Abstract 452: The hypoxic response is differentially regulated in small cell lung carcinoma (SCLC) cells as compared to non-SCLC cells

Abstract

Abstract Here we study the adaptive capacity of small cell lung carcinoma (SCLC) cells to hypoxia and the importance of activation of hypoxia-inducible factor (HIF) transcription factors in these cells. SCLC is an extremely aggressive tumor form and the 5-year survival rate for these patients is only approximately 9-15%. Regions of hypoxia (∼1% oxygen) often appear in solid tumors and are associated with aggressive tumor behaviour and poor outcome in several tumor forms. Tumor cells adapt to a hypoxic environment by changing the transcription of genes involved in a variety of processes, like angiogenesis, cell survival, and metabolism. This adaptive response is primarily regulated by the transcription factors HIF-1α and HIF-2α, which become stable at low oxygen levels. Studies using among others neuroblastoma, breast carcinoma and lung adenocarcinoma cells have demonstrated that HIF-1α primarily mediates the acute hypoxic response, whereas HIF-2α dominates during the more chronic phase of hypoxia. We investigated cell survival in a panel of SCLC cell lines cultured at different oxygen pressures. In these cells we also studied expression levels of well known hypoxia-driven genes using quantitative real-time PCR. Quantitative real-time PCR, Western blot and immunohistochemistry were used to characterise the expression of HIF transcription factors in SCLC cells as well as in SCLC specimens. In all experiments a panel of non-SCLC cells and neuroblastoma cells were included for comparison. Since tumor hypoxia correlates with poor prognosis it is important to elucidate how tumor cells adapt in response to hypoxia. Our results show that SCLC cells survive well at hypoxia, although the proliferation is somewhat reduced with lower oxygen pressure. Even though the SCLC cells have a high adaptive capacity, only a moderate up-regulation was observed for the investigated hypoxia-regulated genes at 1% oxygen. In addition, the expression patterns of HIF-1α and HIF-2α differ in SCLC as compared to non-SCLC, indicating that a “typical” adaptive response to hypoxia does not occur in SCLC cells. Based on these results a gene expression profile of hypoxic SCLC cells using microarray analyses are performed to further characterise the hypoxic adaptive response. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 452.