Mechanosensitive Piezo1 protein as a novel regulator in macrophages and macrophage-mediated inflammatory diseases.

Macrophages are the most important innate immune cells in humans. They are almost ubiquitous in peripheral tissues with a large variety of different mechanical milieus. Therefore, it is not inconceivable that mechanical stimuli have effects on macrophages. Emerging as key molecular detectors of mechanical stress, the function of Piezo channels in macrophages is becoming attractive. In this review, we addressed the architecture, activation mechanisms, biological functions, and pharmacological regulation of the Piezo1 channel and review the research advancements in functions of Piezo1 channels in macrophages and macrophage-mediated inflammatory diseases as well as the potential mechanisms involved.

TP53 mutation is enriched in colorectal cancer liver metastasis in the context of polyclonal seeding.

Cancer metastasis accounts for the majority of cancer motility burden. For colorectal cancer (CRC), the liver is the most common site of distant metastasis. It is still little known that cancer genomic mutations, which are a cell-intrinsic and heritable property, are enriched in CRC liver metastasis. Here, we try to answer the question in the context of polyclonal seeding. In this study, we sequenced 18 pairs of colorectal cancer primary tumors and their matched liver metastasis samples. Together with public available sequencing data, we compared the mutations in 113 primary and metastasis pairs. The TP53 mutation variant allele frequency (VAF) was significantly increased in metastasis compared to the paired primary tumor, although most of the frequently observed mutations in liver metastasis foci were concordant with their matched CRC primary tumors. The results support late metastasis and polyclonal seeding. Consequently, we quantitatively compared the intratumor heterogeneity (ITH) between primary and metastasis tumors, and with the help of in silico metastasis simulation, we inferred that more than 10 cells take part in the CRC liver metastasis.

DNA hydroxymethylation of colorectal primary carcinoma and its association with survival.

METHODS: A total of 71 cases of colorectal carcinoma with hepatic metastasis were enrolled from the Department of Pathology of SIR RUN RUN SHAW Hospital. Paired primary tumors, hepatic metastases, and normal mucosa samples were collected from formalin-fixed paraffin-embedded tissues by manual macrodissection. And global levels of DNA methylation and hydroxymethylation in these tissues, measured by an ELISA-like microplate-based colorimetric methods. The immunohistochemical expression of 5-methylcytosine and 5-hydroxymethylcytosine were analyzed also. RESULTS: The levels of DNA methylation in both primary and metastatic tumors were elevated when compared with normal mucosa, while DNA hydroxymethylation decreased slightly in those tissues. Similar results were observed in immunohistochemical staining. DNA methylation in hepatic metastases differed significantly in lymph node metastases (P = 0.037). And DNA hydroxymethylation in colorectal primary carcinoma was significantly different between tumor grade group (P = 0.018) and gender group (P = 0.048) respectively. And survival analyzes revealed that higher levels DNA hydroxymethylation were associated with better prognosis in colorectal primary carcinoma (P < 0.05). CONCLUSION: DNA hydroxymethylation correlated with less aggressive tumor behavior in colorectal cancer and were identified as an independent prognostic factor in patients' overall survival, and downregulation of DNA hydroxymethylation may serve as a useful biomarker for colorectal cancer prognosis evaluation.

The integrated pathway of TGFß/Snail with TNFα/NFκB may facilitate the tumor-stroma interaction in the EMT process and colorectal cancer prognosis.

Substantial evidence has shown that epithelial-mesenchymal transition (EMT) plays critical roles in colorectal cancer (CRC) development and prognosis. To uncover the pivotal regulators that function in the cooperative interactions between cancer cells and their microenvironment and consequently affect the EMT process, we carried out a systematic analysis and evaluated prognosis in CRC specimens. Tumor buds and their surrounding stroma were captured using laser microdissection. We used gene expression profiling, bioinformatics analysis and regulatory network construction for molecular selection. The clinical significance of potential biomarkers was investigated. We identified potential EMT biomarkers, including BGN, MMP1, LGALS1, SERPINB5, and TM4SF4, all of which participated in the integrated pathway of TGFß/Snail with TNFα/NFκB. We also found that BGN, MMP1, LGALS1, SERPINB5 and TM4SF4 were related to CRC patient prognosis. Patients with higher expression of these individual potential biomarkers had poorer prognosis. Among the identified biomarkers, BGN and TM4SF4 are reported, for the first time, to probably be involved in the EMT process and to predict CRC prognosis. Our results strongly suggest that the integrated pathway of TGFß/Snail with TNFα/NFκB may be the principal axis that links cancer cells to their microenvironment during the EMT process and results in poor prognosis in CRC patients.

S100A8+ stroma cells predict a good prognosis and inhibit aggressiveness in colorectal carcinoma.

Gene microarray and bioinformatic analysis showed that S100A8 was more abundant in the stroma surrounding tumor buddings (TBs) than in the stroma surrounding primary tumor cells in colorectal carcinomas. Here, S100A8+ cells in 419 colorectal carcinoma samples were stained by immunohistochemistry and counted using Image-pro plus 6.0. TBs were also counted and biomarkers associated with the epithelial-mesenchymal transition and apoptosis were assessed by immunohistochemistry. We evaluated the association between S100A8+ cells and clinico-pathological variables as well as survival. Migration and invasion as well as biomarkers of the epithelial-mesenchymal transition and apoptosis were tested in CRC cells, treated with graded concentrations of recombinant human S100A8 protein. We found that the density of S100A8+ cells in the tumor invasive front (S100A8+TIF) clearly distinguished patients with 5-y survival from those who did not survive (p = 0.01). The S100A8+-associated tumor budding (SATB) index determined by the S100A8+TIF and TB was an independent predictor of overall survival (p = 0.001) other than the S100A8+TIF or TB alone. Migration and invasion properties of CRC cells were inhibited by recombinant human S100A8 treatment. The particular S100A8+ cells in the stroma were associated with important biomarkers of the epithelial-mesenchymal transition (E-cadherin and SNAIL) and apoptosis (BCL2). In conclusion, S100A8+ cells in the stroma predict a good prognosis in colorectal carcinoma. An index combining S100A8+ cells and TB independently predicts survival. Recombinant human S100A8 inhibited CRC cell migration and invasion, which was involved in epithelial-mesenchymal transition (E-cadherin and SNAIL) and apoptosis (BCL2).

The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis.

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.