Author of

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  P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11485

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    P2.02-004 - Erk/MAP-kinase signaling pathway and neuroendocrine differentiation of non-small cell lung cancer (ID 918)

    10:21 - 10:38  |  Author(s): J. Huang
    • Abstract

    Background
    Neuroendocrine differentiation (NED) has been observed in approximately 25-33% of all lung tumors. Essentially all small cell lung cancer (SCLC) and carcinoid tumors show distinct histological morphology and stain positive to neuroendocrine markers such as neuroamines, neuropeptides, dense core secretory granules, chromogranin A, neuroendocrine specific protein (NSP), and neuron-specific enolase (NSE). It was later recognized that NED was not limited to SCLC and carcinoid, and it could involve non-small cell lung cancer (NSCLC) such as large cell neuroendocrine carcinoma (LCNEC). Subsequently, it was found that about 10-20% of NSCLC, including adenocarcinomas and squamous cell carcinomas, also exhibit some neuroendocrine properties despite being considered non-neuroendocrine types. It has been postulated that NED of NSCLC represents an intermediary transition between SCLC and NSCLC, or that NED may be a predictor of the response to chemotherapy or radiotherapy, as well as a predictor of shorter survival in patients with stage I adenocarcinoma of the lung. Irrespective of these observations, the clinical significance of NED of NSCLC remains unclear.

    Methods
    We hypothesize that the investigation of the intracellular signal transduction pathway involved with NED of NSCLC cells may reveal potential molecular targets for the treatment of NSCLC with NED. We explore the potential molecular pathway involved in NED of NSCLC and its clinical association, through the induction of NED of a NSCLC cell line NCI –H157 in vitro. We further confirmed our findings using activators vs. inhibitors to these signal transduction pathways in vitro. We conducted immunochemical stains for phopsphorylated ERK1/2 expression of lung tumors know to have NED. ERK1/2 positivity was defined by 5% or more tumor cells stained positive with phospho-Erk½.

    Results
    We discovered that NED of NSCLC was associated with the activation of Erk1/2-MAPK signal transduction pathway, and the inhibition of the Akt signal transduction pathway. Using specific activator (Pb[2+]) and inhibitors (siRNA-Erk1/2, and U0126) to the Erk1/2 /MAP-kinase pathway, as well as the inhibitor (LY294002) to the Akt pathway, we found that Erk1/2/MAP-kinase activation was essential for NED of NCI-H157 cells. Staining of Erk1/2/MAP-kinase pathway reveals a high rate of positivity in NSCLC tumors with NED when compared with other neuroendocrine lung tumors. The positive rate of IHC was 0/10 (0%) for typical carcinoid; 2/10 (20%) for atypical carcinoid; 4/9 (44.4%) for small cell lung carcinoma; and was 7/10 (70%) for large cell neuroendocrine lung carcinoma.The ERK1/2 activation was statistically different (**p<0.01 by two tailed Fisher exact test) comparing all carcinoid tumors (2/20, typical plus atypical) with high-grade neuroendocrine carcinoma (11/19, SCLC plus NSCLC) .

    Conclusion
    Through the in vitro NED induction of NSCLC cell line NCI-H157, and in vivo correlative investigations in lung tumors with NEC, we discovered that NED of NSCLC was associated with the activation of Erk1/2-MAPK signal transduction pathway. To our knowledge, our findings are the first to describe the potential involvement of Erk/MAPK signal transduction pathway of NSCLC in the association with NED. Further investigation of the Erk/MAPK signal transduction pathway of NSCLC may yield discoveries in identifying specific molecular targets for the treatment of NSCLC with NED.