The impact of Wnt5a signaling and tumor associated macrophages in breast cancer

Sammanfattning: Breast cancer is the most common cancer among women worldwide with approximately 1.150.000 new cases each year and accounting for over 400.000 deaths per year. The main cause of death for women with breast cancer is secondary tumors. Downregulation of Wnt5a in primary ductal breast cancer has been correlated with poor outcome and higher tumor grade and found to be an independent predictor of recurrence. The ability of Wnt5a to inhibit tumor progression can partly be explained by Wnt5a induced cell-extracellular adhesion that inhibits cell migration. We found that Wnt5a can further inhibit tumor progression by inducing cell-cell adhesion through CK1α-induced Ser-45 phoshporylation of β-catenin promoting β-catenin/E-cadherin complex formation, hence in line with prior data indicating a beneficial effect of Wnt5a in breast cancer. Macrophages are part of the innate immune system and they can differentiate into tumoricidal pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. The anti-inflammatory M2 macrophages will limit pro-inflammatory activity that in abundance would cause additional tissue damage. Tumor associated macrophages (TAMs) have many features in common with M2 macrophages; they are anti-inflammatory and have a weak tumoricidal capacity. We show that Wnt5a induces an anti-inflammatory tolerogenic macrophage phenotype in a pro-inflammatory environment and we could validate our in vitro data by showing the clinical relevance in both breast cancer and sepsis patients. The CD163 marker has been reported to recognize M2 macrophages, while CD68, on the other hand, is a frequently used pan-macrophage marker that recognizes both pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. We evaluated CD163 as a TAM marker in human breast cancer and compared it to CD68. We revealed and could highlight the clinical importance of analyzing the localization of TAMs in human breast cancer. While TAMs in the tumor nest did not have any correlation with clinicopathological feature or patient outcome, we found TAMs in tumor stroma to be highly relevant. CD163+ TAMs in tumor stroma correlated with unbeneficial clinicopathological features, and dense infiltration of CD68+ TAMs in tumor stroma was an independent risk factor for reduced breast cancer specific survival.