Abstract 449: Hypoxia induces tumor aggressiveness by an acquired stem-like phenotype in pancreatic cancer through HIF-1α signaling

Abstract

Abstract Background: Intratumoral hypoxia is a negative prognostic indicator, as it has been associated with increased aggressiveness and distant metastasis. Although hypoxia can drive the metastatic phenotype secondary to genetic instability and clonal selection of aggressive tumor cells, the interplay underlying them is to be unanswered. We hypothesized that mature cancer cells might acquire the stem-like phenotype under hypoxia, consequently leading to aggressive phenotype. Methods: Under normoxia (20% O2) or hypoxia (1% O2) condition, the expression of CD133 (cancer stem cell marker), CXCR4 (chemokine receptor), HIF-1α, and pimonidazole (hypoxic probe) were examined by quantitative RT-PCR and imuunohistochemistry using human pancreatic cancer cell lines. Moreover, we evaluated the expression of CD133 and hypoxia markers (pimonidazole, HIF-1α, and CA) in xenograft and human pancreatic cancer specimen. Furthermore, we transfected dominant active HIF-1α (HIF-1α ΔODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo. Results: We demonstrated that hypoxia induces tumor aggressive phenotype in pancreatic cancer, including invasiveness and CXCR4 expression. Furthermore, this phenotype is followed distinctively by the subpopulation of CD133+ pancreatic cancer cells, which themselves show hypoxic and invasive properties, indicating that mature cancer cells might reacquire an undifferentiated stem-like phenotype. In addition, both acquired stem-like phenotype and invasiveness under hypoxia are predominantly in a HIF-1α/CXCR4-dependent manner, and dominant active HIF-1αΔODD transfected cells promoted their tumorigenic ability. Surprisingly, orthotopic engraftment of these cells showed liver metastasis, while the engraftment of mock transfected cells did not occur any liver metastasis. Conclusion: We demonstrated that mature cancer cells acquired the stem-like phenotype under hypoxia and showed aggressive phenotype including invasiveness and metastasis through HIF-1α signaling. 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 449.