Function Of Notch Signaling On Polarization Of Macrophages And Its Functions In Tumor

Tumor have been becoming worldwide killer to human for causing severe diseasesrelated to several systems. As growing fast and hiding secretly, tumor is not easy to bedetected at early stage. Passions on tumor research have always remained hot in recentyears. Research targets have shift from tissue to cell then to molecular level in order togradually illustrate possible mechanisms and effective therapies.MPS is mainly constituted of several cell groups including peripheral circulatingmonocyte, monoblast in bone marrow, macrophages and dendritic cells. MPS plays anessential role for body immune system which could protect the body against invadedpathogens, remain tissue homeostasis and activate innate and adaptive immune response.On the other side, malignancy of the MPS might contribute to many human disease liketumor, auto-immune disease, and atherosclerosis etc. Recent researches indicate that once meet the pathogens, monocyte-macrophages could show different functions: activateTh1/Th2response, inert immune response or inhibit immune response. Therein,macrohoages were paid more attention on its correlation with tumor development.Currently Macrophages could be subdivided into two groups according to their functionsand phenotypes: classical activated macrophage (M1) and alternative activatedmacrophage (M2). Both two groups have important effect on tumor disease. M1macrophage plays innate immune response, stimulating inflammatory response, secretinginflammatory cytokines and attracting inflammatory cells and leucocytes in order to killalien pathogens. Well, M2macrophage acts just the opposite way. They could promotetissue remodeling, inhibiting cytokine secretion and playing immune suppressive functionwithin the tumor site. In addition, another group of cells termed MDSCs also withheterogeneity might play important immune suppressive functions to inflammation andtumor disease as well.Notch signaling is a conservative regulatory pathway. The intracellular domain ofNotch receptors could release to the cytoplasm once the ligand contact with Notchreceptors. NICD could have functions on RBP-J which could sequentially activatepromoters with RBP-J binding site. Activation of this pathway could regulate celldifferentiation through Hes family, and regulate proliferation and apoptosis of cells. In theprevious research, scientists have found that Notch signaling had key role in T celldifferentiation. In our latest research, we found Notch signal might regulate Macrophagefunctions through the modulation of macrophage polarization. Then, regarding on theseobservation, we speculated the sub group of macrophages might also be manipulatedunder the control of Notch signaling. However, during tumor development, which kind ofmacrophage were involed in, and the molecular mechanism of regulating macrophagewere unknown. Therefore, we performed several experiments to explore these questions asfollow.1. To maintain and cross Lyz2cre and RBP-Jfloxmice, and gain myeloid specific Notchknockout mice. Building up tumor bearing mice model based on such knockout miceand observe the possible difference on tumor growth compared with wild type mice. 2. To determine the macrophages and leukocytes infiltration within tumor and otherimmune organs by FACS.3. To examine monocyte infiltration conditions within tumors by immune fluorescencestaining technique.4. To observe the functions of Notch signaling on macrophage polarization in vitro.Conclusion: Tumor showed better growing conditions on the Notch knockout mice,namely larger volume and faster growth ratio compared with wildtype mice bearing tumor.Analysis on tumor tissue constitution indicated that there were more monocyte andmacrophage infiltration, and less T cell activation. In other organs, the number of MDSCswas significantly enhanced. In vitro experiments showed macrophages would prefer to M1under Notch signaling regulation. While blocking the Notch signaling, macrophage couldconversely develop into M2. Besides, Notch signaling also has functions on T cellsactivation through regulating macrophages. In a word, Notch might affect tumordevelopment through regulation of macrophage polarization.