Interphase chromatin is organized in distinct nuclear sub-compartments, reflecting its degree of compaction and transcriptional status. In Caenorhabditis elegans embryos, H3K9 methylation is necessary to silence and to anchor repeat-rich heterochromatin at the nuclear periphery. In a screen for perinuclear anchors of heterochromatin, we identified a previously uncharacterized C. elegans chromodomain protein, CEC-4. CEC-4 binds preferentially mono-, di-, or tri-methylated H3K9 and localizes at the nuclear envelope independently of H3K9 methylation and nuclear lamin. CEC-4 is necessary for endogenous heterochromatin anchoring, but not for transcriptional repression, in contrast to other known H3K9 methyl-binders in worms, which mediate gene repression but not perinuclear anchoring. When we ectopically induce a muscle differentiation program in embryos, cec-4 mutants fail to commit fully to muscle cell fate. This suggests that perinuclear sequestration of chromatin during development helps restrict cell differentiation programs by stabilizing commitment to a specific cell fate. PAPERCLIP.

Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are important components of the tumor microenvironment, which have been reported to localize in colorectal carcinomas where they promote tumor progression. One of the crucial effects they exerted is immune-suppression, which was reported recently, however, the overall mechanism has not been fully addressed. In this study, it was shown that TAMs were enriched in colorectal cancer, and their infiltration was associated with VCAM-1 expression. Human colorectal cancer-derived CAFs can promote the adhesion of monocytes by up-regulating VCAM-1 expression in colorectal cancer cells. Furthermore, CAFs can attract monocytes by secreting IL-8 rather than SDF-1 and subsequently promote M2 polarization of macrophages, which synergize with CAFs in suppressing the functioning of natural killer (NK) cells. It was also found that CAFs promoted M2 macrophages recruitment in tumor tissue in vivo, and after VCAM-1 knocking-down in tumor cells or depletion of macrophages, the pro-tumor effect of CAFs was partly abolished, but no change was observed in NK cells infiltration. Collectively, the findings in this work show that TAMs and CAFs function synergistically in the tumor microenvironment and have the capacity to regulate NK cells in colorectal cancer and this presents a novel mechanism.

Mesenchymal stem cells (MSCs) have been reported to localize in colorectal carcinomas, and participate in the formation of the tumor microenvironment. They have recently been isolated from colorectal cancer tissues, and are implicated in the growth, invasion, and metastasis of cancer cells. However, the roles and detailed mechanisms associated with human colorectal cancer-derived MSCs (CC-MSCs) have not been fully addressed. In this study, we found that CC-MSCs increased the migration and invasion of colorectal cancer cells and promoted the tumorigenesis of colorectal cancer through epithelial-to-mesenchymal transition (EMT) in vitro. We also found that CC-MSCs enhanced the growth and metastasis of colorectal cancer in vivo. Mechanistically, we determined that interleukin-6 (IL-6) was the most highly expressed cytokine in the CC-MSC conditioned medium, and promoted the progression of colorectal cancer cells through IL-6/JAK2/STAT3 signaling, which activated PI3K/AKT signaling. We used anti-IL-6 antibody to target IL-6. Collectively, these results reveal that the IL-6 secreted by CC-MSCs enhances the progression of colorectal cancer cells through IL-6/JAK2/STAT3 signaling, and could provide a novel therapeutic or preventive target.