Tumor cells with highly
tumorigenic properties termed as cancer stem cells (CSCs) play a significant
role in tumor progression, spread and therapy failure. Important micro-environmental
signals contribute to maintenance of the CSC phenotype: hypoxia, epithelial to
mesenchymal transition, angiogenesis and inflammation. Interleukin-1 (IL-1), a
major pro-inflammatory cytokine, may affect the growth and invasiveness of
malignant cells, and mechanisms of antitumor immunity.
This work investigates the
role of IL-1 on malignancy patterns induced by CSCs using mice genetically
deficient in expression of the IL-1. The Oct3/4-pGreenZeo promoter reporter
system was transfected into murine luciferase expressing breast carcinoma cell
line as a model for detection of breast CSCs.
Kinetic experiments showed
increase in tumor growth when generated from CSC enriched cells in WT mice. We
observed regression of tumor growth in IL-1 deficient mice, but occurring later
when tumors were generated from CSC enriched cells. We observed positive
correlation between the presence of IL-1 in the micro-environment and number of
CSCs in primary tumors. IL-1 deficient mice contained 1-2% of Oct+ cells in
comparison to 3.5% detected in tumors from IL-1 receptor antagonist deficient
mice. Kinetics of immune cells infiltrating Matrigel plugs spiked with tumor
cells showed that there is a significant decrease in number of myeloid-derived
suppressor cells and an increase in number of cells from monocyte-macrophage
lineage when plugs are spiked with CSC enriched cells. Significantly lower
levels of pro-inflammatory and angiogenic factors were detected in plugs with
CSC enriched cells.
CSCs induce a different
inflammatory/immune microenvironment than those of the whole tumor. IL-1 may be
an important factor allowing switch to stem cell-like stage in the population
of tumor cells, leading to faster tumor progression via CSCs.
