Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was performed to examine the involvement of transforming growth factor-alpha (TGF-alpha) in urothelial tumorigenesis. TGF-alpha urine levels were measured in patients with urothelial carcinoma (n = 68), patients who were tumor-free (n = 58), patients with non-neoplastic inflammatory disease (n = 20), and normal controls (n = 39). Both inflammatory and neoplastic urologic diseases had elevated TGF-alpha urine levels (169.5 ng/gm and 116.7 ng/gm, respectively) as compared to normal controls (39.1 ng/gm) (P = 0.0001). For patients with active cancer, TGF-alpha levels were positively associated with histologic grading (P = 0.009), nodular shape, expression of epidermal growth factor receptor in primary tumor (P = 0.03, respectively). But, there was no important relationship with staging classification, number and size of tumor (P > 0.1, respectively). TGF-alpha urine levels did not correlate with the serum content (n = 26; P > 0.5), or the immunohistochemical expression of TGF-alpha (n = 60) in corresponding tumor (P < 0.05, 0.1). Significant factors in predicting patient survival were clinical staging, nodular shape and size of tumor (P < 0.05, respectively). Our data implies that interaction of urinary TGF-alpha/urothelial epidermal growth factor receptor may play a positive role in the carcinogenesis of human urothelium.
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PMID:Urinary excretion of transforming growth factor-alpha in patients with transitional cell carcinoma. 967 66

Previous studies have demonstrated that high levels of dietary fat exacerbate UV-carcinogenic expression and suppress immunoresponsiveness. The latter may account for the former response. We have explored this possibility through T-lymphocyte transfer studies. Groups of HRA.HRII-c/+/Skh hairless mice were fed isocaloric diets containing high (12%, wt./wt.) or low (0.75%) levels of corn oil and irradiated 5 days/week (1.0 J cm-2/day) for 11 weeks with filtered FS-40 sunlamps. At weeks nine and 12, enriched T-cells from high-fat donors that had received 11 weeks of UV were transferred intravenously to low-fat recipients. Median tumor times for high-fat, low-fat recipient, and low-fat groups were 15.8, 18.5, and 21.6 weeks, respectively. The significantly (P < 0.03) shortened primary tumor latent period in low-fat-fed animals resulting from transfer of relatively low levels of T-cells derived from chronically irradiated high-fat donors demonstrates that the influence of dietary fat upon UV-carcinogenic expression is, at least partially, mediated via immunologic mechanisms. Further studies suggest that fat-modulated carcinogenesis can, itself, be regulated immunologically. A soluble T-14 (mouse squamous carcinoma cell line) cell-free fraction was injected subcutaneously at axillae and inguen of animals fed the high-fat diet during the first three weeks of UV or immediately post-UV. At week four post-UV, animals were challenged with T-14 cells injected subcutaneously at both flanks. 21 days post-challenge the tumor volumes of low-fat and high-fat immunized animals were zero versus 593 mm3 for the high-fat group (P < 0.007). Such treatment significantly (P < 0.03) increases the latent period of UV-induced primary tumors as well, when compared to non-treated high-fat-fed animals.
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PMID:Immunobiology of lipid-modulated UV-carcinogenesis. 975 94

CDKN2 (p16(INK4A)/MTS1) is found to be mutated in a variety of human tumor types. To explore the involvement of CDKN2 in prostate carcinogenesis, alterations of CDKN2 were examined in 116 human prostate tissues and cell lines and xenografts. Markedly reduced expression of CDKN2 mRNA was found in 43% (26 of 60) of untreated primary carcinomas, whereas no alteration was observed in 10 benign prostatic hyperplasias. In 17 matched sets from individual patients, 41% of cancerous tissues in contrast to 6% of noncancerous tissues expressed low levels of CDKN2 mRNA, supporting the role of CDKN2 as a tumor suppressor in prostate cancer. Alteration of CDKN2 was observed in each prostate tumor cell line, including one with a missense mutation, and in one of three xenograft tumor tissues derived from primary carcinomas. Two cell lines (PC-3 and TSU-Pr1) expressed only CDKN2 E1beta transcripts, indicating that the expression of CDKN2 E1alpha and E1beta are under separate control in the prostate. A high level of CDKN2 expression was related to abnormal RB1 in one primary tumor and in the DU145 cell line, which expressed the mutated CDKN2 allele. Analysis of genomic DNA indicated that altered CDKN2 expression in primary carcinomas of the prostate was more frequently due to down-regulation of transcription (five of seven) than deletion of the gene (two of seven). Additionally, CDKN2 mRNA was induced in nonexpressor cell lines by treatment with 5-aza-2'-deoxycytidine. This study demonstrates that alteration of CDKN2 is one of the most frequent genetic abnormalities in prostate cancer and may contribute to prostate carcinogenesis.
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PMID:Frequent alteration of CDKN2 (p16(INK4A)/MTS1) expression in human primary prostate carcinomas. 981 78

We investigated copy number aberrations in 29 primary tumors and 12 cell lines of esophageal squamous cell carcinoma (ESC) using comparative genomic hybridization. In the primary tumors, the most common sites of copy number gains were 3q26.3-27 (45%), 8q24 (41%), 5p15 (38%), Xq27-28 (38%), 14q32 (31%), 11q13 (28%), and 20q13.3 (28%). High-level gains (HLGs) indicative of gene amplifications were identified at 11q13 in two cases, and in one case each at 2q33-34, 3q25-29, 5p15.1-15.2, 7q21-22, 11p11.2, 12p11.2-12, and 13q34. Recurrent losses were observed only at 9p13(17.2%). In the 12 ESC cell lines, the most common sites of HLGs were 5p15.1-15.3 (four cases), 11q13 (four cases), 8q24.1-24.2 (three cases), 20q13.2-13.3 (three cases), 3q26.3 (two cases), and 7p15-22 (two cases). Less frequent HLGs (one case each) were observed at 2p16-22, 3q25, 7p12-14, 7q21-22, 9q34, 10q21, 11p11.2, 14q13-14, 14q31-32, 15q22-26, and 17p11.2. Chromosomes and chromosome arms that showed frequent losses in the cultured lines were 18q (58%), 4 (50%), 9p (50%), and 3p (42%). These findings provide evidence for a number of previously unknown genomic aberrations in ESC, suggesting target regions for positional cloning of genes relevant to carcinogenesis in the esophagus. In particular, we identified a significant amplification of the DPI gene (TFDPI), a transcription factor that forms heterodimers with E2FI, in the single primary tumor that exhibited HLG at 13q34.
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PMID:Comparative genomic hybridization of squamous cell carcinoma of the esophagus: the possible involvement of the DPI gene in the 13q34 amplicon. 1009 32

Activating mutations within the K-ras gene have been found in up to 90% of pancreatic carcinomas. Although multiple Ras effector pathways have been identified, the Raf protein kinases which are upstream regulators of the mitogen-activated protein kinases (MAPK/Erk) are believed to be the primary mitogenic effectors. Constitutive upregulation of this pathway by oncogenic ras is thought to promote cellular transformation. To explore the biological effects of mutated K-ras, we analyzed the Ras signaling pathway in a panel of cell lines derived from human pancreatic carcinomas. We found that despite high levels of Ras-GTP in each cell line expressing mutant K-ras, elevated levels of active Erk1 and Erk2 were not detectable under conditions of exponential growth or serum-starvation. Depending upon the cell line, the block in Erk signaling was observed to occur at either the level of Raf or Erk. Increased levels of active Erk1 and Erk2 were detected in only 2 out of 10 normal tissue-matched primary pancreatic tumors with mutated K-ras. Our results suggest that Erk signaling is not aberrantly upregulated in pancreatic cancers containing oncogenic K-ras mutations. The lack of Erk activation observed in both cell lines and primary tumor tissue suggests that constitutive Erk activation may not be required for tumor maintenance or progression in K-ras transformed pancreatic cells. We hypothesize that other Ras-dependent signaling pathways or an unidentified Raf/Mek-dependent pathway may be important for carcinogenesis in the pancreas. These findings may have important implications for drug treatment strategies which currently target the MAP kinase branch of the Ras signaling pathway.
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PMID:Lack of elevated MAP kinase (Erk) activity in pancreatic carcinomas despite oncogenic K-ras expression. 1040 37

The cell cycle is controlled by positive and negative regulators. Gene abnormalities and aberrant expressions of various cyclins/CDKs and CDK inhibitors may play a pivotal role in stomach carcinogenesis. To clarify the role of cyclin E, CDK inhibitor p27Kip1 and their target molecule, E2F-1 in tumor metastasis, we examined immunohistochemically the expression of cyclin E, p27Kip1 and E2F-1 in 23 gastric carcinomas and metastatic tumors of the lymph node. Most of gastric carcinomas with lymph node metastasis showed reduced p27Kip1 expression. p27Kip1 was negative in 39% (9/23) of primary tumors, while it was so in 52% (12/23) of lymph node metastases. By comparison of p27Kip1 expression in primary and metastatic tumors in individual cases, metastatic tumor cells in the lymph nodes were expressed at weaker levels than in those in primary tumors in 43% (10/23) of the cases. On the other hand, over 70% (17/23) and 50% (12/23) of the cases expressed cyclin E and E2F-1 at nearly the same levels in both primary tumor and lymph node metastasis, respectively. These results suggest that tumor cells with reduced p27Kip1 expression may selectively metastasize to lymph node or distant organs.
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PMID:Expression of p27Kip1, cyclin E and E2F-1 in primary and metastatic tumors of gastric carcinoma. 1042 91

Alterations in the Rb pathway have been described in many different tumors. In order to study this cell cycle regulatory mechanism in murine T cell lymphomas, we have analyzed the RNA and protein expression of the cyclin D1, cdk4 and retinoblastoma genes in primary tumor samples. We have detected overexpression of the cyclin D1 gene and deficient expression of the retinoblastoma gene in 42 and 28% of these tumors, respectively. The immunohistochemical analysis showed that these RT-PCR results are correlated with a significant increase in the number of positive cells for cyclin D1 and a moderate decrease in the expression of Rb protein, respectively. The analysis of cyclin D1, Rb, p15(INK4b) and p16(INK4a) showed that 75% of lymphomas had alterations in these genes and indicates that the Rb pathway is frequently altered in mouse primary T cell lymphomas. Moreover, 31% of lymphomas presented simultaneous alterations in at least two of these genes, suggesting the importance of concurrent alteration of different Rb pathway regulators. In addition, we have characterized these samples for mutational status of the N-ras and K-ras genes. We have only detected mutations in codon 12 of K-ras in six of 49 lymphomas (12%). Interestingly, five of these lymphomas also showed alterations in at least one of the Rb pathway regulators analyzed here. Taken together, these data suggest that deregulation of the Rb pathway regulators and/or oncogenic activation of K-ras may represent a common important clue in progression of murine T cell lymphomas.
Carcinogenesis 1999 Sep
PMID:Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas. 1046 10

Parathyroid hormone-related protein (PTHrP) is produced by prostate carcinoma cells and tumors, but little is known of its role in prostate carcinogenesis. The goal of this study was to evaluate PTHrP expression in the regulation of prostate carcinoma growth using human and animal models. PTHrP expression was assessed in prostate cancer cell lines in vitro. Seven of nine cell lines produced PTHrP, and increased expression was seen during cell proliferation. The MatLyLu rat prostate carcinoma model was used to determine the effects of PTHrP overexpression on prostate tumor growth. PTHrP overexpression did not alter proliferation of the cells in vitro. However, when PTHrP-overexpressing cells were injected into rat hind limbs, primary tumor growth and tumor size were significantly enhanced as compared with control cells. To evaluate PTHrP in human prostate carcinoma patients, immunohistochemistry was performed on metastatic bone lesions. Immunolocalization of PTHrP protein was found in the cytoplasm and nucleus of cancer cells in the bone microenvironment. Because nuclear localization of PTHrP has been associated with an inhibition of apoptosis, the ability of full-length PTHrP to protect prostate cancer cells from apoptotic stimuli was examined. Cells transfected with full-length PTHrP showed significantly increased cell survival after exposure to apoptotic agents as compared with cells producing no PTHrP (plasmid control) or cells transfected with PTHrP lacking its nuclear localization signal. To determine the mechanism of action of PTHrP in prostate cancer cells, the parathyroid hormone/PTHrP receptor status of the cells was determined. These cell lines did not demonstrate parathyroid hormone/PTHrP receptor-mediated binding of iodinated PTHrP or steady-state receptor message by Northern blot analysis, but they did have a detectable receptor message by reverse transcription-PCR analysis. In summary, PTHrP is expressed in many prostate cancer cell lines in vitro and in metastatic bone lesions in vivo. PTHrP expression positively influences primary tumor size in vivo and protects cells from apoptotic stimuli. These data suggest that PTHrP plays an important role in the promotion of prostate tumor establishment and/or progression.
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PMID:Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. 1060 51

Immunotherapy trials using monoclonal antibodies 323/A3 and 17-1A that recognize Ep-CAM, including trials focused on cancer of the lung, currently are underway. Nevertheless, there have been few comprehensive evaluations of the expression of Ep-CAM in specific types of neoplastic processes, including cancer of the lung. The current study of 60 human subjects with squamous cell cancer (SCC) of the lung, selected at random, was undertaken (1) to examine the expression of Ep-CAM in SCC and associated uninvolved bronchial mucosa, bronchial epithelial hyperplasia, and dysplasia, and (2) to correlate the results with established prognostic indicators and survival of patients. In both the uninvolved bronchial mucosa and epithelial hyperplasia, the expression of Ep-CAM in luminal cells was significantly higher compared with its expression in the matched basal cells (P = .003, P < .0001, respectively). When Ep-CAM scores of basal and luminal cells present in uninvolved bronchial mucosa and epithelial hyperplasia were combined, we observed a statistically significant stepwise increase in Ep-CAM expression from uninvolved bronchial mucosa to epithelial hyperplasia to SCC, suggesting its involvement in malignant transformation of SCC. The expression of Ep-CAM was significantly higher in poorly to moderately differentiated SCC compared with well-differentiated SCC (P = .04). An increase in the expression of Ep-CAM with increasing size or local extent of the primary tumor approached statistical significance (P = .09). The expression of Ep-CAM increased significantly with increasing involvement of regional lymph nodes (P = .02). Similarly, the expression of Ep-CAM increased with the increasing TNM stages (P = .04). Kaplan-Meier Survival analysis using the same categorizations showed that increasing tumor size, nodal status, and stage were significantly associated with poor patient survival (P = .04, .01, .01, respectively). There was, however, no statistically significant association between patient survival and staining intensity of carcinomas for Ep-CAM. We conclude that expression of Ep-CAM increased during the progression of SCC of the lung and, therefore, may play a role in the carcinogenesis of this disease.
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PMID:The expression of Ep-CAM (17-1A) in squamous cell cancers of the lung. 1082 96

Previous cytogenetic and molecular genetic analyses suggest that the q21 band of chromosome 13 harbors a tumor suppressor gene(s) involved in prostatic carcinogenesis. The precise genetic location, however, has not been defined. In this study, we examined prostate cancer specimens and cell lines/xenograft for genetic deletions at 13q21, using the methods of tissue microdissection and duplex PCR. Deletions at 13q21 were detected in 13 of 147 (9%) prostate cancer samples. Deletion of the same region was also detected in the LNCaP cell line and the PC-82 xenograft of prostate cancer. The overlapping region of deletion in LNCaP and PC-82 spans 3.1 cM or 2.9 cR, which is equivalent to 1-3 Mb. The endothelin receptor B gene, a possible tumor suppressor gene at 13q21, was not located in the region of deletion. Among the 13 prostate neoplasms with deletion at 13q21, 5 were metastases, and 7 were poorly differentiated primary tumors. The only primary tumor that was not poorly differentiated but had deletion occurred in one of the youngest patients (49 years) at diagnosis. These results provide evidence that 13q21 may harbor an unidentified gene(s) whose inactivation occurs in some aggressive carcinomas of the prostate. In addition, this study provides a framework for the cloning and identification of the 13q21 gene(s).
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PMID:Deletion at 13q21 is associated with aggressive prostate cancers. 1091 63


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