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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New strategies are needed for the detection and treatment of lung cancer and must derive from a fuller understanding of lung carcinogenesis. Frequent molecular genetic abnormalities occur in non-small cell lung cancer (NSCLC), but little is known about which of these precede an invasive carcinoma. We examined the expression of p53, epidermal growth factor receptor (EGFR), and transforming growth factor alpha, the most common molecular genetic abnormalities in NSCLC, in preneoplastic bronchial lesions. Primary NSCLC and associated bronchial lesions were identified by retrospective review of resected tumors at this center. Expression in the invasive carcinomas, the associated bronchial lesions, and normal lung were contrasted using immunohistochemistry. Thirty-four NSCLC associated with 62 bronchial lesions were identified. The invasive tumors included 15 squamous cell carcinomas (SCCs) and 19 non-SCCs. Bronchial lesions included areas of squamous metaplasia (n = 14), inflammatory atypia (n = 19), dysplasia (n = 17), and carcinoma in situ (n = 12). Nineteen (56%) NSCLC and 10 (16%) bronchial lesions exhibited aberrant p53 immunostaining, whereas 18 (53%) NSCLC and 30 (48%) bronchial lesions showed abnormal EGFR immunostaining. Positive staining for transforming growth factor alpha was seen in 16 (47%) NSCLC but occurred inconsistently in the bronchial lesions and in normal bronchial epithelium. Only bronchial lesions associated with squamous cell carcinomas exhibited staining for p53. Aberrant EGFR expression was not associated with a specific type of invasive carcinoma or with specific preneoplastic lesions, although there was a trend toward increased expression in dysplasia and carcinoma in situ relative to metaplasia and atypia. All but one of the NSCLC simultaneously showing aberrant p53 and EGFR staining were SCC. We conclude that: (a) transforming growth factor alpha is variably expressed in normal respiratory epithelium as well as reactive and preneoplastic bronchial lesions; (b) p53 expression is seen in preneoplastic bronchial lesions but is not present in reactive or metaplastic epithelium; (c) aberrant EGFR expression occurs in both reactive and preinvasive bronchial lesions and may be an early marker of neoplastic transformation; and (d) the simultaneous aberrant expression of EGFR and p53 occurs predominantly in SCC and their associated bronchial lesions. These findings indicate that aberrant expression of p53 or the EGFR is frequent in bronchial neoplasia, and coexpression may predispose to the development of squamous cell carcinomas of the lung.
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PMID:Aberrant expression of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. 788 37

p185HER2, the product of the c-erbB-2 or HER2 gene, is a membrane-bound tyrosine kinase that has structural similarity to the epidermal growth factor receptor. Functionally, interaction of HER2 with its ligand or p185HER2 antibodies affects the growth and differentiation of HER2-expressing breast cancer cell lines. As p185HER2 is also expressed in human lung cancers and human lung cancer cell lines, we hypothesized that these cell lines would also respond to p185HER2 antibodies. To test this hypothesis, we cultured human non-small cell lung cancer cell lines in the presence of a p185HER2 monoclonal antibody called 4D5. 4D5 inhibited the growth of p185HER2-expressing cell lines in a dose-dependent fashion. In addition, BEAS.2B, a p185HER2-nonexpressing bronchial epithelial cell line, was transfected with the HER2 cDNA, resulting in high-level p185HER2 expression, and growth of BEAS.HER2 was now inhibited by 4D5 exposure. Mechanistically, 4D5 appeared to have a weak agonist effect on the tyrosine kinase function of p185HER2, as exposure of p185HER2-expressing cell lines to 4D5 resulted in increased p185HER2 phosphorylation. Furthermore, inhibition of tyrosine kinase function with Genistein reversed the 4D5-induced growth inhibition. Therefore, 4D5 can regulate the growth of p185HER2-expressing lung cancer cell lines through agonist effects on p185HER2.
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PMID:Inhibition of human lung cancer cell line growth by an anti-p185HER2 antibody. 810 37

The sensitivity of human breast and lung cancer cell lines to TGF-alpha-PE40, a novel chimeric recombinant cytotoxin composed of two independent domains, (i) TGF-alpha and (ii) a 40 kDa segment of the Pseudomonas exotoxin protein, PE-40, was investigated. Toxicity varied widely, correlated with epidermal growth factor receptor (EGFR) levels (P = 0.01) and was greatly reduced by EGF, indicating that binding of TGF-alpha-PE40 to EGFR is important in mediating toxicity. Cell lines expressing low EGFR levels were most highly protected by EGF, indicating that normal (low EGFR-expressing) tissue may be selectively protected by EGF in vivo. P-glycoprotein did not confer resistance to TGF-alpha-PE40, and toxicity was unaffected by multidrug resistance-modulating agents (cyclosporin A, tamoxifen, verapamil), indicating a role for TGF-alpha-PE40 in the clinical management of drug-resistant tumours.
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PMID:Selective toxicity of TGF-alpha-PE40 to EGFR-positive cell lines: selective protection of low EGFR-expressing cell lines by EGF. 819 91

The development of novel immunotherapy strategies for non-small cell lung cancer (NSCLC) will be facilitated by the identification of tumor-specific targets. Although the epidermal growth factor receptor (EGFR) is overexpressed in many cases of NSCLC, its wide distribution in normal tissue may limit its suitability as an immunotherapeutic target. However, mutations within the EGFR that are unique to malignancies may provide specific targets for immunotherapeutic intervention. For example, one mutant form, the type III deletion mutant of the EGFR, that has been identified in glioblastomas contains a novel peptide sequence in its extracellular domain which is detectable by anti-peptide antisera. In this study, the prevalence of this type of mutation of the EGFR in NSCLC was determined. Thirty-two frozen sections of primary NSCLC were examined by immunocytochemistry to determine the presence of native and mutated EGFR. Native EGFR was overexpressed in 12 of the 32 sections and a diffuse cellular distribution of the EGFR type III deletion mutation was identified in five (16%) of the specimens (2 of 13 squamous, 2 of 2 mixed, 0 of 10 adenocarcinoma, and 1 of 7 undifferentiated). This mutated EGFR was not detected in sections of normal breast, lung, skin, ovary, colon, kidney, endometrium, and placenta. The type III EGFR deletion mutant, expressed in some cases of NSCLC, may be a molecularly defined, tumor-specific antigen in lung cancer.
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PMID:Expression of mutated epidermal growth factor receptor by non-small cell lung carcinomas. 839 18

In an attempt to define the type and temporal sequences of somatic genetic changes that precede the onset of invasive lung cancer, and to search for biological markers useful in screening multiple primary tumors of the upper aerodigestive tract, we have performed a cytogenetic and genetic study using normal bronchial epithelium and primary tumor specimens of 68 patients undergoing pulmonary resection for early stage lung cancer, and normal bronchial epithelium of 5 controls with metastatic sarcomas. Of the 68 lung cancer cases, 31 had a single tumor and 37 displayed multiple synchronous or metachronous tumors. Cytogenetic alterations were observed in 59% (23/39) of the evaluable tumor specimens with complex rearranged karyotypes, particularly involving chromosomes 3 (70%), 17 (39%), 11 (26%), 8, 9, 12 (22%), and 7 (17%). Gene alterations were also detected including overexpression of epidermal growth factor receptor (EGFR) in 63% (36/57), HER2/NEU in 21% (12/56), and p53 mutations in 50% (12/24). The overall frequency of genetic changes (any type) in the tumors was 76% (52/68). In the normal bronchial mucosa, we identified a rearranged karyotype in 20% of the evaluable cases (13/63); particularly simple rearrangements involving chromosomes 3p (6 cases), 7 (6 cases), 17 (3 cases), 9, 11 (2 cases), 8 (1 case); as well as overexpression of EGFR in 39% (20/51) and of HER2/NEU in 14% (7/51). The overall frequency of genetic changes (any type) in the normal epithelium was 46% (30/65). The presence of a rearranged karyotype in the bronchial mucosa was associated with a rearranged karyotype in the tumor sample. Other statistically significant correlations were found between histopathologic and clinical features and the occurrence of the different cytogenetic and genetic changes both in tumors and in the normal bronchial mucosa. No genetic abnormalities were found in the bronchial epithelium of the 5 controls.
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PMID:Genetic changes in lung cancer. 841

The sequences encoding the full-length epidermal growth factor receptor (EGFR) were cloned from a cDNA library prepared from T3M4 cells. A transition (G to A) was identified at codon 497 of EGFR cDNA, resulting in the substitution of a lysine for an arginine. The same substitution was identified by sequencing cDNA derived from 3 of 7 additional human pancreatic cancer cell lines, one endometrial cancer cell line, and one lung cancer cell line, but not in A431 cells. Variant EGFR was always co-expressed with wild-type EGFR. Both sequences were present in genomic DNA from two cell lines expressing the variant receptor and in DNA from normal (3 of 7 individuals) human lymphocytes. These findings indicate that there are two alleles in this region of the EGFR gene, and that expression of variant EGFR is a common occurrence in normal and cancerous cells.
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PMID:Cloning of a variant epidermal growth factor receptor. 846 82

The prognostic role of the epidermal growth factor receptor (EGFR) and the related receptor p185HER-2 in lung cancer is as yet undefined. We investigated the immunohistochemical expression of EGFR (monoclonal antibody R1; Amersham) and p185HER-2 (polyclonal antibody A485; Dako) in cryosections. A total of 186 unselected and systemically untreated patients with non-small-cell lung cancer (NSCLC) diagnosed and treated at Odense University Hospital, Denmark, were included. Median follow-up period was 66 months. EGFR and p185HER-2 was highly expressed in 55% and 26% of cases respectively. Expression of EGFR was independent of p185HER-2 expression. The expression of EGFR was higher in squamous cell carcinomas whereas the level of p185HER-2 staining was higher in adenocarcinomas. Expression of either or both receptors was not correlated with age, histological grading, stage and prognosis. We conclude that immunohistochemical detection of these growth factor receptors failed to demonstrate a prognostic significance in patients operated on for NSCLC.
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PMID:Lack of prognostic significance of epidermal growth factor receptor and the oncoprotein p185HER-2 in patients with systemically untreated non-small-cell lung cancer: an immunohistochemical study on cryosections. 867 64

The genetic and phenotypic properties of cells which ultimately give rise to carcinoma of the lung are not well defined in part because of unavailability of preneoplastic cells from well-characterized dysplastic sites. In order to expand bronchial epithelial cell populations from patients at high risk for lung cancer, endobronchial biopsy specimens were explanted onto collagen- and fibronectin-coated dishes and cultured in serum-free, chemically defined media. One hundred forty-nine biopsy pairs were obtained from smokers and from healthy volunteers for culture and histologic evaluation. The histologic appearances of mucosa adjacent to the site of the cultured biopsies ranged from normal through varying degrees of noninvasive squamous dysplasia to invasive carcinoma. Confluent monolayers of pure epithelial cells were obtained from 68% of the cultured explants. Sites exhibiting high-grade dysplasia were 51% more likely to yield successful cultures than sites exhibiting normal histology (13 of 14 cultures successful versus 52 of 83 cultures successful, P < 0.02). Cultures had a maximum proliferative life span of 81 days and none of the cultures spontaneously became immortalized. Immunolabeling studies revealed that all cultured epithelial cells, regardless of the in situ histologic appearances of the mucosa at the biopsy site, strongly expressed keratin and epidermal growth factor receptor, weakly expressed transferrin receptor and human folate receptor, and were negative for neural cell adhesion molecule and human leukocyte antigen DR (HLADR). Ploidy and karyotypic analyses were performed in a limited number of explants from normal and dysplastic sites and all were found to be diploid without karyotypic abnormality. We conclude that pure bronchial epithelial cell populations can be routinely expanded from histologically normal and dysplastic sites by tissue culture of biopsy explants and that the expanded cell populations may represent a library of normal and preneoplastic cells which are suitable for immunophenotypic, ploidy, genetic, or functional analyses.
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PMID:Expansion of bronchial epithelial cell populations by in vitro culture of explants from dysplastic and histologically normal sites. 881 Jun 33

This study attempts of clarify the oncological significance of the p53 molecular abnormalities and p53 expression in lung cancer (LC) and their relationship with flow cytometry (FC) parameters and epidermal growth factor receptor (EGFR). The study includes 65 samples taken from both LC and normal lung (NL). The p53 molecular abnormalities of exons 4-8 were studied by single strand conformation polymorphisms (SSCP) and the loss of heterozygosity (LOH) of exon 4 by the Metzler method. P53 protein was detected by Western blot. EGFR was determined by a radioligand assay using [125I]EGF. The FC parameters S phase fraction (SPF), DNA index (D.I.), G1G0 and growth rate (G2M + SPF) were evaluated from cellular monosuspensions. The LC with SSCP p53 molecular abnormalities have a significantly higher EGFR content (P < 0.001), SPF (P < 0.007), D.I. (P < 0.017) and a lower proportion of G1G0 cells (P < 0.04) than LC with no molecular abnormalities. No relationship between p53 molecular abnormalities and tumor TN or evolutive events was found. Neither the relationship between the molecular results and p53 expression detected by Western blot nor that of the p53 expression detected by Western with FC parameters or EGFR could be shown. In NL the growth fraction cells decrease significantly (P < 0.05) with the intensity of p53 expression. The lack of biological functionality of p53 with molecular abnormalities seemed to relate to fast growing LC whereas p53 expression detected by Western seemed more related to the wild type of p53.
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PMID:Relationship of p53 molecular abnormalities with flow cytometry and growth factor receptor content in lung cancer. 949 4

The prognostic role of epidermal growth factor receptor (EGFR) remains controversial in patients with lung cancer. Previous assays for EGFR have primarily been qualitative or, at best, semiquantitative. In the present study, using fresh-frozen tissue from 190 unselected lung cancer patients, quantification of EGFR (EGFR(ELISA)) using a recently developed enzyme-linked immunosorbent assay (ELISA) technique was compared with results (EGFR(IHC)) obtained using immunohistochemistry (IHC). Correlation between results obtained by the two different techniques was highly significant (r(s) = 0.63, P < 0.001, n = 190). This correlation improved even further (r(s) = 0.76) when sections were estimated using an IHC score that took into account percentage staining, intensity and relative tumour area. Furthermore, the relationship between clinicopathological features and prognosis was identical for the two methods. The expression of EGFR was highest in squamous cell carcinomas, but it was not correlated with other characteristics such as age, sex, histological grading, stage or prognosis. We conclude that evaluation of EGFR content using IHC and ELISA produces comparable results.
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PMID:Enzyme-linked immunosorbent assay of epidermal growth factor receptor in lung cancer: comparisons with immunohistochemistry, clinicopathological features and prognosis. 966 57


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