Spatial localization of cancer stem cell phenotypes, CD8+ cytotoxic T cells and hypoxia in 4T1 tumors: a mouse model of triple-negative breast cancer

Authors

• RL Moffat
• AL Gonzalez
• LL Coutinho
• L Ridnour
• SJ Lockett
• DA Wink

Abstract

Triple-negative breast cancer (TNBC) is an aggressive disease with a high likelihood of recurrence. Treatment options are limited due to a lack of molecularly targeted therapies. Cancer stem cells (CSCs) increase the likelihood of recurrence and pose crucial complications for treatment of aggressive cancers, because CSCs allow for renewal, differentiation, drug resistance, and tumorigenicity. Hypoxia and inflammation induce stress responses within tumor environments; therefore, it is hypothesized that these stress responses induce CSCs and drive their migration up the oxygen gradient towards vasculature, ultimately causing metastasis. 4T1 tumors are a syngeneic mouse model of human TNBC and when treated with indomethacin the CSC significantly decreased along with significantly increased CD8+ T Cells infiltration. However, contrary to our hypothesis, the CSC decrease was not observed in hypoxic regions of 4T1 tumors or in 4T1 cells grown in a restricted exchange environment chamber that imposes a spatial gradient of oxygen concentration across the cell culture. Furthermore, our results showed spatial proximity of CSCs to CD8+ T cells, suggesting either a bystander role where CD8+ T cells induce stem cell properties of tumor cells or CD8+ T cells hone in to target CSCs. The latter is consistent with our observations that CD44v6+ cells are associated with immune desserts in human ER- breast cancer. The role of hypoxia in CSC induction could be less direct and driven by nitric oxide, because our studies show that hypoxia drives nitric oxide release via NOS2 activation. Therefore, current studies are addressing whether NO induces the CSC phenotype.

Scientific Focus Area: Cancer Biology

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