- Characteristics and clinical significance of CD163+/CD206+M2 mono-macrophage in the bladder cancer microenvironment. - Bladder carcinoma is one of the most common urologic malignancies worldwide and is a heterogeneous disease (Siegel et al., 2018). - In 2019, the American Cancer Society estimated 80,470 new cases of bladder cancer and 17,670 deaths due to bladder cancer in the United States (Siegel et al., 2019). - In China, the incidence and mortality rates of bladder cancer have gradually increased in recent years (Chen et al., 2016. - Zheng et al., 2018). - Bladder cancer and other solid tumors contain a number of infiltrating immune cells, predominantly macrophages (Maniecki et al., 2012).. - High density of M2 mono-macrophages was significantly associated with late clinical staging in patients with bladder cancer. - In response to different environment stimuli, macrophages can appear as a range of different phenotypes (Zhang et al., 2012). - The expression of CD163. - mono-macrophages in bladder cancer tissue are believed to play a key role in the growth, progression and metastasis of tumors by producing growth factors, proteases and cytokines, which promote neoangiogenesis, connective tissue breakdown, scavenging of cellular debris and tumor- cell proliferation (Maniecki et al., 2012). - macrophage marker for M2 macrophages (Maniecki et al., 2012. - Medrek et al., 2012). - Mono-macrophages infiltrating the microenvironment of tumors are usually labeled with the leukocyte marker CD45, and the mono- macrophage marker molecules CD14 and CD45 + CD4 + flow gate strategy defines tissue infiltrating monocyte macrophages (Vidal et al., 2012. - Sylvester et al., 2018).. - Here, CD45 was used to detect leukocytes, rather than examine CD14, as CD45 can eliminate the interference of other cells to the greatest extent, and the measurement is more accurate (Coppin et al., 2017. - Bladder cancer tissue samples and paracarcinoma tissues samples were collected, and the expression of CD163 + cells in tumor tissues was observed. - The results showed that the proportion of CD45 + CD14 + CD163 + mono-macrophage subset infiltrated by tumor tissue was significantly higher than that in paracarcinoma tissues. - In bladder cancer tissue, the expression rate of CD40 in CD45 + CD14 + CD163 - mono-macrophage subset was significantly lower than that in CD45 + CD14 + CD163 + mono-macrophage subset. - Similar results were found in the paracarcinoma tissues.. - CD163 + /CD206 + mono-macrophages in bladder cancer microenvironment are abnormally elevated, and these cells are closely related to tumor progression. - CD40-CD40L also plays a key role in mediating angiogenesis and tumor growth (Gutierrez et al., 2019).. - In recent years, extensive research has suggested that angiogenesis in bladder cancer contributed to tumor growth and progression (Fus and Gĩrnicka, 2016). - By collecting bladder cancer tissue samples, the expressions of CD163 + cells and related membrane molecules in the mono-macrophage subset were analyzed, and the relevant mechanism and clinical significance of how this mono-. - Flow cytometry program for bladder cancer tissue of patients. - (1) Eight patients with primary bladder cancer were included in this study. - (bladder cancer. - Stage and grade in the paracarcinoma group were determined by bladder cancer.. - Tissue cell processing: the cancerous tissue and distal non- cancerous tissue of the same bladder cancer patient was collected (confirmed by pathology as normal tissue, at least 2cm away from the edge of the cancer). - (2) Expression of CD163 + mono-macrophage in the tissue:. - after being resuspended, CD45 + CD14 + was the characteristic of mono- macrophage expression to make gates, and the expression of infiltrating CD45 + CD14 + CD163 + mono-macrophage subset in bladder cancer and adjacent tissues was detected.. - Construct bladder cancer tumor-bearing mouse model. - The murine bladder cancer cell line MB49 was expanded in vitro, and the cell density was adjusted to 1×10 7 /ml, which was implanted subcutaneously in the groin of C57BL/6 mice (200 μL per mouse). - Expression ratio of CD163+ mono-macrophage in bladder cancer tissue. - Mono-macrophages infiltrated in tissue were detected by flow cytometry (Figure 1A). - The expression proportion of CD45+CD14+CD163+ mono-macrophage subset in bladder cancer tissue (n = 8) was significantly higher than that in adjacent normal tissues (n . - It is prompted that CD45+CD14+CD163+ mono-macrophage. - subset is significantly increased in bladder cancer microenvironment, which is one of the characteristics of tumor immune microenvironment.. - mono-macrophage subset in bladder cancer tissue Monocyte macrophages are mainly involved in immune regulation and neovascularization in the tumor microenvironment (Arnold et al., 2019). - Tie-2, CD31 and VEGFR2 are associated with neovascularization (Loges et al., 2007. - Xu et al., 2019). - Therefore, we chose the above molecules (Goto et al., 2019). - The expression rate of Tie-2 in CD45 + CD14 + CD163 - mono- macrophage subset was significantly higher than that in CD45 + CD14 + CD163 + subset . - However, the expression rate of CD40 in CD45 + CD14 + CD163 - mono-macrophage subset was significantly lower than that in CD45 + CD14 + CD163 + subset p = 0.001) (Figure 2B). - Expression ratio of CD163 + mono-macrophage in bladder cancer tissue. - Mono-macrophages infiltrating the tissue were detected by flow cytometry (A). - Approximately, 17.5% mononuclear macrophages were detected in 80.3% of leukocytes in the preceding gate. - The expression of the CD45 + CD14 + CD163 + mono-macrophage subset in bladder cancer tissues (n = 8) was significantly higher than that in adjacent normal tissues (B and C) (n vs. - suggested that CD163 + mono-macrophage subset was manifested as the phenotype of Tie-2 low CD40 high in cancer tissues.. - mononuclear macrophage subset in adjacent tissues of bladder cancer. - In contrast to the cancerous tissue, the expression rate of CD40 in CD45 + CD14 + CD163 - mono-macrophage subset was significantly lower than that. - in CD45 + CD14 + CD163 + mono-macrophage subset (67.9. - This suggested that the CD163 + mono-macrophage subset in normal adjacent tissues was only manifested as the phenotype of CD40 high . - For the comparison of cancer tissues and adjacent tissues, CD40 high is a common feature of CD163 + mono-macrophage subset,. - Phenotype identification of CD163 - and CD163 + mono-macrophage subsets in 8 bladder cancer tissues (A) and 3 adjacent tissues of 3 bladder cancer cases (C). - Then, the expression levels of Tie-2, CD31, pd-l1, CD40 and VEGFR2 in CD163 - and CD163 + mono-macrophage subsets were detected. - suggesting that this molecule may play an important role in biological functions of the CD163 + mono-macrophage subset.. - Dynamic expression of CD206+ mononuclear mac- rophage in bladder cancer tumor-bearing mouse model Construct tumor-bearing mouse model using MB49.. - Mono-macrophages were delineated by CD11b + F4/80. - The highly concerned immuno- logical factors are the myeloid derived cells represented by mono-macrophages (Fukuda et al., 2012. - Thevenot et al., 2014). - Mono-macrophages in the tumor microenviron- ment can promote tumor growth and metastasis in the fol- lowing several ways (Sica and Mantovani, 2012. - Chanmee et al., 2014). - Dynamic expression of CD206 + mono-macrophages in a bladder cancer tumor-bearing mouse model. - (B and C) Mono-macrophages were delineated by CD11b + F4/80. - and the expression changes in the CD206 + subset were detected and statistically analyzed. - Like all solid tumors, bladder cancer requires an active angiogenesis to support its growth and progression, Bladder tumor-associated angiogenesis is emerging as an important prognostic factor and represents a promising potential therapeutic target for cancer treatment. - Mono- macrophages in the tumor microenvironment can reach the pre-metastatic organs prior to the tumor, and create an immune microenvironment suitable for tumor growth.. - Hiratsuka et al., 2006. - Gil- Bernabé et al., 2012. - Thus, it can be seen that mono-macrophages in the tumor microenviron- ment play a major role in promoting tumor invasion and metastasis.. - This study found that the expression of CD40 in CD45 + CD14 + CD163 + mono-macrophage subset was significantly higher than that in CD45 + CD14 + CD163 - mono-macrophage subset in both cancer tissues and adjacent tissues (Figures 2B and 2D), suggesting that CD40 may play an important role in the biological function for this subset. - CD40-CD40L signal can also upregulate the expression of inflammatory cytokines such as Interleukelin-6 (IL-6), VEGF and tumor necrosis factor-α (TNF-α), participate in tumor angiogenesis and promote tumor invasion and metastasis (Chakrabarti et al., 2010. - Selvaraj et al., 2014).. - Additionally, it has been reported that CD40 plays a key role in myeloid-derived suppressor T cell (Treg) expansion (Pan et al., 2010).. - mono-macrophages characterized as Tie-2 + are also presumed to be involved in the neovascularization of tumors. - In the present study, the expression rate of Tie-2 in the CD45 + CD14 + CD163 - mono-macrophage subset was significantly higher than that in the CD45 + CD14 + CD163 + subset (Figures 2A and 2B). - It was well known that TAMs with an M2-like phenotype (markers CD163, CD204, and CD206) promote tumor growth while M1-like TAMs (CD68, CD80, and CD86) may inhibit tumor growth (Wu et al., 2020). - Here, we speculate that CD206 may become a therapeutic target in bladder cancer, and clinically we can also actively detect the expression of CD206 to calculate tumor load, determine treatment responses, and observe patient prognosis (Wang et al., 2020).. - In summary, we compared and analyzed the expression characteristics of mono-macrophages in the bladder cancer microenvironment. - Functional experiments require the adequate tumor infiltration of mono-macrophages in bladder cancer, which restricts functional research on bladder cancer. - 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