Author(s): Fan Fan 1, Rui Wang 1, Delphine R. Boulbes 1, Huiyuan Zhang 2, Stephanie S. Watowich 2, Ling Xia 1, Xiangcang Ye 1, Rajat Bhattacharya 1, Lee M. Ellis 1,*
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States . Several clinical trials have led to the approval of new drugs for patients with metastatic CRC (mCRC) within the past few years; however, the prognosis remains poor, and most patients will develop resistance to therapy within one year [1-3]. Thus, finding method to combat resistance to therapy is critical if we are to improve the survival of patients with mCRC.
Cancer stem cells (CSCs), a subpopulation of cancer cells that are thought to drive tumor growth and metastasis, have been identified in multiple types of malignancies, including CRC [4-13]. CSCs are thought to not only initiate and sustain tumor growth but also mediate chemoresistance [14-20], mostly through key signaling pathways such as Wnt, Notch, and Hedgehog . Notably, results from our laboratory and others suggest that CSCs exist in a state of flux and that the CSC phenotype can be enhanced by micro-environmental influences [22-26]. Currently most therapies targeting the bulk of the tumor cells ultimately fail as they do not successfully eliminate CSCs. Therefore, understanding the CSC-microenvironment relationship and the development of CSC- or microenvironment-targeting strategies that could eliminate or deplete the CSC population are critical for improving the clinical outcomes of patients with mCRC.
The tumor microenvironment is complex and made up of various cell types, including tumor associated macrophages (TAMs) (reviewed in ). Macrophages have been previously shown to interact with stem cells , and a growing body of evidence suggests that TAMs are critical for the self-renewal and maintenance of CSCs in established tumors [29-31]. Recent studies have sought to characterize the relationship and cross-talk between TAMs and CSCs (reviewed in ) and have demonstrated that TAMs are able to increase the number of CSCs and cell phenotypes in hepatocellular carcinoma and pancreatic ductal carcinoma [32-34]. Also, it was shown that TAMs can increase both tumorigenicity and drug resistance in CRC both in vitro and in vivo . These effects were due to coordinated activation of Stat3 and Sonic Hedgehog (SHH) signaling in CRC stem cells. However, despite these exciting results, there is still a tremendous amount to learn about the interactions between TAMs and CSCs, particularly in CRC.
Typically, macrophages are divided into two main classes, M1 (classically activated macrophages; antitumor activities) and M2 (alternatively activated-macrophages: protumor activities) [29,36]. However, the role of different macrophages in the CRC microenvironment are not well defined and remains a point of controversy (reviewed in [37-39]). In vitro, exposure to lipopolysaccharide (LPS) polarizes macrophages toward an M1 phenotype, whereas exposure to IL-4 or IL-13 polarizes them towards an M2 phenotype. In this study, we examined the effects of classically LPS-activated macrophage CM on the acquisition of the CSC phenotype in CRC cells. Our studies demonstrated that the CM of LPS-activated macrophages is...