Infiltration of tumor‐associated macrophages is involved in CD44 expression in clear cell renal cell carcinoma

Cancer stem‐like cells (CSC) or cancer‐initiating cells are now considered to be an important cell population related to cancer recurrence and the resistance to anti‐cancer therapy. Tumor‐associated macrophages (TAM) are a main component of stromal cells and are related to cancer progression in clear cell renal cell carcinoma (ccRCC). Because the detailed mechanisms allowing the maintenance of CSC in cancer tissues remain unclear, we investigated the relationship between TAM and CD44‐expressing cancer cells in ccRCC. CD44 was used as a marker for CSC, and CD163 and CD204 were used as markers for TAM. CD44‐positive cancer cells were detected in 37 of the 103 cases. Although statistical analysis showed no relationship between CD44‐positive cancer cells and the clinical course, the distribution of CD44‐positive cancer cells was significantly associated with a high density of TAM. Our in vitro study using RCC cell lines and human macrophages demonstrated that CD44 expression was upregulated by direct co‐culture with macrophages. Silencing of TNF‐alpha on macrophages abrogated the upregulation of CD44 expression in cancer cells. Macrophage‐induced CD44 overexpression was also suppressed by NF‐κB inhibitors. These results suggest that TNF‐alpha derived from TAM is linked to CD44 overexpression via NF‐κB signaling in ccRCC.