The role of mast cells in colorectal cancer: Finding the new Horcrux

Abstract

Colorectal cancer (CRC) is the third most common diagnosed cancer in both women and men. It is the second leading cause of cancer deaths worldwide. Mast cells are one of immune cells abundantly present in CRC tissue and their density correlates with the disease progress. By using 2D and 3D coculture model, this thesis was to investigate the impact of human mast cells on colon cancer growth and delineate the molecular mechanism of how these cells interact with each other. Understanding mast cell biology in colon cancer may help to develop new strategy for CRC treatment. Chapter 2 describes a plethora of non-IgE stimuli that induce mast cell activation. Receptors for the stimuli, induced biological responses, models of mast cells and pharmacological inhibition agents are included in this review. In Chapter 3, we describe the successful generation of human mast cells derived from peripheral CD34+ stem cell concentrates. This model was phenotypically and functionally characterized and its transcriptome profile was shown. Moreover, we further optimized the culture protocol and compared this model with current used human mast cell models in the aspect of source accessibility, culture duration, phenotype, response to stimuli and application. In Chapter 4, the current knowledge of mast cells in CRC progression is described. In this review, we summarize the correlation of mast cells with clinical outcomes and response to therapy in human CRC and attempt to explain the contradictory observation. Next, we discuss the role of mast cells in mouse colon cancer models. The interaction of mast cells with colon cancer cells and the tumor immune microenvironment is described. Finally, we discuss the potential of mast cells to mobilize cytotoxic lymphocytes and how to employ mast cells for anti-tumor immune responses. In Chapter 5, the impact of human mast cells on colon cancer growth is shown. In this study, we used 2D and 3D coculture models to investigate the interplay between human mast cells and colon cancer cells. We unraveled the molecular signals by which these cells may communicate with each other. This is followed by Chapter 6, which presents a possible mechanism how colon cancer cells may educate mast cells to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal (e.g. TLR2 ligand) may modify their responses in the tumor milieu. The final experimental part of this thesis, Chapter 7 describes an inhibitory receptor, Siglec-6, on human mast cells. Its functional effect upon engagement on mast cells was investigated. Next, mast cell Siglec-6 expression was measured in the mimicked milieu of CRC. Finally, in situ expression of Siglec-6 and its ligands was analyzed in human CRC tissues. A general discussion in the context of the current knowledge regarding mast cells in CRC and the tumor immune microenvironment accompanied by future perspective is presented in Chapter 8.