bluuebunny/crossref_metadata_2025 huggingface dataset:
CD66b, CD66c and carcinoembryonic antigen (CEA) are independently regulated markers in sera of tumor patients
Authors: Grunert Fritz , Daniel Susanne , Nagel Gerhard , Kleist Sabine Von , Jantscheff Peter
Published: February 2007

Non‐specific cross‐reacting antigens (NCA‐95 = CD66b and NCA‐50/90 = CD66c) are members of the CEA (carcinoembry‐onic antigen = CD66e) family. Analysis of mRNA levels of CD66c in colon tumors suggests that this antigen is strongly up‐regulated compared to its normal counterpart and could, therefore, be of clinical interest. CD66c is also expressed in normal lung and spleen tissues and, above all, on granulocytes. The appearance of CD66b in serum, the only strictly granulocyte‐specific antigen, could point to the involvement of granulocytes in disease. Specific sandwich ELISAs have been established to determine CEA, CD66b and CD66c levels in serum. Controls have been carried out by testing sera from patients with benign tumors or inflammatory diseases and from healthy individuals. In sera of most patients suffering from solid tumors, sensitivities for CD66c are comparable to or lower than those for CEA. CD66c showed a much higher sensitivity in early colon tumor stages. Sensitivities over 40% have been determined for CD66b in sera of patients with uterine and kidney carcinomas. CML patients revealed sensitivities of 84% for CD66c and 47% for CD66b. Investigations of sera from patients with inflammatory colon diseases which are negative for CEA showed high sensitivity for CD66c but not for the granulocyte‐specific CD66b. Patients with mastopathy revealed sensitivities of over 40% for both CD66c and CD66b. CD66b, CD66c and CEA are independently regulated proteins in a high percentage of patients. The simultaneous determination of CEA and CD66b/c can increase the sensitivities for malignant tumors but high sensitivities of CD66b/c for benign diseases limit their usefulness as tumor markers. CD66b may be interesting as a marker for kidney and corpus carcinomas, for which good markers are not yet available.
Selective sensitivity of solid tumors to suramin in primary cultures of tumor cells from patients
Authors: Csoka Katalin , Nygren Peter , Graf Wilhelm , Påhlman Lars , Glimelius Bengt , Larsson Rolf
Published: February 2007

The antineoplastic activity of suramin is currently the subject of clinical trials. We therefore used the semi‐automated fluoro‐metric microculture cytotoxicity assay (FMCA) to evaluate the cytotoxicity of suramin in vitro in primary cultures of cells from patients with hematological or solid tumors. The activity patterns of some standard cytotoxic agents were included for comparison. A total of 159 samples were tested using continuous drug exposure. Suramin showed relatively high activity against solid tumors, with colorectal, adrenal and kidney carcinomas being the most sensitive, whereas hematological malignancies were more resistant. Suramin and standard drugs showed very low cross‐resistance. The results indicate that suramin is differentially active against some solid tumors with comparatively little activity against hematological tumors. The study provides an experimental motive for evaluation of suramin therapy in patients with solid tumors and exploration of less toxic suramin analogues.
Lack of interleukin‐2 (IL‐2) expression and selective expression of IL‐10 mRNA in human renal cell carcinoma
Authors: Nakagomi Hiroshi , Pisa Pavel , Pisa Eva K. , Yamamoto Yasuyoshi , Halapi Eva , Backlin Karin , Juhlin Claes , Kiessling Rolf
Published: February 2007

Freshly isolated tumor‐infiltrating lymphocytes (TIL) are often functionally deficient. Since one of the key functional parameters of an immune response is the local production of cytokines, we studied the expression of cytokine genes in freshly isolated renal cancer tissue. Using a PCR‐assisted mRNA amplification assay, the constitutive expression of mRNA for 10 different cytokines was assessed in renal cancer tissue. We compared the cytokine mRNA expression in freshly isolated samples of renal carcinomas, renal cancer cell lines established from the tumor samples, peripheral blood mononuclear cells (PBMC) and non‐tumor kidney tissue isolated from the same patients. IL‐10 mRNA expression was detected only in tumor samples, while renal cancer lines, PBMC and non‐tumorous kidney tissues were devoid of this cytokine. One‐third of the tumor samples but none of the normal kidney samples also expressed G‐CSF mRNA. IL‐6, TNF‐α and IFN‐γ mRNA were expressed non‐selectively in tumors, PBMC and normal renal tissue. Expression of IL‐2, IL‐3 and IL‐4 mRNA was not detected in any of the tissues analyzed. Established renal cancer lines exhibited expression of IL‐lα, IL‐6, TNF‐α and GM‐CSF. Culture of tumor‐derived T cells with anti‐CD3 monoclonal antibody (MAb) resulted in expression of IL‐2, IL‐3 and IL‐4 mRNA. In contrast, none of these cytokines was detected in culture with recombinant human IL‐2 alone. Since IL‐10 is known to suppress antigen presentation, these findings have important implications for the possible in vivo role of IL‐10 as a suppressor of local anti‐tumor response.
Growth of ovarian‐carcinoma cell lines at physiological folate concentration: Effect on folate‐binding protein expression in vitro and in vivo
Authors: Miotti Silvia , Facheris Patrizia , Tomassetti Antonella , Bottero Federica , Bottini Cristina , Ottone Francesca , Colnaghi Maria I. , Bunni Marlene A. , Priest David G. , Canevari Silvana
Published: February 2007

Ovarian‐carcinoma cell lines (OVCAR3, IGROVI, OVCA432, SW626 and SKOV3), grown in standard medium containing supra‐physiological (2.3 μM) folate concentration, display different levels of reactivity with the anti‐folate‐binding‐protein (FBP) monoclonal antibody MOv18, which recognizes the α‐iso‐form of the protein. Gel‐filtration and absorption experiments indicated that on IGROVI cells this molecule accounts for all folic‐acid binding at nanomolar concentrations. The aim of the study was to investigate the effect of extracellular folate levels on cells adapted to grow in medium containing physiological folate concentration (20 n M). By the ternary complex assay, all cell lines showed a marked depletion of intracellular reduced folates, compared with those in standard folate medium. The monitoring of FBP by MOv18 showed on IGROVI cells a transient up‐regulation of the protein, whereas on the other cell lines, except SKOV3, no changes were detected. These data suggest that in these cells further over‐expression of the molecule cannot generally be induced by lowering the extracellular folate concentration. On SKOV3, Scatchard analysis of 125I‐MOv18 binding, as well as the evaluation of total folate binding capacity, showed a 2‐ to 3‐fold stable increase of FBP expression after long‐term growth in low‐folate medium. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis indicated in these cells a 1.5‐fold increase in α‐FBP mRNA. SKOV3 cells, maintained in vitro in medium containing supra‐physiological and physiological (i.e., low‐folate) concentrations were injected into nude mice. Weight differences, though not statistically significant, were observed in favour of low‐folate‐derived tumors. Immunohistochemical and immunochemical analysis of the tumor samples showed that in SKOV3 cells the receptor modulation can also be induced by restoring the physiological folate concentration in vivo.
Modulation of cisplatin sensitivity and accumulation by interferon α‐2A in human squamous carcinoma cell lines
Authors: Gupta Vicram , Jani Jitesh P. , Emerson Erling O. , Xu Bing H. , Scalamogna Domenic , Xia Hong , Katoh Arthur , Zaren Howard A. , Singh Shivendra V.
Published: February 2007

This study was undertaken to elucidate the mechanism(s) of potentiation of cisplatin (CDDP) cytotoxicity by interferon α‐2a (IFN α‐2a) in human squamous carcinoma cell lines SCC‐25 and SCC‐4. IFN α‐2a treatment significantly increased the cytotoxicity of CDDP in both cell lines in a dose‐dependent manner. In SCC‐25 cells, the cytotoxicity of CDDP was increased by about 2‐ and 4‐fold, respectively, by treating the cells with 400 and 800 1U/ml IFN α‐2a. Sensitivity of SCC‐4 cells to CDDP was increased by about 3‐ and 7‐fold, respectively, by 400 and 800 1U/ml IFN α‐2a treatment. Drug uptake experiments revealed approximately 1.4‐ to 5‐fold higher platinum accumulation in IFN α‐2a‐treated cells as compared to respective controls. Cellular levels of glutathione (GSH) and GSH transferase, which have been suggested to be important determinants of tumor cell sensitivity to CDDP, were not altered by IFN α‐2a treatment in either of the cell lines. Northern blot analysis showed a moderate increase (about 30–40%) in the level of MT‐IIA mRNA by IFN α‐2a treatment in these cells. Our results suggest that IFN α‐2a‐mediated sensitization of SCC‐25 and SCC‐4 cell lines to CDDP in vitro may be due to an increase in intracellular platinum accumulation.
Ethnic segregation of HTLV‐I and HTLV‐II carriers among South American native Indians
Authors: Fujiyoshi Toshinobu , Yashiki Shinji , Fujiyama Chihaya , Kuwayama Masahiro , Miyashita Hiroki , Ohnishi Hiroshi , Blank Michelle , Zaninovic Vladimir , Blank Abraham , Cartier Luis , Byrnes John J. , Harrington William J. , Miura Tomoyuki , Hayami Masanori , Tajima Kazuo , Sonoda Shunro
Published: February 2007

Thd investigate the genetic background of human T‐cell leukemia virus type I (HTLV‐I) and II (HTLV‐IIhd carriers among South American native Indians, we analyzed HLA DRBI*‐DQBI * haplotypes of the virus carriers from Andes highlands and Orinoco lowlands by the PCR‐RFLP genotyping method. It was revealed that the HTLV‐I‐carrying Andes natives had one of the 5 HLA haplotypes: DRBI*‐DQBI* 0403‐0302, 0802‐0402, 0901‐0303, 1406‐0302 and 0407‐0302, and that the Orinoco HTLV‐II carriers had one of the 3 HLA haplotypes: DRBI*‐DQBI* 1402‐0301, 1602‐0301 and 0404‐0302. The HLA haplotypes of Andes HTLV‐I carriers and Orinoco HTLV‐II carriers were mutually exclusive. The haplotypes associated with HTLV‐I carriers were commonly found among the Andes Indians and Japanese, which is the known HTLV‐I endemic population, while the haplotypes associated with HTLV‐II carriers were specifically found among the Orinoco Indians and North American Indians, among whom HTLV‐II is endemic. These reults suggested that HLA haplotypes might be ethnically segregated among South American natives and might be involved in the susceptibility to HTLV‐I and HTLV‐II infections.
Constitutional and somatic mutations in the WTI gene in wilms' tumor patients
Authors: Nordenskjöld Agneta , Friedman Eitan , Sandstedt Bengt , Söderhäll Stefan , Anvret Maria
Published: February 2007

Whdlms' tumor development, like most tumors, involves multiple genetic alterations affecting divershd genes. Only one of these has thus far been identified, the Wilms' tumor I (WTI) gene on 11p 13, which functions as a tumor suppressor gene. We assessed the involvement of the WTI gene constitutionally and somatically in 26 Wilms' tumor patients. Of these, the clinical data suggest a constitutional pre‐disposition in 12 bilateral cases and 7 cases with early onset. We employed Southern blot analysis and PCR‐based markers for analyses of somatic allelic losses in chromosome bands 11 p 13, 11 p 15 and 16q and screened for point mutations in exons 2–10 of the WTI gene with denaturing gradient gel electrophoresis (DGGE). Of the 12 cases with multiple tumors, I exhibited a constitutional 11 p 13 deletion and a somatic stop mutation in exon 4 of the WTI gene and 2 harbored constitutional mutations in the WTI gene: a pre‐mature stop codon in exon 6 in a boy with bilateral cryptorchidism and bilateral Wilms' tumors and an intragenic deletion in a girl with bilateral WT. Three additional bilateral tumors displayed WTI rearrangements or allelic losses with 11 p 13 markers. Four of 7 patients with an early onset of unilateral tumor had losses of 11p 13, though no WTI mutations were detected. Two of the remaining cases that did not show any somatic or constitutional 11 p 13 alterations had Beckwith‐Wiedemann syndrome, known to involve the 11 p 15 region.
Oncogenic transformation alters cisplatin‐induced apoptosis in rat embryo fibroblasts
Authors: Basu Alakananda , Cline Jeffrey S.
Published: February 2007

We have investigated whether cellular transformation by different oncogenes alters their responsiveness to the chemotherapeutic agent cis‐diamminedichloroplatinum(lI) (cDDP). Rat‐6 (R6) embryo fibroblasts transformed by v‐myc, rc‐mos (rearranged mouse c‐mos), v‐src and activated c‐H‐ras oncogenes displayed differential sensitivities to cDDP, and the lC50 values of cDDP decreased by approximately 3.0‐, 1.2‐, 2.0‐ and 1.5‐fold, respectively. Over‐expression of rnyc, but not ras, srcor mos, induced apoptosis in R6 cells. Nevertheless, all oncogenes influenced cellular susceptibility to apoptosis triggered by cDDP as judged by the appearance of condensed chromatin, formation of apoptotic bodies and internucleosomal cleavage of genomic DNA to 180 bp multimers, yielding a “laddered” ectrophoretic profile on agarose gel. There was a correlation between the time‐ and concentration‐dependent enhancement of cDDP‐induced DNAfragmentation and potentiation of cDDP sensitivity by various oncogenes. Oncogenic transformation led to a decrease in expression of the PKCr isoform, and stable transfection of PKCr in R6 cells prevented cDDP‐induced apoptosis and protected cells against cDDP cytotoxicity. Our results indicate that the differential sensitivity of oncogenetransformed cells to cDDP may be associated with the ability of various oncogenes to influence cDDP‐induced apoptosis.
Anti‐tumor and anti‐angiogenic effects in mice of heparin conjugated to angiostatic steroids
Authors: Derbyshire Elaine J. , Comin Georgina A. , Yang Yong‐Ching , Overholser Jay , Watkins Linda , Thorpe Philip E.
Published: February 2007

Heparin‐steroid conjugates have been prepared by linking a non‐anti‐coagulating derivative of heparin, which binds to endothelial cells, to an angiostatic steroid, which suppresses endothelial cell division. One such conjugate, heparin adipic hydrazide (HAH) linked to cortisol, has previously been shown to inhibit both angiogenesis and the growth of solid tumors in mice. In the present study, heparin hydrazide (HH) was linked to tetrahydro S, tetrahydrocortisone and tetrahydrocortisol, which are devoid of glucocorticoid and mineralocorticoid activity and hence were predicted to have low toxicity to animals. The tetrahydro steroid conjugates were compared with the cortisol conjugate for therapeutic effectiveness against solid Lewis lung carcinoma growing in mice. HAH‐cortisol reduced tumor growth by up to 75% whereas a simple mixture of HAH and cortisol was not significantly inhibitory. In contrast to HAH‐cortisol, the 3 tetrahydro steroid conjugates did not significantly inhibit tumor growth. The differences in anti‐tumor properties of the conjugates correlated with their ability to inhibit angiogenesis in a Matrigel implant model in mice. The tetrahydro steroid conjugates did not significantly inhibit angiogenesis whereas HAH‐cortisol inhibited angiogenesis by greater than 90%. Therefore, HAH‐cortisol is the most effective heparin‐steroid conjugate so far developed. © 1995 Wiley‐Liss, Inc.
Regulation of EGF‐induced tenascin‐C by steroids in tenascin‐C‐non‐producing human carcinoma cells
Authors: Sakai Takao , Kawakatsu Hisaaki , Furukawa Yusuke , Saito Masaki
Published: February 2007

Tenascin‐C, a 6‐armed extracellular matrix glycoprotein, is expressed in a temporally and spatially restricted pattern during tumorigenesis in association with stromal‐epithelial interactions. We have previously shown that de novo synthesis of tenascin‐C is induced by the diffusible factor EGF in tenascin‐C‐non‐producing human epidermoid carcinoma cells in stromal‐epithelial interactions. We now demonstrate that the addition of human tenascin‐C or tenascin‐C peptides to the culture medium of these cells had little effect on the induction of tenascin‐C. The physiological regulators of tenascin‐C induction through the EGF receptor, however, have not yet been characterized. We show that steroid hormones down‐regulate EGF‐induced tenascin‐C glycoprotein and its mRNA in these tenascin‐C‐non‐producing carcinoma cells. Of the steroids examined, hydrocortisone most effectively inhibited the secretion of tenascin‐C. These steroids did not affect EGF‐induced autophosphorylation or de novo synthesis of EGF receptors, nor did they compete for the binding of EGF to its receptor. Our results indicate that the induction of tenascin‐C by EGF and its down‐regulation by steroids might proceed in these carcinoma cells through separate signal transduction pathways. © 1995 Wiley‐Liss, Inc.
The essential role of endogenous IFN α/β in the anti‐metastatic action of sensitized T lymphocytes in mice injected with friend erythroleukemia cells
Authors: Gresser Ion , Maury Chantal , Kaido Thomas , Bandu Marie‐Thérèse , Tovey Michael G. , Maunoury Marie‐Thérèse , Fantuzzi Laura , Gessani Sandra , Greco Giampaolo , Belardelli Filippo
Published: February 2007

Adoptive transfer of splenic T lymphocytes from DBA/2 mice immunized against Friend erythroleukemia cells (FLC) inhibited the development of visceral metastases and increased the survival time of DBA/2 mice challenged i.v. with parental FLC 24 hr to 2 months later. Immune spleen cells were ineffective in mice pre‐treated with potent neutralizing antibody to mouse IFN α/β (but not to IFN γ), demonstrating the essential participation of endogenous IFN α/β in the inhibitory action of immune T lymphocytes against FLC metastases. These findings suggest that the reported inability of immune T lymphocytes to exert an anti‐FLC effect in immunodeficient DBA/2 mutant beige (bg/bg) mice (unless these mice had also been treated with IFN α/β), may have been due to lower levels of endogenous IFN α/β in DBA/2 bg/bg mice than in normal DBA/2 +/bg mice. Experimental results in support of this hypothesis are presented. © 1995 Wiley‐Liss, Inc.
Effects of aminoglutethimide, alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters
Authors: Visser Corjan J. T. , Meijers Michiel , Van Garderen‐Hoetmer Annemarie , Klijn Jan G. M. , Foekens John A. , Woutersen Ruud A.
Published: February 2007

The present 12‐month study was carried out to investigate the effects of the aromatase inhibitor aminoglutethimide, alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine‐treated rats and N‐nitrosobis(2‐oxopropyl)‐amine‐treated hamsters. Treatment of the animals started 4 months after the last injection with the carcinogen. They were surgically castrated and/or treated with aminoglutethimide. Aminoglutethimide‐treated rats developed less pancreatic tumours than did untreated controls. Multiplicity of (pre‐)‐neoplastic acinar lesions was lower in orchiectomized rats than in intact rats. Inhibition of pancreatic carcinogenesis was most pronounced in rats that were both orchiectomized and treated with aminoglutethimide. These effects were statistically significant after 8 months, but not after 4 months, of treatment. In hamsters, aminoglutethimide showed an enhancing rather than an inhibitory effect on the formation of ductular pancreatic tumours. Castration appeared to have no effect on the development of N‐nitrosobis(2‐oxopropyl)amine‐induced ductular lesions in the pancreas, either alone, or in combination with aminoglutethimide. The present findings indicate that aminoglutethimide, alone and in combination with surgical castration, might be of value for the treatment of pancreatic acinar tumours, whereas the usefulness of aminoglutethimide for treatment of ductular adenocarcinomas of the pancreas is somewhat doubtful. © 1995 Wiley‐Liss, Inc.
Delayed development of retinoblastoma associated with loss of a maternal allele on chromosome 13
Authors: Kato Mitsuo V. , Ishizaki Kanji , Shimizu Takashi , Toguchida Junya , Kaneko Akihiro , Sasaki Masao S.
Published: February 2007

Loss of heterozygosity (LOH) on chromosome 13, which is associated with the functional inactivation of the retinoblastoma (RB) gene, is critical for the development of RB. To date, we have found that LOH‐negative tumors develop earlier than LOH‐positive tumors in hereditary cases of RB, an observation which suggests that loss of one allele on chromosome 13 may be disadvantageous with respect to growth of RB tumors. In this study, the parental origin of the lost allele on chromosome 13 and the age at operation of 13 patients with non‐hereditary RB tumors that had been enucleated at the same stage were studied, in an attempt to determine whether there are any differences between tumors with loss of a maternal allele on chromosome 13 and tumors with loss of a paternal allele. Six tumors had lost the maternal allele and 7 tumors had lost the paternal allele on chromosome 13. The age (average 694 days) of patients at operation in the case of tumors with loss of the paternal allele was significantly lower than the age (average 1,079 days) of patients at operation for removal of tumors with loss of the maternal allele. RB tumors that had lost the maternal allele on chromosome 13 developed later than tumors that had lost the paternal allele. The possibility is discussed that loss of the maternal allele on chromosome 13 might be disadvantageous for growth of RB tumors. © 1995 Wiley‐Liss, Inc.
The proto‐oncogene/translation factor eIF4E: A survey of its expression in breast carcinomas
Authors: Kerekatte Vaishali , Smiley Kyle , Hu Bei , Smith Albert , Gelder Frank , De Benedetti Arrigo
Published: February 2007

The eukaryotic translation initiation factor elF‐4E binds to the cap structure of mRNAs as one component of the elF‐4 translation initiation complex, which mediates the recruitment of mRNA to the ribosomes. Overexpression of elF‐4E can result in oncogenic transformation and uncontrolled growth of mammalian cells, presumably by facilitating the expression of growth‐control gene products which are normally translationally repressed. Whereas the mechanism of elF‐4E‐mediated transformation is being actively pursued, clinical investigations into the expression of elF‐4E in prevalent human cancers are lacking. We have recently initiated a screen of breast carcinomas by probing with elF‐4E antiserum. Using Western blots, we have analyzed the level of elF‐4E in 38 carcinomas, 7 normal samples and 3 fibroadenomas. We found that elF‐4E was elevated 3‐ to 10‐fold in virtually all the carcinomas we analyzed, but not in fibroadenomas. This analysis was also confirmed by immunohistological staining in situ, showing that overexpression of elF‐4E can be readily identified at the single‐cell level. Our results suggest that an elevation of elF‐4E may be an essential component in the development of breast cancer. © 1995 Wiley‐Liss, Inc.
The mutational status of p53 protein in gastric and esophageal adenocarcinoma cell lines predicts sensitivity to chemotherapeutic agents
Authors: Nabeya Yoshihiro , Loganzo Frank , Maslak Peter , Lai Lawrence , De Oliveira Alice R. , Schwartz Gary K. , Blundell Maude L. , Altorki Nasser K. , Kelsen David P. , Albino Anthony P.
Published: February 2007

Resistance to chemotherapy remains a serious problem in the successful treatment of gastric and esophageal cancers. DNA‐damaging agents alter levels of p53 protein in several cell types and it has been speculated that regulation of p53 can be involved in the resistance or sensitivity of cancer cells to some chemotherapeutic drugs, depending on whether cells have mutant or wild‐type p53; however, little is known about the relationship of p53 to drug sensitivity in gastric/esophageal cancers. Here we have examined human gastric/esophageal adenocarcinoma cell lines for p53 mutational status, chemorensitivity to 5‐fluorouracil, mitomycin C, and cis‐dichlorodiammin‐eplatinum(II), alteration in p53 levels following exposure of cells to these drugs, and the mechanisms involved in regulating p53 levels. Our results indicate that wild‐type p53 protein levels increase after treatment with each of these drugs via either post‐translational and/or translational mechanisms and that this increase in wild‐type p53 appears to be required for effective chemotherapeutic growth control of gastric/esophageal adenocarcinoma cells. In contrast, gastric/esophageal cancer cells expressing either mutated p53 protein or no p53 protein are more resistant to the growth‐inhibitory effects of these drugs, despite the fact that drug exposure can also increase mutant p53 levels by a translational mechanism. Thus, these data indicate that the mutational status of p53 is predictive of chemosensitivity of gastric and esophageal adenocarcinomas, and suggest a mechanism in which p53 protein contributes to the cellular response to chemotherapy. © 1995 Wiley‐Liss, Inc.
p53 gene mutations in early colorectal carcinoma. de novo vs. adenoma‐carcinoma sequence
Authors: Hasegawa Hirotoshi , Ueda Masakazu , Furukawa Kazuo , Watanabe Masahiko , Teramoto Tatsuo , Mukai Makio , Kitajima Masaki
Published: February 2007

p53 gene mutations in early and advanced colorectal cancer were detected by PCR‐SSCP analysis. Early colorectal cancer was classified intode novo cancer and polyp‐forming cancer, respectively, according to morphology and presence of adenomatous components. A total of 94 paraffin‐embedded tissue specimens from patients with colorectal cancer were analysed.p53 gene mutations were detected in 40.0% (12/30) of de novo cancer, 36.7% (11/30) of polyp‐forming cancer, and 44% (15/34) of advanced cancer. p53 mutations were detected at a high frequency in both types of early colorectal cancer as well as in advanced cancer. No correlations were found between p53 mutations and clinicopathological data. Our data suggest that the p53 gene mutations occurred in the early colorectal cancer stage of carcinogenesis regardless of the pathway. © 1995 Wiley‐Liss, Inc.
Significance of tenascin serum level as tumor marker in primary colorectal carcinoma
Authors: Riedl Stefan , Bodenmüller Heinz , Hinz Ulf , Holle Rolf , Möller Peter , Schlag Peter , Herfarth Christian , Faissner Andreas
Published: February 2007

Tenascin serum levels were evaluated in 118 patients with primary colorectal carcinoma and in a control group of 51 healthy persons in a double‐sided sandwich ELISA. The data were correlated with post‐operative TNM‐staging. Patients with colorectal carcinomas had significantly higher serum levels of tenascin than the control group. At the 95% level of specificity, sensitivity was 25%. Tumor grading obviously had no influence on the level of tenascin in serum. With increasing pT‐category, tenascin levels increased as well. In patients with distant metastatic disease, serum tenascin levels were significantly higher than in patients without distant metastases. These data suggest that, in colorectal carcinoma, the preoperative level of serum tenascin reflects the total tumor burden and correlates with metastatic disease. Our observation warrants a prospective study of the relevance of tenascin serum levels with regard to prognosis and as an indicator of relapse. © 1995 Wiley‐Liss, Inc.
Neoplastic progression of human colorectal cancer is associated with overexpression of the stromelysin‐3 and BM‐40/SPARC genes
Authors: Porte Henri , Chastre Eric , Prevot Sophie , Nordlinger Bernard , Empereur Sylvie , Basset Paul , Chambon Pierre , Gespach Christian
Published: February 2007

The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. This study was designed to evaluate the potential implication of stromelysin‐3 (ST3), a newly identified member of the matrix‐degrading metalloproteinase family, and of BM‐40/SPARC, a glycoprotein associated with the extracellular matrix, during the progression of human colorectal cancers. We analyzed the relative abundance of ST3 and BM‐40/SPARC transcripts by Northern blot, and their distribution by in situ hybridization, in normal mucosa, benign adenomas, and primary colorectal adenocarcinomas and their liver metastases. The ST3 and BM‐40/SPARC transcripts were overexpressed in primary colorectal cancers and their liver metastases compared to non‐neoplastic mucosa. These transcripts were localized in stromal fibroblasts adjacent to the neoplastic foci. Overexpression of ST3 correlated with the progression of human colorectal tumors toward local invasion and liver metastasis. Induction of these genes also occurred in diverticulitis and digestive neoplasms such as gastric and esophageal carcinomas. © 1995 Wiley‐Liss, Inc.
Detection of tumour cells in peripheral blood and bone marrow from ewing tumour patients by rt‐pcr
Authors: Pfleiderer Christa , Zoubek Andreas , Gruber Bernadette , Kronberger Martina , Ambros Peter F. , Lion Thomas , Fink Franz‐Martin , Gadner Helmut , Kovar Heinrich
Published: February 2007

The Ewing family of tumours (et) is characterised at the cytogenetic level by unique chromosome 22 rearrangements. The breakpoints have been cloned and were shown to fuse the EWS gene on chromosome 22 to one of two closely related ETS proto‐oncogenes, FLI‐L or EFG, which reside on chromosomes 11 and 21, respectively. The rearrangement results in the expression of chimaeric transcripts, which can be identified by means of reverse transcriptase‐polymerase chain reaction (RT‐PCR). We applied this method for the monitoring of Et cells circulating in the peripheral blood or infiltrating the bone marrow. The presence of tumour cells could be detected with a sensitivity of I in I × 106 nucleated cells. When samples were kept at 4c, tumour cells could still be identified after 48 hr of storage. Positive RT‐PCR signals originated from intact ET cells rather than from free RNA released by ruptured tumour cells. We analysed peripheral blood, bone marrow samples and peripheral blood stem cell collections from 16 ET patients. At diagnosis, bone marrow specimens collected from 6 patients and 1 peripheral blood specimen tested positive for EWS chimaeric RNA. During therapy tumour cells were detected in bone marrow aspirations obtained from 2 patients. Our results show that ET cells infiltrating the bone marrow or circulating in peripheral blood can be identified by RT‐PCR. The clinical implications for the presence of ET cells in samples detected by RT‐PCR at diagnosis and during therapy requires further evaluation. © 1995 Wiley‐Liss, Inc.
Association between rb‐1 gene alterations and factors of favourable prognosis in human breast cancer, without effect on survival
Authors: Berns Els M. J. J. , De Klein Annelies , Van Putten Wim L. J. , Van Staveren Iris L. , Bootsma Aart , Klijn Jan G. M. , Foekens John A.
Published: February 2007

The retinoblastoma (RB) tumour suppressor gene has been associated not only with retinoblastoma but also with several other tumours like osteosarcoma, small cell lung carcinoma and prostate and breast cancer. We have studied the incidence of RB gene alterations in 96 primary breast tumours using Southern blotting techniques. The outcome has been related with patient and tumour characteristics, oncogene amplifications, p53 mutations and prognosis. RB gene alterations were found to occur more frequently in estrogen receptor (ER)‐positive than in ER‐negative tumours and less frequently in tumours with oncogene amplification than in tumours without oncogene amplification of HHR2/neu, c‐myc or 11q13. RB gene alteration was observed in tumours both with and without a p53 gene mutation. Data on 87 patients (mean age, 59.6 years; median follow‐up, 108 months) and RB gene alterations revealed a significant association between the frequency of RB gene alterations and node‐negative patients (p < 0.01) or smaller (<2 cm) tumours (p < 0.01), but no relation with age, differentiation grade or (relapse‐free) survival. Patients with and without RB gene alterations showed the same relapse‐free and overall survival. © 1995 Wiley‐Liss, Inc.
Microsatellite instability in primary and metastatic colorectal cancers
Authors: Ishimaru Gosei , Adachi Jun‐Ichi , Shiseki Masayuki , Yamaguchi Naohito , Muto Tetsuichiro , Yokota Jun
Published: February 2007

Microsatellite instability characterizes a sub‐set of sporadic colorectal cancers (CRCs) as well as CRCs from patients with hereditary non‐polyposis colorectal cancer (HNPCC). In order to clarify when the cells acquire a replication‐error phenotype (RER) during colorectal‐tumor progression, we examined the incidence of RER in 80 primary tumors and 36 liver metastases at 8 microsatellite loci; I mono‐, 5 di‐, I tetra‐ and I penta‐nucleotide. RER were detected in 20.1% (17/80) of primary tumors, including 5 tumors showing RER at 2 or more loci (RER2), while the incidence of RER in liver metastases (22.2%, 8/36) was almost the same as that in primary tumors, and there was only one RER2 case in metastases. There were 3 cases in which both primary tumors and liver metastases had the same type of RER at the same locus, and there were 2 cases that showed RER in primary tumors but not in liver metastases. In contrast, there was no case in which RER was detected in a metastasis but not in the corresponding primary tumor. The RER phenotype did not show correlation with any clinicopatho‐logical parameters of cancer‐cell aggressiveness, such as clinical staging, histological grade and survival. These results indicate that a sub‐set of CRCs acquire the RER phenotype in the relatively early stages of colorectal carcinogenesis, and that the RER phenotype is not associated with aggressiveness of CRCs. © 1995 Wiley‐Liss, Inc.
Expression of cd44 splice variants in human cutaneous melanoma and melanoma cell lines is related to tumor progression and metastatic potential
Authors: Manten‐Horst Eveliene , Danen Erik H. J. , Smit Lia , Snoek Margriet , Caroline Poole I. Le , Van Muijen Goos N. P. , Pals Steven T. , Ruiter Dirk J.
Published: February 2007

Expression of CD44, particularly of certain splice variants, has been linked to tumor progression and metastasis formation in a number of different animal and human cancers. Because human cutaneous melanoma is among the most aggressive human cancers, we explored expression of CD44 isoforms (CD44v) in lesions of melanocytic tumor progression. In addition, by RT‐PCR and FACS analysis we assessed CD44v RNA species and cell surface expression of CD44v in cultured melanocytes isolated from human foreskin and in a panel of 2 non‐, 2 sporadically and 2 highly metastatic human melanoma cell lines. We observed that all melanocytic lesions examined showed strong uniform expression of standard CD44 (CD44s) epitopes. We did not detect CD44v6 expression in the melanocytic lesions. However, CD44 isoforms containing v5 or v10 were differentially expressed. V5 was expressed in 16%, 0%, 20%, 67% and 58% of common nevi, atypical nevi, early primary melanomas (± 1.5 mm), advanced primary melanomas (> 1.5 mm) and metastases, respectively, and hence was related to tumor progression. In contrast, CD44vl0 was expressed in all common nevi, whereas part of the atypical nevi and most primary melanomas and metastases lacked v10. CD44v RNA patterns were closely similar in cultured melanocytes and all melanoma cell lines. Melanocytes expressed high levels of CD44s but no CD44v, whereas all melanoma cell lines expressed CD44v at the surface. Interestingly, expression of v5 was strongly increased in the highly metastatic cell lines. Our results suggest a role for CD44 variant domains, particularly v5 and v10, in human melanocytic tumor progression. © 1995 Wiley‐Liss, Inc.
Increased expression of the nme1 gene is associated with metastasis in epithelial ovarian cancer
Authors: Leary Jennifer A. , Kerr Judith , Chenevix‐Trench Georgia , Doris Claire P. , Hurst Terry , Houghton C. Roger S. , Friedlanders Michael L.
Published: February 2007

The genetic events involved in the development of metastases of epithelial ovarian cancer are largely unknown. One gene postulated to play a role in tumour metastasis suppression is NMEI (nm23‐HI), and an inverse relationship between NMEI expression and metastatic potential has been observed for some solid tumours. In this study we have investigated the levels of mRNA expression of the 2 isoforms of the NME gene, NMEI and NME2. A maximum of 45 tumour samples from 33 patients were available for Northern blot analysis. We observed variable levels of expression of NMEI and NME2 mRNA. The average level of NMEI, but not NME2, mRNA expression was statistically higher in metastatic biopsies when compared with primary tumour biopsies. To examine the possible tumour suppressor gene role of NMEI in ovarian tumours, 76 patients were investigated by Southern blot analysis to determine the rate of allelic deletion. Allele loss at 5 other chromosome 17 loci (D17S5, TP53, NF1, D17S74, D17S4) was also evaluated for many of these 76 patients. Allele loss was observed in 22/30 (73%) informative patients at the NME1 locus. We also observed high rates of allele loss at the other loci evaluated. No correlations with clinical stage, histological subtype or patient survival were observed in either mRNA or DNA analyses. We have established that tumour progression in ovarian cancer is accompanied by over‐expression of the NME1 gene; however, despite high rates of allele loss at the NME1 locus, the concept that NME1 may be a candidate tumour suppressor gene in ovarian cancer cannot be confirmed by this study. © 1995 Wiley‐Liss, Inc.
TP53 and RAS mutations in metachronous tumors from patients with cancer of the upper aerodigestive tract
Authors: Yang Han‐Kwang , Ilona Linnoila R. , Conrad Nicholas K. , Krasna Mark J. , Aisner Seena C. , Johnson Bruce E. , Kelley Michael J.
Published: February 2007

Patients who initially develop an upper aerodigestive tract cancer have an increased risk of second primary cancers. We examined TP53 and RAS mutations and p53 protein in 21 tumors from 10 patients with upper aerodigestive tract cancer who developed a metachronous tumor, to assess the genetic changes that occur in multiple primary tumors from the same individual. Thirteen of 21 (62%) tumors were found to have mis‐sense mutations of either TP53 or RAS. Six tumors had TP53 mutations in codons 5 to 8 and 10 tumors from 7 patients had mutations of codons 12 or 13 of K‐RAS. Only one patient had concordance of a mutation in 2 tumors; this mutation occurred in K‐RAS and was accompanied by discordance of TP53 mutation. Three patients had tumors discordant for both T53 and RAS mutations. Smoking‐related tumors had TP53 and RAS mutations which were transversions in 11 (9 G:C to T:A and 2 G:C to C:G) and transitions in 3 (2 G:C to A:T and 1 A:T to G:C). Tumors not associated with smoking contained only transitions (both G:C to A:T). p53 protein was detected by immunohisto‐chemistry in 7 of 13 (54%) tumors and was concordant in the multiple tumors of 3 patients. Three of the 7 tumors staining for p53 also had TP53 mutations. Thus, genetic alterations are discordant in multiple primary cancers and the pattern of mutations is similar to that found in patients with a single primary tumor, supporting the concept that these cancers arise independently. © 1995 Wiley‐Liss, Inc.
Exon scanning for mutations of the nf2 gene in pediatric ependymomas, rhabdoid tumors and meningiomas
Authors: Slavc Irene , Maccollin Mia M. , Dunn Michael , Jones Susan , Sutton Leslie , Gusella James F. , Biegel Jaclyn A.
Published: February 2007

Deletions of chromosome 22 have been identified in 3 types of childhood primary brain tumor: meningiomas, rhabdoid or atypical teratoid tumors (ATT) and ependymomas. This implicates the involvement of tumor suppressor genes on chromosome 22 in the genesis of these rare tumors. One such candidate tumor suppressor gene is the recently cloned neurofibromatosis 2 (NF2) locus. The purpose of our study was to determine the frequency of germ‐line and somatic NF2 mutations in a selected group of brain tumors in children. Using single‐strand conformation polymorphism (SSCP) assays we screened 17 exons of the NF2 gene in 13 pediatric brain tumors and 9 matched normal blood DNA samples. Tumors included 3 meningiomas, 2 rhabdoid or ATTs, 7 ependymomas and 1 malignant tumor of glial lineage. In addition, lymphoblastoid cell lines from 3 patients with rhabdoid/ATT in whom no tumor tissue was available were analyzed for germ‐line mutations. Migration shifts were not detected in any of the normal DNA samples analyzed. Of the 13 tumors screened by SSCP, 1 meningioma with monosomy 22 produced a migration shift in exon 13. DNA sequencing of exon 13 revealed a deletion of a single guanine nucleotide (base 1397) in codon 466, causing a frame shift. While not all mutations might have been picked up by this technique, the data suggest that, similar to adult sporadic meningiomas, some pediatric meningiomas may result from somatic mutations in the NF2 gene. For rhabdoid tumors and ependymomas it appears that a locus distinct from NF2 might be responsible for tumorigenesis. © 1995 Wiley‐Liss, Inc.
Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas
Authors: Bellacosa Alfonso , De Feo Daniela , Godwin Andrew K. , Bell Daphne W. , Cheng Jin Quan , Altomare Deborah A. , Wan Minghong , Dubeau Louis , Scambia Giovanni , Masciullo Valeria , Ferrandina Gabriella , Panici Pierluigi Benedetti , Mancuso Salvatore , Neri Giovanni , Testa Joseph R.
Published: February 2007

The AKT2 gene is one of the human homologues of v‐akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine‐threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. To confirm and extend these findings, we conducted a large‐scale, multicenter study of AKT2 alterations in ovarian and breast cancer. Southern‐blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2 alteration was detected in 24 benign or borderline tumors. Northern‐blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. The difference in the incidence of AKT2 alterations in ovarian and breast cancer suggests a specific role for this gene in ovarian oncogenesis. No significant association was found between AKT2 amplification and amplification of the proto‐oncogenes MYC and ERBB2, suggesting that amplification of AKT2 defines an independent subset of breast and ovarian cancers. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness. © 1995 Wiley‐Liss, Inc.
p53 and human papillomavirus dna in renal pelvic and ureteral carcinoma including dysplastic lesions
Authors: Furihata Mutsuo , Yamasaki Ichiro , Ohtsuki Yuji , Sonobe Hiroshi , Morioka Masaaki , Yamamoto Akihiro , Terao Naotami , Kuwahara Morimasa , Fujisaki Nobuta
Published: February 2007

Ninety‐eight cases of transitional‐cell carcinoma (TCC) of the renal pelvis and ureter, including dysplastic lesions, were studied for tumor incorporation of human papillomavirus (HPV) type‐16 and type‐18 DNA by in situ hybridization (ISH) with DNA probes for each HPV viral type. Immunohistochemical analysis of p53 expression was also performed. Fresh tumor tissues from 26 patients were also studied for p53 mutations in exons 4 through 9 by direct sequencing and for HPV infection by polymerase chain reaction (PCR). Thirty‐two tumors were positive for HPV DNAs, including 6 double‐positive cases. Among these tumors, adjacent dysplastic lesions in 21 cases (66%) also revealed identical reactivity. Overexpressed p53 was detected in 26 cases. Expression of p53 was also detected in dysplastic lesions in 19 out of these 26 cases (73%). Three cases were positive for both HPV DNA and p53 antibody. p53 point mutation was detected in 7 of 26 cases, 6 of which were also positive for p53. HPV type‐16 DNA was detected in 6 cases by PCR, 4 of which were also ISH‐positive. Overexpressed p53 was frequently detected in invasive and non‐papillary tumors (p < 0.01) and in high‐grade tumors (p < 0.05). HPV infection was more common in non‐invasive and papillary tumors (p < 0.05). These findings suggest that HPV infection or overex‐pression (mutation) of p53 may be an early event and be related to phenotypes of tumor‐cell growth patterns and progression. © 1995 Wiley‐Liss, Inc.
CD26 (dipeptidyl peptidase IV/DPP IV) as a novel molecular marker for differentiated thyroid carcinoma
Authors: Tanaka Tetsuji , Umeki Kazumi , Yamamoto Ikuo , Sakamoto Fujio , Noguchi Shiro , Ohtaki Sachiya
Published: February 2007

In this report we show that CD26 (dipeptidyl peptidase IV/DPP IV) is a novel molecular marker for differentiated thyroid carcinoma. Northern‐blot analysis of 22 various thyroid tissues revealed that CD26 is a more specific marker of differentiated thyroid carcinoma than 3 proto‐oncogenes previously reported to increase mRNA expression in thyroid carcinomas: c‐met, c‐erbB‐2 and EGF‐R. A comparative study of 3 CD26 assays, Northern blotting, immunohistochemical staining and activity staining clearly showed that CD26 enzyme activity staining is the most specific assay for differentiated thyroid carcinoma, yet the easiest to perform. Activity staining of 216 thyroid tissues detected CD26 in all 52 papillary carcinomas and all 5 follicular carcinomas, while all 58 cases of Graves' disease were CD26‐negative. Among benign neoplasms, 54 of 55 adenomatous goiters and 29 of 33 follicular adenomas were CD26‐negative. Staining intensity of the enzyme activity was relative to the degree of CD26 mRNA expression. Southern‐blot study showed no gene amplification or major translocation of the CD26 gene in 7 papillary carcinomas examined. Based on this study, ectopic expression of CD26 in differentiated thyroid carcinomas is thought to be mainly caused by increased CD26 mRNA expression. In conclusion, CD26 activity staining is a simple, specific assay which should be added to the usual pathological examinations in order to distinguish differentiated thyroid carcinomas from benign thyroid diseases. © 1995 Wiley‐Liss, Inc.
Frequency and prognostic evaluation of 3p21‐22 allelic losses in non‐small‐cell lung cancer
Authors: Thiberville Luc , Bourguignon Jeannette , Metayer Josette , Bost Frederic , Diarra‐Mehrpour Maryam , Bignon Jean , Lam Stephen , Martin Jean‐Pierre , Nouvet Georges
Published: February 2007

Previous loss of heterozygosity (LOH) studies of chromosome 3p loci have displayed a 60% deletion frequency in non‐small‐cell lung cancers (NSCLC), as opposed to small‐cell lung cancers, in which the 3p deletion is consistently found. However, the high stromal‐cell admixture found in NSCLC and the use of the Southern‐blot method lead to under‐evaluation of this frequency. In this study, we used a very precise microdissection technique followed by PCR amplification of 6 3p21‐22 polymorphic genomic sequences to analyze LOH in 86 NSCLC and in normal adjacent tissue. We found the sensitivity of the microdissection‐PCR‐based LOH technique higher than the sensitivity of the Southern‐blot technique: 87% of the squamous‐cell carcinomas and 84% of the large‐cell undifferentiated carcinomas showed a clear LOH for a 3p21‐22 locus. All doubly informative cases but 4 showed concordant deletion at all 3p21‐22 loci. The analysis of 3p microsatellite sequences displayed only 2 cases of genomic instability, one of them also displaying features of tumoral heterogeneity as regards the instability genotype. Four carcinomas in situ adjacent to these NSCLC showed the same allelic profile as the invasive tumors. The only prognostic factors in this study were the disease stage and histology. The 3p21‐22 deletion was not related to the stage of the disease and did not appear to be a significant prognostic factor of survival. 3p21‐22 loss appears, so far, to be the most frequent and the earliest genetic alteration described in NSCLC, but does not seem to carry significant prognostic information in invasive tumors. © 1995 Wiley‐Liss, Inc.