Abnormal architecture of the
tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue
oxygen tension exposing
tumor and stromal cells to cycling
hypoxia.
Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of
tumor progression. As cycling
hypoxia is known to participate in
tumor aggressiveness, the purpose of this study was to evaluate its role in
tumor-promoting
inflammation. Firstly, we assessed the impact of cycling
hypoxia in vitro on endothelial inflammatory response induced by
tumor necrosis factor α. Results showed that endothelial cells exposed to cycling
hypoxia displayed an amplified proinflammatory phenotype, characterized by an increased expression of inflammatory
cytokines, namely,
interleukin (IL)-6 and IL-8; by an increased expression of adhesion molecules, in particular
intercellular adhesion molecule-1 (ICAM-1); and consequently by an increase in THP-1 monocyte adhesion. This exacerbation of endothelial inflammatory phenotype occurs through nuclear factor-κB overactivation. Secondly, the role of cycling
hypoxia was studied on overall
tumor inflammation in vivo in
tumor-bearing mice. Results showed that cycling
hypoxia led to an enhanced
inflammation in
tumors as
prostaglandin-endoperoxide synthase 2 (
PTGS2),
IL-6, CXCL1 (C-X-C motif
ligand 1), and
macrophage inflammatory protein 2 (murine IL-8 functional homologs)
mRNA expression was increased and as a higher leukocyte infiltration was evidenced. Furthermore, cycling
hypoxia-specific inflammatory phenotype, characterized by a simultaneous (baculoviral inhibitor of apoptosis repeat-containing 5)(low)/
PTGS2(high)/ICAM-1(high)/IL-6(high)/IL-8(high) expression, is associated with a poor prognosis in human
colon cancer. This new phenotype could thus be used in clinic to more precisely define prognosis for
colon cancer patients. In conclusion, our findings evidenced for the first time the involvement of cycling
hypoxia in
tumor-promoting
inflammation amplification.