Eph receptor tyrosine kinases are critical for cell-cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow-derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3stromal cells with an EphA3 agonist leads to cell contraction, cell-cell segregation, and apoptosis. Treatment of mice with an agonistic a-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy. Cancer Res; 74(16); 4470-81. Ó2014 AACR.

Abstract. Period2 (Per2) is a key mammalian circadian clock protein, and additionally has a tumor suppressive function. The present study aimed to investigate its role in drug resistance in A549/cisplatin (DDP) lung adenocarcinoma cells. Per2 knockdown and overexpression in A549/DDP cells were used to compare cell proliferation (by MTT assay), apoptosis (active-caspase 3 western blot) and clone forming assay. The activation of AKT/mechanistic target of rapamycin (mTOR) was investigated by a western blot assay. The Per2 expression level was decreased in A549/DDP cells compared with A549 cells. Per2 knockdown by short hairpin RNA protects A549/DDP cells from apoptosis, and promotes proliferation and migration. Per2 knockdown results in increased activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway. Overexpression of Per2 in A549/DDP cells may reduce the activity of the PI3K/AKT/mTOR signaling pathway, and promote apoptosis of A549 cells. The results of the present study suggest that Per2 participates in AKT-mediated drug resistance in A549/DDP lung adenocarcinoma cells.

Abstract. CD133 is one of the most commonly used markers of lung cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical value and significance of CD133 in lung cancer remains controversial. Due to the limited size of the individual studies, the association between CD133 and the clinicopathological characteristics of lung cancer had not been fully elucidated. A meta-analysis based on published studies was performed with the aim of evaluating the effect of CD133 on the clinicopathological characteristics of lung cancer and to investigate the role of CSCs in the prognosis of lung cancer. A total of 15 eligible studies were included in this meta-analysis and our results indicated that a positive CD133 expression was significantly associated with poor differentiation and lymph node metastasis, although it was not associated with tumor stage or histological type. Therefore, CD133 may be considered as a prognostic maker of lung cancer. Further clinical studies, with larger patient samples, unified methods and cut-off levels to detect CD133 expression, classified by tumor stage, therapeutic schedule, follow-up time and survival events, are required to determine the role of CD133 in clinical application and the association between CD133 and the prognosis of lung cancer.