Abstract LB-210: Macrophage dependent Cox2 PGE2 signaling promotes expansion of cancer stem cells
Authors: Xi He, Edward H. Lin, Paloma M. Giles, Linheng Li
Journal: Cancer Research (2017)

Abstract One of the most challenging issues in cancer treatment is relapse caused by treatment-resistant cancer cells. Accumulated evidence has shown that cancer stem cells (CSCs) enrich treatment-resistant cancer cells. However, the cellular and molecular mechanism underlying CSC resistance to treatment remains largely unaddressed. Here, we test a hypothesis that the microenvironment or niche can protect CSCs from stress and also stimulate CSC expansion in response to stress. We used APCmin adenoma mouse model to test this hypothesis as it is a very reliable model with 100% rate in forming adenoma. Furthermore, our clinical observation showed that addition of cyclooxygenase (Cox)2 inhibitor, celecoxib, to the patients with late stage (IV) colorectal cancer who received chemotherapy increased the overall survival (OS) rate from on average 24 months (for those who only received capecitabine treatment) to 92 months. This raises a possibility that Cox2, through PGE2, is one of the niche factors that promotes CSC expansion via the PGE2-Ptger pathway. Mimicking the clinical protocol, we applied capecitabine (a pro-drug of 5FU), which resulted in largely eliminated proliferating cells, but at the same time, this treatment also induced CSC expansion (see below). However, combination treatment with capecitabine and celecoxib dramatically reduced the number and size of adenomas. Using CD44hiCD24lo as CSC marker, we further found that there was a significant reduction of CSC population following the combination treatment. Performing RNA-seq analysis on CSCs that received different treatments, we observed upregulation of Ptger (EP2&amp;4) in the chemo-treatment group, accompanied with an increased Akt3 and Wnt signaling; intriguingly, this upregulation of EP2&amp;4 as well as Akt3 and Wnt signaling was suppressed in the Cox2 and combination treatment groups. We next asked what is the resource of PGE2 and further found that macrophage (CD11b+) was significantly increased and often adjacent to CD44hi (greater than 100-fold increase compared to Wt crypt cells) adenoma clones and in some cases to Bmi+-GFP CSCs, forming a CSC microenvironment. Furthermore, we also saw chemotherapy induced macrophage correlated with an increased production of Cox2-PGE2, using immunofluorescent staining, which in turn enhanced Wnt/beta-catenin activity, thus promoting CSC expansion. We then depleted macrophages using clodrosome and observed a reduction in a subset of macrophage (CD11c+, CD11blo,hi, MHCII+) tumor associated macrophage (TAM), and a corresponding reduction in CSC populations. Our observations support the conclusion that TAM forms a microenvironment to protect CSCs, and also promotes CSC expansion in response to chemotherapy via the Cox2-PGE2-EP pathway; combination treatment simultaneously targets both proliferating tumor cells (via capecitabine) and CSCs (via inhibiting macrophage produced Cox2-PGE2), and thus efficiently controlled the tumor growth. Note: This abstract was not presented at the meeting. Citation Format: Xi He, Edward H. Lin, Paloma M. Giles, Linheng Li. Macrophage dependent Cox2 PGE2 signaling promotes expansion of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-210. doi:10.1158/1538-7445.AM2017-LB-210