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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human pancreatic cancers overexpress the epidermal growth factor (EGF) receptor (EGFR) and all 5 ligands that bind to this receptor, including amphiregulin. It is not known, however, whether amphiregulin contributes in an autocrine manner to enhance pancreatic cancer cell growth. Therefore, we used an amphiregulin antisense oligonucleotide (AR-AS) to suppress amphiregulin expression in T3M4 human pancreatic cancer cells. These cells express high levels of EGFR and amphiregulin. AR-AS abolished amphiregulin immunoreactivity in T3M4 cells, decreased amphiregulin release into the medium and inhibited cell growth in a dose-dependent manner. Exogenous amphiregulin reversed AR-AS-mediated growth inhibition. A random oligonucleotide (AR-R) did not alter either cell growth or cellular amphiregulin immunoreactivity. AR-AS also increased cellular EGFR protein levels and enhanced the growth-inhibitory actions of TP40, a chimeric protein consisting of transforming growth factor-alpha coupled to Pseudomonas exotoxin that internalizes into cells via EGFR. These findings indicate that there is an important EGFR/ amphiregulin autocrine loop in T3M4 cells and raise the possibility that modalities aimed at abrogating amphiregulin action may prove useful in pancreatic cancer, especially when used in conjunction with EGFR-targeted therapy.
Int J Cancer 1997 Jul 29
PMID:Amphiregulin antisense oligonucleotide inhibits the growth of T3M4 human pancreatic cancer cells and sensitizes the cells to EGF receptor-targeted therapy. 924 97

Tumorigenesis is the result of sequential or multiple genetic alterations. The overexpression or amplification of various oncogenes in diverse human brain tumors have been observed. While numerous studies on the immunohistochemical demonstration of EGFR-overexpression have been reported, little has been found in the literature about the c-erbB-2 protein in human astrocytic tumors. In the present study, we evaluated the expression of EGFR and c-erbB-2 protein in 33 astrocytic tumors with immunohistochemistry. According to the World Health Organization brain tumor classification, the study included 9 low-grade astrocytomas (grade 2), 15 anaplastic astrocytomas (grade 3), and 9 glioblastomas multiforme (grade 4). The positive EGFR immunoreactivity was detected in 28 (85%) of 33 tumors. The expression of EGFR increased with the grade of malignancy in low-grade astrocytomas (67%), anaplastic astrocytomas (87%), and glioblastomas (100%). For the expression of c-erbB-2 protein, 17 (51.5%) of 33 tumors were positive immunostain, including 3 low-grade astrocytomas (37.5%), 9 anaplastic astrocytomas (81.8%), and 5 glioblastomas (62.5%). Different degrees of immunoreactivity for c-erbB-2 protein were found in variant grades of astrocytomas. However, the positive immunostain of EGFR displayed moderate or strong reactivity. The coexpression of EGFR and c-erbB-2 protein was found in 17 (15.5%) of 33 tumors. The results emphasize that the overexpression of EGFR parallels astrocytoma progession and higher frequency of c-erbB-2 immunoreactivity was seen in snaplastic astrocytomas and glioblastomas than in low-grade astrocytomas.
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PMID:Expression of epidermal growth factor receptors and c-erbB-2 proteins in human astrocytic tumors. 926 Apr 61

Chromosome microdissection-fluorescence in situ hybridization and comparative genomic hybridization (CGH) were performed in parallel to identify the native location of amplified DNA in a human non-small cell lung cancer (NSCLC) cell line exhibiting a homogeneously staining region (hsr) and double minutes (dmin). The native locations of microdissected DNA from the hsr and dmin were 7p12-13 and 8q24, respectively. Southern analysis revealed coamplification of EGFR (7p12) and MYC (8q24). CGH detected amplification of DNA not only from 7p12-13 and 8q24, but also from 9p24 and 10q22.
Genes Chromosomes Cancer 1997 Oct
PMID:Combined chromosome microdissection and comparative genomic hybridization detect multiple sites of amplification DNA in a human lung carcinoma cell line. 933 73

The p16INK4a gene product acts as a negative regulator of the cell cycle by binding to cyclin-dependent kinases (CDKs) 4 and 6, thereby inhibiting the formation of an active CDK/cyclin D complex. Deletion of the p16 locus has been observed in tumor cell lines and, less frequently, in primary human neoplasms. We analyzed 31 glioblastomas and identified 6 cases with hemizygous and 6 with homozygous deletions of the p16 locus. Eight of these cases showed a concurrent amplification of the EGFR gene (epidermal growth factor receptor) while the overall frequency was 35%. This close correlation suggests that deletion of the p16 chromosomal region constitutes another genetic hallmark of the primary glioblastoma, which rapidly develops de novo, without a less malignant precursor lesion and for which EGFR amplification is a characteristic genetic change. The p16 protein was not detectable in 15 of 22 glioblastomas but only 4 of these showed homozygous deletion of the gene. The alternative transcript p16 beta, for which a growth-suppressing function has been suggested, was co-expressed with p16 alpha mRNA in most cases. Hypermethylation of CpG islands in the 5' region of the p16 gene was identified in only 1 case, suggesting that this alternative mechanism of gene silencing is rarely responsible for loss of p16 expression in glioblastomas. Likewise, only 1 glioblastoma carried a p16 mutation and in addition, unexpectedly, a homozygous deletion of p16 in approximately 80% of tumor cells. This mutation, Arg24Pro, has previously been identified in a melanoma kindred.
Int J Cancer 1997 Sep 26
PMID:Hemizygous or homozygous deletion of the chromosomal region containing the p16INK4a gene is associated with amplification of the EGF receptor gene in glioblastomas. 933 10

We and others have shown that fatty acids are important regulators of breast cancer cell proliferation. In particular individual fatty acids specifically alter EGF-induced cell proliferation in very different ways. This regulation is mediated by an EGFR/G-protein signaling pathway. Understanding the molecular mechanisms of how this signaling pathway functions and how fatty acids regulate it will provide important information on the cellular and molecular basis for the association of dietary fat and cancer. Furthermore these in vitro studies may explain data previously obtained from in vivo animal studies and identify "good" as well as "bad" fatty acids with respect to the development of cancer.
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PMID:Fatty acids and breast cancer cell proliferation. 936 15

Loss of heterozygosity (LOH) from chromosome 10 is a hallmark of glioblastoma, the most malignant (grade IV) form of glioma. A candidate tumor suppressor gene, PTEN/MMAC1, that may be targeted for deletion in association with chromosome 10 LOH has recently been identified. Here we have investigated 63 glioblastomas for PTEN/MMAC1 alterations and identified DNA sequence changes that would affect the encoded protein in 17 (27%) tumors. Microsatellite analyses of normal-tumor DNA pairs were performed on 14 of these cases and revealed LOH at locations flanking and/or near PTEN/MMAC1 in all but 1 instance, suggesting that deletion of the remaining wild-type allele had occurred in the large majority of tumors with PTEN/MMAC1 mutations. Competitive PCR assays were developed to address the possible occurrence of PTEN/MMAC1 homozygous deletions in glioblastomas, and this analysis identified three samples having loss of both PTEN/MMAC1 alleles. EGFR amplification was determined to occur at similar frequencies among cases with or without PTEN/MMAC1 homozygous deletions or mutations, suggesting that a growth-promoting effect resulting from amplification-associated increases in epidermal growth factor receptor signaling is not necessarily dependent on the inactivation of PTEN/MMAC1.
Cancer Res 1997 Dec 01
PMID:PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. 939 44

Prostate carcinoma (PCA) is the most commonly diagnosed malignancy in American men. Our knowledge of PCA growth regulation lags behind that of other cancers, such as breast and colon carcinomas. Among receptor tyrosine kinases, the ErbB family is most frequently implicated in neoplasia. We report here the expression of ErbB family kinases and their ligands in PCA cell lines and a xenograft. While ErbB1/EGFR, ErbB2/NEU, and ErbB3 were always observed in a distinct pattern, ErbB4 was not observed. Interestingly, while TGF-alpha was expressed in the majority of PCA lines, the ligand Neu Differentiation Factor/Heregulin (NDF) was expressed only in an immortalized, non-transformed prostate epithelial line. Concomitantly, there was a significant difference in biological response to these ligands. NDF inhibited LNCaP growth and induced an epithelial-like morphological change, in contrast to TGF-alpha, which accelerated cell growth. We also performed the first comprehensive analysis of NDF signaling in a prostate line. LNCaP stimulated with NDF demonstrated crosstalk between ErbB3 and ErbB2 which did not involve ErbB1. NDF also turned on several cascades, including those of PI3-K, ERK/MAPK, mHOG/p38 and JNK/SAPK, but not those of PLCgamma or the STAT family. This signaling pattern is distinct from that of TGF-alpha. The activation of mHOG by ErbB2 or ErbB3 has not been reported, and may contribute to the unusual phenotype. PI3-K activation is characterized by the formation of a striking 'activation complex' with multiple tyrosine-phosphorylated species, including ErbB3. Our studies provide a framework in which to dissect the growth and differentiation signals of prostate cancer cells.
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PMID:ErbB kinases and NDF signaling in human prostate cancer cells. 940 Sep 97

The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/ myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. (ABSTRACT TRUNCATED)
Cancer Immunol Immunother
PMID:Clinical experience with CD64-directed immunotherapy. An overview. 943 76

Human pancreatic cancers overexpress a number of important tyrosine growth factor receptors and their ligands. These include the epidermal growth factor (EGF) receptor (EGFR) and related receptors, multiple ligands that bind to EGFR, certain fibroblast growth factors (FGF) receptors (FGFR) and ligands, and insulin-like growth factor I (IGF-I) and its receptor. The excessive activation of mitogenic signaling cascades that are modulated by these overexpressed ligands and receptors is compounded by the presence of mutations in the K-ras oncogene. Pancreatic cancers also overexpress transforming growth factor betas (TGF-betas) that usually inhibit the growth of epithelial cells. Pancreatic cancers, however, underexpress the type I TGF-beta receptor and harbor mutations in the smad4 gene, alterations that prevent TGF-betas from inhibiting cancer cell growth but that do not confer onto pancreatic actions that promote cancer growth in vivo. Together, these perturbations confer onto pancreatic cancer cells a tremendous growth advantage.
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PMID:Role of growth factors in pancreatic cancer. 944 85

Specific gene families, e.g. encoding members of signal transduction pathways, show a gene dosage sensitivity. We report on the determination of the gene dosages of egfr and c-erbB-2 in relation to the intratumoral concentration of the tyrosine kinase receptor protein EGFR and p185c-erbB-2 and the clinical outcome of breast cancer patients in a retrospective study. Prognostic unfavorable subgroups were determined in a life-table analysis by (a) an average gene copy number of egfr of less than 0.4 and greater than 1.6 and an intratumoral EGFR concentration of more than 56 fmol/mg, (b) an intratumoral p185c-erbB-2 concentration above 26 HNU/mg and (c) a quotient of egfr and c-erbB-2 average gene copy numbers of less than 0.15 and greater than 4.35.
Cancer Lett 1997 Oct 14
PMID:Translational research studies of erbB oncogenes: selection strategies for breast cancer treatment. 945 4


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