Background Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear. Methods Immunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial–mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients’ prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis. Results Clinically, CD163 + TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC–conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively. Conclusions Our data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment. Electronic supplementary material The online version of this article (10.1186/s12943-019-0976-4) contains supplementary material, which is available to authorized users.
Background: Tumor microenvironment (TME) is a complex environment containing tumor cells, tumor-associated macrophages (TAMs), interstitial cells, and non-cellular components. Epithelial-mesenchymal transition (EMT), as a major actor in cancer tumorigenicity and metastasis, was involved in the interaction between TAMs and tumor cells. However, the potential mechanisms of EMT and how EMT-programmed tumor cells affect M2-like TAMs still need further exploration. Methods: An integrated analysis of nine CRC miRNA expression datasets was performed. Functional assays, including the EdU, clone formation, wound healing, and transwell assays, were used to determine the anticancer role of miR-195-5p in human CRC progression. Furthermore, RNA immunoprecipitation, RNA decay, and dual-luciferase reporter assays were used to determine the mechanism of miR-195-p CRC progression. Then co-culture, migration, and ELISA assays were applied to determine the role of miR-195-5p in macrophage recruitment and alternative polarization. Xenograft mouse models were used to determine the role of miR-195-5p in CRC tumorigenicity and TAM polarization in vivo. Results: An integrated analysis confirmed that miR-195-5p was significantly downregulated in CRC tissues, and patients with a low level of miR-195-5p had significantly shortened overall survival as revealed by the TCGA-COAD dataset. Altered miR-195-5p in colon cancer cells led to distinct changes of proliferation, migration, invasion, and EMT. Mechanistically, miR-195-5p regulated NOTCH2 expression in a post-transcriptional manner by directly binding to 3′-UTR of the Notch2 mRNA. Subsequently, miR-195-5p/NOTCH2 suppressed GATA3-mediated IL-4 secretion in CRC cells and ultimately inhibited M2-like TAM polarization. Conclusions: miR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.
Optical logic operations lie at the heart of optical computing, and they enable many applications such as ultrahighspeed information processing. However, the reported optical logic gates rely heavily on the precise control of input light signals, including their phase difference, polarization, and intensity and the size of the incident beams. Due to the complexity and difficulty in these precise controls, the two output optical logic states may suffer from an inherent instability and a low contrast ratio of intensity. Moreover, the miniaturization of optical logic gates becomes difficult if the extra bulky apparatus for these controls is considered. As such, it is desirable to get rid of these complicated controls and to achieve full logic functionality in a compact photonic system. Such a goal remains challenging. Here, we introduce a simple yet universal design strategy, capable of using plane waves as the incident signal, to perform optical logic operations via a diffractive neural network. Physically, the incident plane wave is first spatially encoded by a specific logic operation at the input layer and further decoded through the hidden layers, namely, a compound Huygens' metasurface. That is, the judiciously designed metasurface scatters the encoded light into one of two small designated areas at the output layer, which provides the information of output logic states. Importantly, after training of the diffractive neural network, all seven basic types of optical logic operations can be realized by the same metasurface. As a conceptual illustration, three logic operations (NOT, OR, and AND) are experimentally demonstrated at microwave frequencies.
Background: The interaction and crosstalk between tumor-associated macrophages (TAMs) and epithelial-mesenchymal transition (EMT) has been demonstrated to play a critical role in the progression and metastasis of multiple cancers. However, the roles of the M2-polarized TAMs in different tumor location in EMT and prognosis of colorectal cancer (CRC) have not been elucidated. Therefore, the present study was designed to set up a reliable ratio of CD163 + /CD68 + to assess M2-polarized TAMs infiltration in the tumor center (TC) and tumor invasive front (TF) and to further evaluate their prognostic value and biological effects on tumor cells in CRC. Methods: TAMs markers (CD68 and CD163) and EMT markers (E-cadherin and Vimentin) expression were evaluated by immunohistochemistry in 81 patients with CRC. Circulating tumor cells (CTCs) of peripheral blood from above patients was also isolated. The correlation of CD163 + /CD68 + ratio in different locations, EMT and CTCs counts were further analyses. Kaplan-Meier and the model analyses of univariate Cox proportional hazards were utilized to compare the survival of patients with high CD163 + /CD68 + ratio with those with low CD163 + /CD68 + ratio. Furthermore, the effects of the M2-polarized TAMs on growth, migration and invasion of CRC cells were explored in vivo and in vitro co-culture system. Results : The results showed that the level of CD163 + /CD68 + ratio in TF was significant higher than that in TC, and higher CD163 + /CD68 + TF ratio were closely correlated with enhanced lymphovascular invasion, tumor invasion and TNM stage. Interestingly, higher CD163 + /CD68 + TF ratio were also significantly associated with EMT program and CTCs counts. Meanwhile, Kaplan-Meier analysis showed that CD163 + /CD68 + TF was associated with both recurrence-free survival (RFS) and overall survival (OS) of patients with CRC. Multivariate Cox regression analyses demonstrated that CD163 + /CD68 + TF remained an independent prognostic factor for RFS and OS. Further receiver operating characteristic (ROC) curve analysis found that CD163 + /CD68 + TF was a better prognosticator compared with CD68 + TF and CD163 + TF for CRC patients. What's more, M2-polarized TAMs secreted TGF-β to facilitate the EMT, growth, proliferation and invasion of CRC cells by in vivo and ...
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