Soluble Epidermal Growth Factor Receptor: A Biomarker of Epithelial Ovarian Cancer

Baron, Andre T.; Lafky, Jacqueline M.; Boardman, Cecelia H.; Cora, Elsa M.; Buenafe, Marites C.; Liu, Dachao; Rademaker, Alfred; Fishman, David A.; Podratz, Karl C.; Reiter, Jill L.; Maihle, Nita J.

doi:10.1007/978-0-387-98094-2_9

Cited by 52 publications

(76 citation statements)

References 56 publications

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“…Although only isoform D has been reported to be cell membrane associated (21,44), it is tempting to speculate that both isoforms C and D may interact with and stabilize membranous oncoproteins and thereby promote aggressiveness, as was recently shown for the interaction between the ECD of the full-length EGFR and the glucose transporter SGLT1 (24). MYC is known to directly enhance the expression of glucose and glutamate transporters (38), which might be interaction partners for ectodomain EGFR.…”

Section: Discussionmentioning

confidence: 98%

Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer

Halle¹,

Lando²,

Svendsrud³

et al. 2011

Clinical Cancer Research

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Purpose: We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.Experimental Design: Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.Results: Membranous expression of ectodomain isoforms alone, without the coexpression of the fulllength receptor, showed correlations to poor clinical outcome that were highly significant for lymph nodenegative patients (locoregional control, P ¼ 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P ¼ 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.Conclusion: Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer.

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Section: Discussionmentioning

confidence: 98%

Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer

Halle¹,

Lando²,

Svendsrud³

et al. 2011

Clinical Cancer Research

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“…EGFR has been utilized as a biomarker associated with lung, ovarian, and breast cancers (12)(13)(14). In this study, we have isolated secreted EGFR (sEGFR) from the cell line using a polyclonal antibody specific for the secreted form.…”

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confidence: 99%

Identification of Potential Glycan Cancer Markers with Sialic Acid Attached to Sialic Acid and Up-regulated Fucosylated Galactose Structures in Epidermal Growth Factor Receptor Secreted from A431 Cell Line

Taylor

et al. 2013

Molecular & Cellular Proteomics

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We have used powerful HPLC-mass spectrometric approaches to characterize the secreted form of epidermal growth factor receptor (sEGFR). We demonstrated that the amino acid sequence lacked the cytoplasmic domain and was consistent with the primary sequence reported for EGFR purified from a human plasma pool. One of the sEGFR forms, attributed to the alternative RNA splicing, was also confirmed by transcriptional analysis (RNA sequencing). Two unusual types of glycan structures were observed in sEGFR as compared with membrane-bound EGFR from the A431 cell line. The unusual glycan structures were di-sialylated glycans (sialic acid attached to sialic acid) at Asn-151 and N-acetylhexosamine attached to a branched fucosylated galactose with N-acetylglucosamine moieties (HexNAc-(Fuc)Gal-GlcNAc) at Asn-420. These unusual glycans at specific sites were either present at a much lower level or were not observable in membrane-bound EGFR present in the A431 cell lysate. The observation of these di-sialylated glycan structures was consistent with the observed expression of the corresponding ␣-N-acetylneuraminide ␣-2,8-sialyltransferase 2 (ST8SiA2) and ␣-N-acetylneuraminide ␣-2,8-sialyltransferase 4 (ST8SiA4), by quantitative real time RT-PCR. The connectivity present at the branched fucosylated galactose was also confirmed by methylation of the glycans followed by analysis with sequential fragmentation in mass spectrometry. We hypothesize that the presence of such glycan structures could promote secretion via anionic or steric repulsion mechanisms and thus facilitate the observation of these glycan forms in the secreted fractions. We plan to use this model system to facilitate the Cancers are disease-associated with considerable morbidity, such as disease recurrence, anxiety, and side effects of treatment and mortality (1). Early diagnosis often significantly improves survival rates compared with late stage cancer detection, such as for breast, lung, and colon cancers (2-4). Proteins in the blood hold enormous promise for early stage cancer diagnostic tests, but the complexity and dynamic range of blood have confounded the search for cancer biomarkers. Nevertheless, the pressing need for a clinical assay has prompted us to investigate a different approach toward discovering new breast cancer biomarkers circulating in blood (5-7). In addition, the use of a panel of cancer cell lines, representing cancers with different subtypes, could alleviate the difficulty of analyzing the plasma samples directly. Although there is no substitute for the direct study of clinical samples, genetic and molecular aberrations found in cell lines can be translated to similar dysregulations in tumors (8). Cell lines, through the proteins they secrete or shed, should be a complementary model system for the discovery of circulating blood markers. For cancer biomarkers, the change of gene or protein sequence, such as mutation, is often a preclusion for cancers. A similar argument could also be true for the change of protein glycan structures, which re...

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“…The response rate observed in our trial is worthy of attention; the response rate with gemcitabine as a single agent reported in several published studies is nearly 20%, with a 1-year survival rate up to 35% depending on the series [22,23].…”

Section: Discussionmentioning

confidence: 98%

“…9 In primary osteosarcoma, leukopenia during adjuvant chemotherapy was associated with a reduced risk of relapse. 23 In gastric cancer, chemotherapy-induced neutropenia was 86 found to be an independent prognostic factor for survival. None of the examined SNPs evolved in DNA repair mechanisms were associated with the presence of neutropenia, disease characteristics, response rates, or survival.…”

mentioning

confidence: 99%

“…9 In primary osteosarcoma, leukopenia during adjuvant chemotherapy was associated with a reduced risk of relapse. 23 In gastric cancer, chemotherapy-induced neutropenia was found to be an independent prognostic factor for survival. It has to be kept in mind that the retrospective analyses on the association between neutropenia and survival may be hampered by statistical bias, eg, patients with poor chemotherapy tolerance, because of metastases and poor performance status, may receive lower doses, and as such, might show a false positive doseresponse relationship.…”

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confidence: 99%

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Análisis molecular y de marcadores pronóstico en sangre periférica en pacientes con cáncer no microcítico de pulmón en estadio localmente avanzado

Gonzalez-Cruz¹

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Que la tesis doctoral titulada "Análisis molecular y de marcadores pronóstico en sangre periférica en pacientes con cáncer no microcítico de pulmón en estadio localmente avanzado", que presenta Dña. Vega Iranzo González-Cruz para optar al grado de Doctor por la Universitat Politècnica de València, ha sido realizada bajo su dirección y reúne los requisitos adecuados para ser presentada como tesis doctoral ante el tribunal correspondiente para su lectura y defensa.Y para que conste a los efectos oportunos, firma el presente certificado, Que la tesis doctoral titulada "Análisis molecular y de marcadores pronóstico en sangre periférica en pacientes con cáncer no microcítico de pulmón en estadio localmente avanzado", que presenta Dña. Vega Iranzo González-Cruz para optar al grado de Doctor por la Universitat Politècnica de València, ha sido realizada bajo su dirección y reúne los requisitos adecuados para ser presentada como tesis doctoral ante el tribunal correspondiente para su lectura y defensa.Y para que conste a los efectos oportunos, firma el presente certificado, A mis directores de Tesis, el Dr. Carlos Camps y el Dr. Rafael Sirera, por haber creído en mi desde el principio, por haber insistido desde mis primeros años de residencia como Oncólogo en mis posibilidades como investigadora. Por todo lo que me han enseñado, por las oportunidades que me han ofrecido, por su atención y dedicación durante todos estos años. Y a la Dra Eloisa Jantus, por sus buenos consejos.A todos los que habéis contribuido de algún modo en este proyecto: Kino, Javi, Mire, David. Gracias por haber estado ahí, recogiendo datos, revisando historias y bibliografía haciendome así más fácil y llevadero este proyecto.A mis padres, gracias por inculcarme el amor que siento por la Medicina. Por enseñarme valores tan importantes como la fidelidad, la fortaleza y la prudencia. A Román y a Sisi, mis hermanos, gracias por estar ahí incondicionalmente.Y sobretodo, gracias Antonio, mi amor, por hacerme reir y por hacerme soñar; por haberme dado lo mejor que tengo en mi vida: Vega y Rocío. RESUMENEl cáncer de pulmón es uno de los principales problemas de salud del mundo; es una enfermedad frecuente, grave y con incidencia en aumento. A estas características, se añade la complejidad de su tratamiento -cirugía, quimioterapia y radioterapia-, que es agresivo y habitualmente costoso siendo necesaria la colaboración organizada de numerosos profesionales distintos. En este sentido integral de la atención al paciente oncológico, la aportación de la biología molecular con nuevos conceptos y retos como la oncofarmacogénetica y oncofarmacogenómica ha permitido no sólo el desarrollo de fármacos usando biomarcadores para predecir la respuesta; sino también el análisis del comportamiento de las células tumorales; el estudio de mutaciones de genes, polimorfismos, metilaciones, etc.; estudios anatomopatológicos más precisos; y la individualización del tratamiento gracias al mejor conocimiento de los factores pronóstico y sobre todo, de los factores predictivos de ...

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Soluble Epidermal Growth Factor Receptor: A Biomarker of Epithelial Ovarian Cancer

Cited by 52 publications

References 56 publications

Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer

Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node–Negative Cervical Cancer

Identification of Potential Glycan Cancer Markers with Sialic Acid Attached to Sialic Acid and Up-regulated Fucosylated Galactose Structures in Epidermal Growth Factor Receptor Secreted from A431 Cell Line

Análisis molecular y de marcadores pronóstico en sangre periférica en pacientes con cáncer no microcítico de pulmón en estadio localmente avanzado

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