Preventing
tumor neovascularisation is one of the strategies recently developed to limit the dissemination of
cancer cells and apparition of
metastases. Although these approaches could improve the existing treatments, a number of unexpected negative effects have been reported, mainly linked to the hypoxic condition and the subsequent induction of the pro-oncogenic
hypoxia inducible factor(s) resulting from
cancer cells'
oxygen starvation. Here, we checked in vivo on
colon cancer cells an alternative approach. It is based on treatment with
myo-inositol trispyrophosphate (ITPP), a molecule that leads to increased oxygenation of
tumors. We provide evidence that ITPP increases the survival of mice in a model of
carcinomatosis of human
colon cancer cells implanted into the peritoneal cavity. ITPP also reduced the growth of subcutaneous
colon cancer cells xenografted in nu/nu mice. In the subcutaneous
tumors, ITPP stimulated the expression of the homeobox gene Cdx2 that is crucial for intestinal differentiation and that also has an anti-tumoral function. On this basis, human
colon cancer cells were cultured in vitro in hypoxic conditions.
Hypoxia was shown to decrease the level of
Cdx2 protein,
mRNA and the activity of the Cdx2 promoter. This decline was unrelated to the activation of HIF1α and HIF2α by
hypoxia. However, it resulted from the activation of a
phosphatidylinositol 3-kinases-like
mitogen-activated protein kinase pathway, as assessed by the fact that
LY294002 and
U0126 restored high Cdx2 expression in
hypoxia. Corroborating these results,
U0126 recapitulated the increase of Cdx2 triggered by ITPP in subcutaneous colon
tumor xenografts. The present study provides evidence that a chemical compound that increases
oxygen pressure can antagonize the hypoxic setting and reduce the growth of human colon
tumors implanted in nu/nu mice.