Hypoxia induces tumor aggressiveness and the expansion of CD133-positive cells in a hypoxia-inducible factor-1α-dependent manner in pancreatic cancer cells.

BACKGROUND: Intratumoral hypoxia is known to lead to increased aggressiveness and distant metastasis. However, the interplay underlying these actions is still unknown.

OBJECTIVE: We explored whether cancer cells might acquire a stem-like phenotype under hypoxia, consequently leading to an aggressive phenotype, including invasiveness and metastasis.

METHODS: Under normoxia (20% O(2)) or hypoxia (1% O(2)), the expression of CD133 (cancer stem cell marker), CXC chemokine receptor 4 (CXCR4) and hypoxia-inducible factor-1α (HIF-1α) was examined by RT-PCR and immunostaining using human pancreatic cancer cell lines. We also examined if hypoxia facilitates the invasiveness of CD133+ cancer cells. Furthermore, we transfected dominant active HIF-1α (HIF-1αΔODD) by the retroviral gene transfer and examined the effects both in vitro and in vivo.

RESULTS: Compared with normoxia, hypoxia elevated the expression of CD133, CXCR4 and HIF-1α. Moreover, hypoxia facilitated the invasiveness of CD133+ pancreatic cancer cells. The behavior of HIF-1αΔODD-transfected cells under normoxia was compatible with that of the parent cells under hypoxia. Furthermore, a xenograft model of HIF-1αΔODD cells showed aggressiveness, including metastasis and highly tumorigenic ability.

CONCLUSION: Hypoxia induces tumor aggressiveness associated with the expansion of CD133+ pancreatic cancer cells in a predominantly HIF-1α-dependent manner.