Hypoxia-induced stem-like cancer cells resistance to VEGFR inhibition

Developing strategies to overcome the frequent resistance to VEGF/VEGFR inhibitors in patients is a major challenge in antiangiogenic therapy for cancer. Targeting the VEGF pathway in vivo induces hypoxia and therefore enables to study drug-induced hypoxia in tumors. Hypoxia also occurs in the spontaneous evolution of cancers, particularly around areas of necrosis. Using cell markers such as CD133, CXCR4, or ALDH1, we identified stem-like cells in peri-necrotic areas in human biopsies and xenografts models of renal cancers. These stem-like cells were able in vitro to self-renew, form carcinoma spheres and had a tumorigenic potency, thus showing characteristics of stem-like cancer cells. In xenografted human renal cell carcinoma, we further demonstrated a strong link between necrosis, either spontaneous or treatment-induced, and the presence of CD133/CXCR4 double positive stem-like cells. Hypoxia increased their tumorigenic potency, induced overexpression of metallothionein2A, which we here identified as critical regulator of resistance to VEGFR-inhibition. 6 sample were collected and analysed for gene expression: 2 samples are human tumors xenografted into nude mice, 2 samples are human tumor renal kidney spheres cultured under hypoxic conditions and 2 other samples are human tumor renal kidney spheres cultured under normoxic conditions Two DNA samples were analysed with CGH array : 1 tumor stem cell cultured in normoxic condition and one human renal carcinoma xenografted into nude mice.