Glucose transporter-1 in pulmonary neuroendocrine carcinomas: expression and survival analysis

Özbudak, İrem Hicran; Shilo, Konstantin; Távora, Fábio; Rassaei, Negar; Chu, Wei; Fukuoka, Junya; Jen, Jin; Travis, William D.; Franks, Teri J.

doi:10.1038/modpathol.2009.6

Cited by 27 publications

(31 citation statements)

References 17 publications

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“…Glut1 was highly expressed in patients with LCNEC and SCLC, but Glut3 expression was low in pulmonary NE tumors. Ozbudak et al has documented that Glut1 expression was observed in 7% of TC, 74% of LCNEC and 78% of SCLC, and significantly correlated with neuroendocrine differentiation/tumor type and poor prognosis (20). In addition, a statistically significant difference in the prognosis according to Glut1 expression was seen for stage I-II (p<0.001) but not stage III-IV (p=0.4) neuroendocrine carcinomas.…”

Section: Discussionmentioning

confidence: 97%

Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors

Kaira

Ohde²,

Endo³

et al. 2011

Oncol Rep

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Abstract. 4F2hc (CD98) has been associated with tumor growth, and is highly expressed in various tumors. The aim of this study was to evaluate the clinicopathological significance of 4F2hc expression in pulmonary neuroendocrine (NE) tumors. Surgically-resected patient tumors including 16 large cell neuroendocrine carcinoma (LCNEC), 12 small cell lung cancer (SCLC), 1 atypical carcinoid (AC) and 5 typical carcinoid (TC) samples were included in this study. Tumor sections were immunohistochemically stained for 4F2hc (CD98), glucose transporter 1 (Glut1) and 3 (Glut3), hypoxia-inducible factor-1α (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessel density (CD34), epidermal growth factor receptor (EGFR), Akt/mammalian target of rapamycin (mTOR) signaling pathway (p-Akt, p-mTOR and p-S6K) and for a cell cycle regulator (p53). 4F2hc was overexpressed in 0% of the pulmonary carcinoids (TCs and ACs), 62.5% of the LCNECs and 50.0% of the SCLCs. A positive 4F2hc expression was significantly associated with age, histology and Glut1 expression. Moreover, a significant correlation was found between 4F2hc expression, and Glut1, HIF-1α, p-Akt, p-mTOR and p-S6K. The expression of 4F2hc was also significantly associated with poor overall survival. The expression of 4F2hc expression tended to increase from low-grade to high-grade pulmonary NE tumors. Our results suggest that 4F2hc may play a significant role in tumor progression, hypoxic conditions and poor outcome in patients with pulmonary NE tumors. IntroductionNeuroendocrine (NE) tumors of the lung arise from Kulchitzky cells, which are normally present in the bronchial mucosa and share the common morphological features of neuroendocrine tumors, including organoid nesting, palisading, rosettes, or a trabecular growth pattern. These tumors are represented by a wide range of pathological entities (1-5). It is now widely recognized that NE tumors of the lung include a spectrum that ranges from low-grade typical carcinoid (TC) and intermediate-grade atypical carcinoid (AC) to high-grade large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinomas (SCLC) (1-4). However, there has been no established clinical marker, which correlates with the response to the treatment and the prognosis in patients with pulmonary NE tumors. 4F2hc (CD98) is a disulphide-linked 125-kDa heterodimeric membrane glycoprotein, which is found on the cell surface of most normal cells. It was first identified on the cell surface of T lymphocytes (5). However, 4F2hc has been shown to be involved in the cellular proliferation, transformation, fusion, and adhesion and also in the L-type amino acid transport (LAT) system, in addition to regulating integrin activation, and therefore, integrin signaling and anchorage-independent growth. 4F2hc is reconstituted and expressed at high levels on the surface of many types of tumor cells. The overexpression of 4F2hc has been shown to result in cellular transformation (6,7). Recent studies have documented that 4F2hc expression is in...

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Section: Discussionmentioning

confidence: 97%

Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors

Kaira

Ohde²,

Endo³

et al. 2011

Oncol Rep

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“…All the genes specifically targeted in these pathways have been associated with cancer. Some of them have already been linked to neuroendocrine neoplasms: SLC2A1, coding for the glucose transporter 1, has already been reported in lung neuroendocrine tumors as being positively associated with adverse outcome [22]; RPS6KA3, coding for ribosomal protein S6 kinase, is a pivotal molecule in the mTOR pathway [23], which is overactivated in the majority of lung carcinoids [24]; IGF1R and IRS2 belong to the IGF receptor type 1 pathway and have been shown to be active in neuroendocrine cancer cells [25]. Among others, 3 genes were of particular interest, since all have already been demonstrated to be strongly associated with cancer but have never been investigated in neuroendocrine neoplasms.…”

Section: Discussionmentioning

confidence: 99%

Identification of MicroRNAs Differentially Expressed in Lung Carcinoid Subtypes and Progression

et al. 2015

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Aim: To extensively explore microRNA expression profiles in lung carcinoids in correlation with clinical and pathological features. Methods: A PCR-based array was employed in the screening phase to analyze 752 microRNAs in a discovery set of 12 lung carcinoids, including 6 typical (3 with lymph node metastasis) and 6 atypical (3 with lymph node metastasis). The results were validated by means of real-time PCR in 37 carcinoids, including 22 typical (4 with lymph node metastasis) and 15 atypical (7 with lymph node metastasis), and 19 high-grade neuroendocrine carcinomas. Results: Unsupervised cluster analysis segregated the pilot cases into 3 distinct groups. Twenty-four microRNAs were differentially regulated in atypical versus typical carcinoids, and 29 in metastatic versus nonmetastatic cases. Eleven microRNAs were selected for validation. All but 1 were significantly different among lung neuroendocrine tumor histotypes. Moreover, 5 (miR-129-5p, miR-409-3p, miR-409-5p, miR-185 and miR-497) were significantly upregulated in typical compared to atypical carcinoids. MiR-409-3p, miR-409-5p and miR-431-5p were also significantly downregulated in carcinoids metastatic to the lymph nodes. Predictive in silico analysis of specific target genes showed that these 3 latter microRNAs linked to metastatic potential are implicated in several cellular functions and highlighted several novel genes which may be worth exploring. Conclusions: Our findings demonstrate that lung carcinoids have distinct microRNA expression profiles as compared to high-grade neuroendocrine carcinomas and that specific microRNAs might have potential implications as diagnostic tools or clinical biomarkers.

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“…9,16,17 Glucose transporters are overexpressed in hepatocarcinomas, breast cancer, neuroendocrine carcinomas, lymphoblastic leukemia and others. [18][19][20][21] It has been proposed that the high glucose uptake in cancer cells favors cell proliferation more than energy production because glucose metabolism mainly supports fatty acid and ribose-5-phosphate synthesis 5,22 ( Fig. 1).…”

Section: Warburg Effect or Aerobic Glycolysismentioning

confidence: 99%