scholarly journals Abnormal Epithelial Cell Polarity and Ectopic Epidermal Growth Factor Receptor (EGFR) Expression Induced in Emx2 KO Embryonic Gonads

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5893-5904 ◽  
Author(s):  
Masatomo Kusaka ◽  
Yuko Katoh-Fukui ◽  
Hidesato Ogawa ◽  
Kanako Miyabayashi ◽  
Takashi Baba ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Epithelial Cells ◽  
Tight Junction ◽  
Tyrosine Phosphorylation ◽  
Growth Factor Receptor ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Viral Oncogene Homolog

The gonadal primordium first emerges as a thickening of the embryonic coelomic epithelium, which has been thought to migrate mediodorsally to form the primitive gonad. However, the early gonadal development remains poorly understood. Mice lacking the paired-like homeobox gene Emx2 display gonadal dysgenesis. Interestingly, the knockout (KO) embryonic gonads develop an unusual surface accompanied by aberrant tight junction assembly. Morphological and in vitro cell fate mapping studies showed an apparent decrease in the number of the gonadal epithelial cells migrated to mesenchymal compartment in the KO, suggesting that polarized cell division and subsequent cell migration are affected. Microarray analyses of the epithelial cells revealed significant up-regulation of Egfr in the KO, indicating that Emx2 suppresses Egfr gene expression. This genetic correlation between the two genes was reproduced with cultured M15 cells derived from mesonephric epithelial cells. Epidermal growth factor receptor signaling was recently shown to regulate tight junction assembly through sarcoma viral oncogene homolog tyrosine phosphorylation. We show through Emx2 KO analyses that sarcoma viral oncogene homolog tyrosine phosphorylation, epidermal growth factor receptor tyrosine phosphorylation, and Egfr expression are up-regulated in the embryonic gonad. Our results strongly suggest that Emx2 is required for regulation of tight junction assembly and allowing migration of the gonadal epithelia to the mesenchyme, which are possibly mediated by suppression of Egfr expression.

scholarly journals Heterogeneity of Epidermal Growth Factor Receptor Status and Mutations of KRAS/PIK3CA in Circulating Tumor Cells of Patients with Colorectal Cancer

2013 ◽  
Vol 59 (1) ◽  
pp. 252-260 ◽  
Author(s):  
Christin Gasch ◽  
Thomas Bauernhofer ◽  
Martin Pichler ◽  
Sabine Langer-Freitag ◽  
Matthias Reeh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Egfr Gene ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Viral Oncogene Homolog

BACKGROUND Molecular characterization of circulating tumor cells (CTCs) is pivotal to increasing the diagnostic specificity of CTC assays and investigating therapeutic targets and their downstream pathways on CTCs. We focused on epidermal growth factor receptor (EGFR) and genes relevant for its inhibition in patients with colorectal cancer (CRC). METHODS We used the CellSearch® system for CTC detection in peripheral blood samples from 49 patients with metastatic CRC (mCRC) and 32 patients with nonmetastatic CRC (nmCRC). We assessed EGFR expression in 741 CTCs from 27 patients with mCRC and 6 patients with nmCRC using a fluorescein-conjugated antibody with the CellSearch Epithelial Cell Kit. DNA of a single CTC isolated by micromanipulation was propagated by whole-genome amplification and analyzed by quantitative PCR for EGFR gene amplification and sequencing for KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), BRAF (v-raf murine sarcoma viral oncogene homolog B1), and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α) mutations. RESULTS At least 2 CTCs were detected in 24 of 49 patients with mCRC and 7 of 32 patients with nmCRC. In 7 of 33 patients, CTCs with increased EGFR expression were identified. Heterogeneity in EGFR expression was observed between CTCs from the same patient. EGFR gene amplification was found in 7 of 26 CTCs from 3 patients. The investigated BRAF gene locus was not mutated in 44 analyzed CTCs, whereas KRAS mutations were detected in 5 of 15 CTCs from 1 patient and PIK3CA mutations in 14 of 36 CTCs from 4 patients. CONCLUSIONS Molecular characterization of single CTCs demonstrated considerable intra- and interpatient heterogeneity of EGFR expression and genetic alterations in EGFR, KRAS, and PIK3CA, possibly explaining the variable response rates to EGFR inhibition in patients with CRC.

scholarly journals Companion Biomarkers: Paving the Pathway to Personalized Treatment for Cancer

2013 ◽  
Vol 59 (10) ◽  
pp. 1447-1456 ◽  
Author(s):  
Michael J Duffy ◽  
John Crown
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Severe Toxicity ◽  
Viral Oncogene ◽  
Anaplastic Lymphoma ◽  
Epidermal Growth ◽  
Viral Oncogene Homolog

BACKGROUND Companion biomarkers are biomarkers that are used in combination with specific therapies and that prospectively help predict likely response or severe toxicity. In this article we review the role of companion biomarkers in guiding treatment in patients with cancer. CONTENT In addition to the established companion biomarkers such as estrogen receptors and HER2 (human epidermal growth factor receptor 2) in breast cancer, several new companion biomarkers have become available in recent years. These include v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations for the selection of patients with advanced colorectal cancer who are unlikely to benefit from anti–epidermal growth factor receptor antibodies (cetuximab or panitumumab), epidermal growth factor receptor (EGFR) mutations for selecting patients with advanced non–small cell lung cancer (NSCLC) for treatment with tyrosine kinase inhibitors (gefitinib or erlotinib), v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations for selecting patients with advanced melanoma for treatment with anti-BRAF agents (vemurafenib and dabrafenib), and anaplastic lymphoma receptor tyrosine kinase (ALK) translocations for identifying patients with NSCLC likely to benefit from crizotinib. SUMMARY The availability of companion biomarkers should improve drug efficacy, decrease toxicity, and lead to a more individualized approach to cancer treatment.

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