and progression of a variety of human malignancies. To clarify the role of cyclin B1 in the pathogenesis and prognosis of renal cell carcinoma (RCC), protein expression was compared with clinicopathological characteristics of patients as well as the long-term survival after surgical therapy. Expression analysis was carried out by immunohistochemistry and tissue microarray analysis. The microarrays that represented the primary tumors, their invasion front and normal peritumoral renal parenchyma contained 753 tissue cores obtained from 251 randomly selected nephrectomy specimens. Immunopositivity within the primary tumors was significantly associated with tumor stage (pT) (p < 0.01), lymph node status (pN) (p < 0.01) as well as the presence of systemic metastatic disease (p = 0.01). Subcellular expression in the cytoplasm of tumor cells significantly correlated with pT (p = 0.02) and pN (p = 0.03). When peritumoral tissue samples exhibited a relative amount of <10% of positively reacting epithelial cells, cyclin B positivity was identified to predict long-term survival of patients in univariate analysis (p < 0.01) whereas borderline significance was observed in multivariate statistical analysis (p = 0.05). Increased intratumoral cyclin B1 positivity and aberrant localization of signals within the cytoplasm of tumor cells is positively correlated with the tendency towards tumor progression, indicating the significant role of cyclin B1 in the development and pathogenesis of RCC. The result of uni- and multivariate statistical analysis suggests the prognostic value of cyclin B1 for RCC patients. © 2006 Wiley-Liss, Inc. [source] Identification and prevalence of CD8+ T-cell responses directed against Epstein-Barr virus-encoded latent membrane protein 1 and latent membrane protein 2INTERNATIONAL JOURNAL OF CANCER, Issue 1 2002Pauline Meij Abstract Epstein-Barr virus (EBV) is associated with several human malignancies that each show different viral gene expression profiles. In malignancies such as Hodgkin's disease and nasopharyngeal carcinoma only Epstein-Barr nuclear antigen 1 (EBNA1) and varying levels of latent membrane proteins 1 and 2 (LMP1 and -2) are expressed. Since endogenously expressed EBNA1 is protected from CTL recognition, LMP1 and LMP2 are the most likely target antigens for anti-tumor immunotherapy. Therefore, we sought to identify in a systematic way CD8+ T-cell responses directed against eptitopes derived from LMP1 and LMP2. Using IFN,-ELISPOT assays of interferon-, release, peripheral blood mononuclear cells (PBMC) of healthy donors were screened with peptide panels (15 mer overlapping by 10) spanning the LMP1 and LMP2 sequences of the prototype EBV strain B95.8. When positive responses were found, CD4+ or CD8+ T cells were depleted from donor PBMC to determine the origin of the responder population. We detected CD8+ T-cell responses to LMP1 in 9/50(18%) donors and to LMP2 in 15/28 (54%) donors. In addition to the already described epitopes, 3 new LMP1- and 5 new LMP2-derived CD8+ epitopes were identified. In most donors LMP1- and LMP2-specific CD8+ precursor frequencies were low compared with precursors against immunodominant EBV epitopes from latent (EBNA3A, -3B and -3C) and lytic cycle antigens. These results demonstrate that CD8+ memory T cell responses to LMP1 and especially to LMP2 do exist in Caucasians, albeit at low levels and could potentially be exploited for therapeutic use. © 2002 Wiley-Liss, Inc. [source] A new multiplex assay allowing simultaneous detection of the inhibition of cell proliferation and induction of cell deathJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2005Józefa W, sierska-G Abstract The efficacy of distinct anti-cancer drugs used in the chemotherapy of human malignancies varies between tumor tissues and depends largely on the ability of the therapeutic agents to simultaneously inhibit cell proliferation and to eliminate malignant cells by apoptosis. Especially, detection of early apoptotic changes seems to be important because early stages of apoptosis differ from those of necrosis. Therefore, the development of a novel test allowing fast and concomitant screening of the anti-proliferative and pro-apoptotic action of a number of anti-cancer drugs is of great interest. For this purpose, we choose as an experimental model a well characterized anti-proliferative and pro-apoptotic effect of cisplatin (CP) on human cervical carcinoma HeLaS3 cells. As previously reported, exposure of HeLaS3 to CP resulted in a concomitant inhibition of cell proliferation and induction of apoptosis in a dose- and time-dependent manner. In the present study we performed two independent approaches. In the first approach, we examined the cell proliferation and activity of caspases-3/7 in two separate microtiter plates using the CellTiter-GloÔ Luminescent Cell Viability Assay and the Caspase-GloÔ 3/7 Assay, respectively. In the second approach, we determined the same parameters sequentially in one microtiter plate by a mutiplexing assay using CellTiter-BlueÔ Cell Viability Assay and Caspase-GloÔ 3/7 Assay. The both approaches gave very similar results indicating that this new multiplexing assay offers an important advantage for simultaneous detection of cell number and activation of caspases-3/7. The new multiplexing assay offers a range of benefits over standard assays. © 2005 Wiley-Liss, Inc. [source] Endoglin: An accessory component of the TGF-,-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignanciesJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2001Ester Fonsatti Endoglin (CD105) is a cell membrane glycoprotein over-expressed on highly proliferating endothelial cells in culture, and on endothelial cells of angiogenetic blood vessels within benign and malignant tissues. CD105 binds several factors of the Transforming Growth Factor (TGF)-, superfamily, and its over-expression modulates cellular responses to TGF-,1. The complex of experimental findings accumulated in the last few years strongly indicate that CD105 is a powerful marker of angiogenesis, and that it might play a critical role in the pathogenesis of vascular diseases and in tumor progression. In this paper, we will review the structural, biological and functional features of CD105, as well as its distribution within normal and neoplastic tissues, emphasizing its foreseeable role as a molecular target for new diagnostic and bioimmunotherapeutic approaches in human malignancies. © 2001 Wiley-Liss, Inc. [source] Ets-1 immunohistochemical expression in non-melanoma skin carcinomaJOURNAL OF CUTANEOUS PATHOLOGY, Issue 1 2004Connie A. Keehn Background:, Ets-1 oncoprotein is a transcription factor known to regulate the expression of numerous genes important in extracellular matrix remodeling and angiogenesis. Up-regulation of Ets-1 has been shown to be important in a variety of human malignancies and to correlate with prognosis. To our knowledge, this oncoprotein has not been examined in non-melanoma skin carcinomas. Design:, A series of 26 primary cutaneous skin lesions with patient records were independently examined for diagnosis confirmation and immunohistochemical expression by two dermatopathologists. The immunohistochemical expression for Ets-1 (Novocastra, Newcastle Upon Tyne, England, UK) was scored by an average of the mean labeling intensity (MLI), where no nuclear staining = 0, weak nuclear staining = 1, moderate nuclear staining = 2, and strong nuclear staining = 3. Results:, All basal cell carcinoma (BCC) and Merkel cell carcinoma (MCC) cases exhibited negative nuclear staining, for an average MLI of 0. Keratoacanthomas, squamous cell carcinoma in situ (SIS), and well-differentiated squamous cell carcinomas (SCCs) exhibited negative to weak nuclear staining, for an average MLI of 0.4 ± 0.3. Moderately differentiated SCCs exhibited moderate nuclear staining, for an average MLI of 1.8 ± 0.6. Poorly differentiated SCCs and metastatic SCCs exhibited very strong nuclear staining, with an average MLI of 2.8 ± 0.2. Conclusions:, Ets-1 is not expressed in cutaneous BCC or MCC and is weakly expressed in SIS and forms of well-differentiated SCC. Although the intensity of Ets-1 immunostaining distinguished between well-differentiated and poorly differentiated SCC (p < 0.0001), it failed to discriminate between in situ and well-differentiated SCCs. The preliminary data suggests Ets-1 may be important in the pathogenesis of invasive SCC. [source] Review article: a conceptual approach to understanding the molecular mechanisms of cancer development in Barrett's oesophagusALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2001R. F. Souza Oesophageal adenocarcinoma is one of the most deadly human malignancies. Gastro-oesophageal reflux disease (GERD) has been established as a strong risk factor for oesophageal adenocarcinoma, and more than 40% of adult Americans experience regular GERD symptoms. GERD can be complicated by oesophagitis, and by replacement of oesophageal squamous mucosa with metaplastic, intestinal-type epithelium (Barrett's oesophagus) that is predisposed to malignancy. Cancers in Barrett's oesophagus arise through a sequence of genetic alterations which endow unlimited proliferative capacity upon the cells by affecting components of the cell cycle clock apparatus,the pivotal molecular machinery in the cell nucleus that controls whether a cell will proliferate, differentiate, become quiescent or die. This report describes how the genetic abnormalities that have been recognized in Barrett's oesophagus might promote carcinogenesis through effects on the cell cycle clock machinery. The goal of this review is to provide the clinician with a useful conceptual basis for evaluating studies on the molecular mechanisms underlying the progression from metaplasia to carcinoma in Barrett's oesophagus. [source] Quantitative mass spectrometry to investigate epidermal growth factor receptor phosphorylation dynamicsMASS SPECTROMETRY REVIEWS, Issue 1 2008Sven Schuchardt Abstract Identifying proteins of signaling networks has received much attention, because an array of biological processes are entirely dependent on protein cross-talk and protein,protein interactions. Protein posttranslational modifications (PTM) add an additional layer of complexity, resulting in complex signaling networks. Of particular interest to our working group are the signaling networks of epidermal growth factor (EGF) receptor, a transmembrane receptor tyrosine kinase involved in various cellular processes, including cell proliferation, differentiation, and survival. Ligand binding to the N -terminal residue of the extracellular domain of EGF receptor induces conformational changes, dimerization, and (auto)-phosphorylation of intracellular tyrosine residues. In addition, activated EGF receptor may positively affect survival pathways, and thus determines the pathways for tumor growth and progression. Notably, in many human malignancies exaggerated EGF receptor activities are commonly observed. An understanding of the mechanism that results in aberrant phosphorylation of EGF receptor tyrosine residues and derived signaling cascades is crucial for an understanding of molecular mechanisms in cancer development. Here, we summarize recent labeling methods and discuss the difficulties in quantitative MS-based phosphorylation assays to probe for receptor tyrosine kinase (RTK) activity. We also review recent advances in sample preparation to investigate membrane-bound RTKs, MS-based detection of phosphopeptides, and the diligent use of different quantitative methods for protein labeling. © 2007 Wiley Periodicals, Inc., Mass Spec Rev 27:51,65, 2008 [source] In silico mining of EST databases for novel pre-implantation embryo-specific zinc finger protein genes,MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 3 2001Kong-Bung Choo Abstract Progress in the understanding of early mammalian embryo development has been severely hampered by scarcity of study materials. To circumvent such a constraint, we have developed a strategy that involves a combination of in silico mining of new genes from expressed sequence tags (EST) databases and rapid determination of expression profiles of the dbEST-derived genes using a PCR-based assay and a panel of cDNA libraries derived from different developmental stages and somatic tissues. We demonstrate that in a random sample of 49 independent dbEST-derived zinc finger protein genes mined from a mouse embryonic 2-cell cDNA library, more than three-quarters of these genes are novel. Examination of characteristics of the human orthologues derived from these mouse genes reveals that many of them are associated with human malignancies. Expression studies have further led to the identification of three novel genes that are exclusively expressed in mouse embryos before or up to the 8-cell stage. Two of the genes, designated 2czf45 and 2czf48 (2czf for 2 -cell zinc finger), are zinc finger protein genes coding for a RBCC protein with a RFP domain and a protein with three C2H2 fingers, respectively. The third gene, designated 2cpoz56, codes for a protein with a POZ domain that is often associated with zinc finger proteins. These three genes are candidate genes for regulatory or other functions in early embryogenesis. The strategy described in this report should generally be applicable to rapid and large-scale mining of other classes of rare genes involved in other biological and pathological processes. Mol. Reprod. Dev. 59:249,255, 2001. © 2001 Wiley-Liss, Inc. [source] Fatty acid synthase expression in squamous cell carcinoma of the tongue: clinicopathological findingsORAL DISEASES, Issue 4 2008SD Silva Background:, Overexpression of fatty acid synthase (FAS), the cytosolic enzyme responsible for the conversion of dietary carbohydrates to fatty acids, has been reported in several human malignancies and pointed as a potential prognostic marker for some tumors. This study investigated whether FAS immunohistochemical expression is correlated with the clinicopathological characteristics of oral squamous cell carcinoma (OSCC). Materials and methods:, The clinical features of 102 patients with OSCC of the tongue treated in a single institution were obtained from the medical records and all histopathological diagnoses were reviewed. The expression of FAS was determined by the standard immunoperoxidase technique in formalin-fixed and paraffin-embedded specimens and correlated with the clinicopathological characteristics of the tumors. Results:, Eighty-one cases (79.41%) were positive for FAS. Microscopic characteristics such as histological grade (P < 0.05), lymphatic permeation (P < 0.001), perineural infiltration (P < 0.05), and nodal metastasis (P < 0.02) were associated with FAS status. A significantly lower survival probability for patients with advanced clinical stage (log-rank test, P < 0.001), lymph nodes metastasis (log-rank test, P < 0.001), presence of vascular permeation (log-rank test, P = 0.05), and perineural invasion (log-rank test, P = 0.01) was observed in the studied samples. Conclusion:, The expression of FAS in OSCC of the tongue is associated with the microscopic characteristics that determine disease progression and prognosis. [source] Peroxisome proliferator-activated receptor gamma in human prostate carcinomaPATHOLOGY INTERNATIONAL, Issue 5 2009Yasuhiro Nakamura Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear hormone receptor superfamily of transcription factors. Peroxisome proliferator-activated receptor gamma (PPAR,) plays an important role in the regulation of lipid homeostasis, adipogenesis, insulin resistance, and development of various organs. Agonists of PPAR, have been also reported to inhibit proliferation of prostate carcinoma cells as in other human malignancies, and these synthetic ligands have been used in differentiation-mediated therapy of various human carcinomas associated with high levels of PPAR,. The significance of PPAR, expression, however, was unknown in human prostate carcinoma tissues. The purpose of the present study was therefore to examine the immunolocalization of PPAR, in human prostate cancer tissues (40 cases) and correlate the findings with clinicopathological features of the patients in order to evaluate its possible biological significance. Twenty-nine patients were positive for PPAR, immunoreactivity (73%) and a significant inverse correlation was detected between PPAR, immunoreactivity, pT stage (P = 0.036), and serum concentration of prostate-specific antigen (P = 0.0004). In conclusion, PPAR, immunoreactivity is considered to be a new clinicopathological parameter of human prostate cancer. [source] The Challenging Estrogen Receptor-Negative/ Progesterone Receptor-Negative/HER-2-Negative Patient: A Promising Candidate for Epidermal Growth Factor Receptor-Targeted Therapy?THE BREAST JOURNAL, Issue 4 2006Kalliopi P. Siziopikou MD Abstract: While epidermal growth factor receptor (EGFR)-targeted therapy has been very promising in a number of human malignancies, to date these targeted biologic agents have not proven effective in breast cancer. However, the EGFR tyrosinase inhibitors have been used indiscriminately against all types of breast tumors, perhaps missing a subpopulation of patients who may be prime candidates for EGFR-targeted therapy. In this communication we propose that patients with estrogen receptor (ER)-negative/progesterone receptor (PR)-negative/HER-2-negative tumors, which currently present a therapeutic challenge for the oncologist, may be the subgroup of breast cancer patients that might benefit from specific EGFR-targeted therapies., [source] Combined radiation therapy and dendritic cell vaccine for treating solid tumors with liver micro-metastasisTHE JOURNAL OF GENE MEDICINE, Issue 4 2005Zhuang Chen Abstract Background Tumor metastasis and relapse are major obstacles in combating human malignant diseases. Neither radiotherapy alone nor injection of dendritic cells (DCs) can successfully overcome this problem. Radiation induces tumor cell apoptosis and necrosis, resulting in the release of tumor antigen and danger signals, which are favorable for DC capturing antigens and maturation. Hence, the strategy of combined irradiation and DC vaccine may be a novel approach for treating human malignancies and early metastasis. Methods To develop an effective combined therapeutic approach, we established a novel concomitant local tumor and liver metastases model through subcutaneous (s.c.) and intravenous (i.v.) injection. We selected the optimal time for DC injection after irradiation and investigated the antitumor effect of combining irradiation with DC intratumoral injection and the related mechanism. Results Combined treatment with radiotherapy and DC vaccine could induce a potent antitumor immune response, resulting in a significant decrease in the rate of local tumor relapse and the numbers of liver metastases. The related mechanisms for this strong antitumor immunity of this combined therapy might be associated with the production of apoptotic and necrotic tumor antigens and heat shock proteins after irradiation, phagocytosis, migration and maturation of DCs, and induction of more efficient tumor-specific cytotoxic T lymphocyte activity through a cross-presentation pathway. Conclusions Co-administration of local irradiation and intratumoral DC injection may be a promising strategy for treating radiosensitive tumors and eliminating metastasis in the clinic. Copyright © 2004 John Wiley & Sons, Ltd. [source] Expression of human telomerase reverse transcriptase and cyclin-D1 in olfactory neuroblastoma,APMIS, Issue 1 2007SHENG-LAN WANG Olfactory neuroblastoma is an uncommon neoplasm. Typically, these tumors are indolent with long-standing symptomatology, but the fact that the lesions are indeed malignant has been proven by the repeated demonstration that they can metastasize to distant organs. Suitable prognostic factors are lacking and therapeutic strategy still remains controversial. Expression of human telomerase reverse transcriptase (hTERT) is associated with most human malignancies and high levels have been correlated with poor prognosis in many cancers. In comparison, overexpression of cyclin-D1 occurs in several malignancies and has been associated with aggressive tumor behavior and poorer prognosis. In this study, we collected 16 olfactory neuroblastomas from the Kaohsiung Medical University Hospital. The aim was to investigate the value of immunoexpression of hTERT and cyclin-D1 in correlation with clinicopathologic features of olfactory neuroblastoma. Low and high cyclin-D1 expression was found in 6 and 10 cases, respectively. For hTERT, low and high protein expression was detected in 5 and 11 tumors, respectively. Cyclin-D1 expression was not correlated with selected parameters. However, high hTERT expression was significantly correlated with high Kadish stage. In conclusion, high hTERT expression can be considered a potential indicator of aggressive olfactory neuroblastoma. [source] Colorectal tumors frequently express phosphorylated mitogen-activated protein kinaseAPMIS, Issue 4-5 2004SUG HYUNG LEE Mounting evidence suggests that activation of the mitogen-activated protein (MAP) kinase pathway plays an important role in tumorigenesis. MAP kinase/ERK kinase (MEK), a crucial constituent of this pathway, is activated by phosphorylation, and the phosphorylated MEK (pMEK) in turn activates ERK kinase. The expression of pMEK has been described in some human malignancies, but not in primary human colon tumors. In this study, we analyzed the expression of pMEK in 123 colorectal tumors by immunohistochemistry. pMEK was detected either in the cytoplasm (63 cases) or nucleus (40 cases) in 93 of the 123 tumors (76%). Tubular adenomas and villous adenomas also expressed pMEK in 30% and 40% of the tumors, respectively. By contrast, the epithelial cells in the normal colonic mucosa showed no or only weak expression of pMEK in the cytoplasm. Taken together, these results indicate that MEK is frequently phosphorylated in colorectal tumors, and suggest that phosphorylation of MEK may play a role in the development of colorectal tumors. [source] Crystallization and preliminary X-ray analysis of the complexes between a Fab and two forms of human insulin-like growth factor IIACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 9 2009Janet Newman Elevated expression of insulin-like growth factor II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon and liver cancer. As IGF-II can deliver a mitogenic signal through both the type 1 insulin-like growth factor receptor (IGF-IR) and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is an attractive therapeutic option. One method of doing this would be to find antibodies that bind tightly and specifically to the peptide, which could be used as protein therapeutics to lower the peptide levels in vivo and/or to block the peptide from binding to the IGF-IR or IR-A. To address this, Fabs were selected from a phage-display library using a biotinylated precursor form of the growth factor known as IGF-IIE as a target. Fabs were isolated that were specific for the E-domain C-terminal extension and for mature IGF-II. Four Fabs selected from the library were produced, complexed with IGF-II and set up in crystallization trials. One of the Fab,IGF-II complexes (M64-F02,IGF-II) crystallized readily, yielding crystals that diffracted to 2.2,Å resolution and belonged to space group P212121, with unit-cell parameters a = 50.7, b = 106.9, c = 110.7,Å. There was one molecule of the complete complex in the asymmetric unit. The same Fab was also crystallized with a longer form of the growth factor, IGF-IIE. This complex crystallized in space group P212121, with unit-cell parameters a = 50.7, b = 107, c = 111.5,Å, and also diffracted X-rays to 2.2,Å resolution. [source] Small interfering RNA-mediated down-regulation of SPAG9 inhibits cervical tumor growthCANCER, Issue 24 2009Manoj Garg PhD Abstract BACKGROUND: The expression of the SPAG9 is associated with various human malignancies. Earlier work revealed a significant association of SPAG9 expression with the early spread of cervical cancer, making it an attractive therapeutic target. Here, the authors investigated the role of SPAG9 in carcinogenesis of squamous cell carcinoma (SCC) of the cervix. Furthermore, they sought to determine whether ablation of SPAG9 expression reduces the tumor growth of cervical SCC in vivo. METHODS: A plasmid-based small interfering RNA approach was used to specifically knock down the expression of SPAG9 in SiHa cells derived from SCC of the cervix in vitro and in vivo. Reverse transcriptase polymerase chain reaction, immunofluorescence staining, flow cytometry, cellular growth, colony formation, migration, invasion, and wound healing assays were studied to characterize SPAG9 in vitro. Furthermore, a cervical cancer xenograft model in nude mice was established to investigate whether knockdown of SPAG9 reduces the tumor growth of cervical SCC in vivo. RESULTS: The results demonstrated that silencing the SPAG9 by small interfering RNA resulted in inhibition of cell growth, colony formation, migration, and invasion. The authors showed for the first time that the knockdown of SPAG9 expression by small interfering RNA significantly suppressed the tumor growth of cervical SCC in vivo. CONCLUSIONS: These results suggest that SPAG9 expression may play a pivotal role in tumor growth and could contribute to the early spread of cervical cancer. Small interfering RNA-mediated down-regulation of SPAG9 represents a promising therapeutic approach for the treatment of cervical cancer. Cancer 2009. © 2009 American Cancer Society. [source] Expression of C4.4A at the invasive front is a novel prognostic marker for disease recurrence of colorectal cancerCANCER SCIENCE, Issue 10 2010Ken Konishi Metastasis-associated gene C4.4A is a glycolipid-anchored membrane protein expressed in several human malignancies. The aim of this study was to explore the expression and clinical relevance of C4.4A in colorectal cancer. By quantitative RT-PCR, 154 colorectal cancer tissues were examined for C4.4A mRNA. We examined 132 colorectal cancer tissues by immunohistochemistry using a new polyclonal antibody that recognizes the C4.4A protein C-terminus containing the glycosylphosphatidyl-inositol anchor signaling sequence. A significant difference in 5-year overall survival was found between samples with high and low expression of C4.4A mRNA (P = 0.0005). Immunohistochemistry showed strong membranous staining of C4.4A at the invasive front of colorectal cancer tumors and at the frontier of metastatic lesions to lymph node and lung. The membranous staining with enhanced intensity at the invasive front of the primary colorectal cancer (Type A: 34/132, 25.6%) was associated with depth of invasion (P = 0.033) and venous invasion (P = 0.003), and was a significant independent prognostic factor (5-year overall survival in the entire series [n = 132; P = 0.004] and disease-free survival in stage II and III colorectal cancers [n = 82; P = 0.003]). Moreover, Type A C4.4A expression was linked to shorter liver metastasis-free survival rate, lung metastasis-free survival rate, or hematogenous metastasis-free survival (P = 0.0279, P = 0.0061, and P = 0.0006, respectively). Our data indicate that expression of the C4.4A protein at the invasive front acts as a novel prognostic marker in colorectal cancer, possibly through invasion-related mechanisms. (Cancer Sci 2010) [source] From tumor lymphangiogenesis to lymphvascular nicheCANCER SCIENCE, Issue 6 2009Satoshi Hirakawa Metastasis in sentinel lymph nodes indicates the initial spread of tumors from a primary site. The recent discovery of tumor-associated growth of lymphatic vessels clarified that tumor lymphangiogenesis actively promotes enhanced draining/sentinel lymph node metastasis. Studies of experimental carcinogenesis have further established that tumors continue to induce lymphangiogenesis in metastatic foci such as draining lymph nodes. Lymphangiogenesis within draining lymph nodes probably contributes to enhanced distant lymph node and distant organ metastases. Lymph node lymphangiogenesis has recently been identified in several human malignancies, such as cutaneous malignant melanoma. Tumor-associated lymphangiogenesis thus has potential significance not only at the primary site, but also in lymph nodes. Primary tumors induce new lymphatic vessel growth in draining lymph nodes before metastasis. The remarkable enlargement of sinusoidal lymphatic endothelium might facilitate tumor cell transport to the lymph nodes, and potentially contribute to the migration, residence, and/or survival of metastatic tumor cancer stem cells by inducing a specific tumor microenvironment. Therefore, the novel concept of ,lymphvascular niche' is proposed herein to explain lymphatic network expansion. This concept might help to improve understanding of the molecular mechanism of lymph node metastasis, and change therapeutic approaches to treating cancer metastasis. (Cancer Sci 2009; 100: 983,989) [source] ITCH is a putative target for a novel 20q11.22 amplification detected in anaplastic thyroid carcinoma cells by array-based comparative genomic hybridizationCANCER SCIENCE, Issue 10 2008Takaya Ishihara Anaplastic thyroid carcinoma (ATC) is one of the most virulent of all human malignancies, with a mean survival time among patients of less than 1 year after diagnosis. To date, however, cytogenetic information on this disease has been very limited. During the course of a program to screen a panel of ATC cell lines for genomic copy-number aberrations using array-based comparative genomic hybridization, we identified a high-level amplification of the ITCH gene, which is mapped to 20q11.22 and belongs to the homologous to the E6-associated protein carboxylterminus ubiquitin ligase family. The expression of ITCH was increased in 4 of 14 ATC cell lines (28.6%), including 8305C in which there was a copy-number amplification of this gene, and six of seven primary cases (85.7%). Among the primary thyroid tumors, a considerable number of ITCH high expressers was found in ATC (40/45, 88.9%), papillary thyroid carcinoma (25/25, 100%), and papillary microcarcinoma (25/25, 100%). Furthermore, knockdown of ITCH by specific small interfering RNA significantly inhibited the growth of ITCH-overexpressing cells, whereas ectopic overexpression of ITCH promoted growth of ATC cell lines with relatively weak expression. These observations indicate ITCH to be the most likely target for 20q11.22 amplification and to play a crucial role in the progression of thyroid carcinoma. (Cancer Sci 2008; 99: 1940,1949) [source] The basic and clinical implications of ABC transporters, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignanciesCANCER SCIENCE, Issue 1 2003Michihiko Kuwano In our laboratories, we have been studying molecular targets which might be advantageous for novel cancer therapeutics. In this review, we focus on how ATP-binding cassette (ABC) transporter superfamily genes, Y-box-binding protein-1 (YB-1), and tumor angiogenesis-associated factors could contribute to the development of novel strategies for molecular cancer therapeutics. ABC transporters such as P-glycoprotein/MDR1 and several MRP family proteins function to protect cells from xenobiotics, drugs and poisons, suggesting that ABC transporters are a double-edged sword. In this regard, P-glycoprotein/MDR1 is a representative ABC transporter which plays a critical role in the efflux of a wide range of drugs. We have reported that gene amplification, gene rearrangements, transcription factor YB-1 and CpG methylation on the promoter are involved in MDR1 gene overexpression in cultured cancer cells. Among them, two mechanisms appear to be relevant to the up-regulation of MDR1 gene in human malignancies. We first reported that MDR1 gene promoter is activated in response to environmental stimuli, and is modulated by methylation/demethylation of CpG sites on the MDR1 promoter. We also demonstrated that YB-1 modulates not only transcription of various genes associated with cell growth, drug resistance and DNA synthesis, but also translation, mRNA stabilization and DNA repair/self-defense processes. Angiogene-sis is also involved in tumor growth, invasion and metastasis of various malignancies, and so angiogenesis-related molecules also offer novel molecular targets for anticancer therapeutics. (Cancer Sci 2003; 94: 9,14) [source] Peroxisome Proliferator-activated Receptor Gamma Activation Induces Cell Cycle Arrest via the p53-independent Pathway in Human Anaplastic Thyroid Cancer CellsCANCER SCIENCE, Issue 12 2002Sung Hwa Chung Anaplastic thyroid carcinoma is one of the most aggressive human malignancies. Outcomes of intensive multimodal therapy have been far from satisfactory. Furthermore, p53 gene dysfunction, often found in this type of cancer, is known to impair the efficacy of the therapeutic agents. Specific ligands for peroxisome proliferator activated receptor gamma (PPAR-,) induce growth suppression in some tumor cells. In this study, we investigated the role of PPAR-, in anaplastic thyroid cancer cell lines (OCUT-1, ACT-1). PPAR-, was expressed and functional in both cell lines. Activation of PPAR-, with its specific ligands, troglitazone and 15-deoxy-,12, 14 -prostaglandin J2, inhibited cell growth in a dose-dependent manner through inducing G1 cell cycle arrest. P53 protein expression differed in OCUT-1 and in ACT-1, though the levels stayed constant irrespective of ligand exposure in both cell lines. In contrast, p21 and p27 proteins were induced in a dose-dependent manner in both situations. This study showed that PPAR-, ligands were able to induce growth suppression in anaplastic thyroid cancer cells via a p53-independent, but p21- and p27-dependent cytostatic pathway. These tumor-suppressive effects of PPAR-, may provide a novel approach to the treatment of anaplastic thyroid cancer. [source] Nonselective DNA damage induced by a replication inhibitor results in the selective elimination of extrachromosomal double minutes from human cancer cellsGENES, CHROMOSOMES AND CANCER, Issue 10 2007Noriaki Shimizu Gene amplification plays a pivotal role in human malignancy. Highly amplified genes frequently localize to extrachromosomal double minutes (dmin), which usually segregate to daughter cells in association with mitotic chromosomes. We and others had shown that treatment with low-dose hydroxyurea (HU) results in the elimination of dmin and reversion of the cancer cell phenotype. HU treatment in early S-phase, when dmin are replicated, results in their detachment from chromosomes at the next M-phase, leading to the appearance of micronuclei enriched in dmin, followed by their elimination. In this article, we examined the effect of low-dose HU on the behavior of dmin in relation to DNA damage induction by simultaneously monitoring LacO-tagged dmin and phosphorylated histone H2AX (,H2AX). As expected, treatment with low-dose HU induced numerous ,H2AX foci throughout the nucleus in early S-phase, and these rarely coincided with dmin. Most chromosomal ,H2AX foci disappeared by metaphase, whereas, unexpectedly, those that persisted frequently associated with dmin. We found that these dmin aggregated, detached from anaphase chromosomes, and apparently formed micronuclei. Because ,H2AX foci likely represent DNA double strand breaks (DSBs), the response to DSBs sustained by extrachromosomal dmin appears to be different from that sustained by chromosomal loci, which may explain why DSB-inducing agents cause the selective elimination of dmin. © 2007 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||