Liver metastases develop in more than half of patients with colorectal cancer (CRC) and are associated with a poor prognosis. The factors influencing liver metastasis of CRC are poorly characterized, but this information is urgently needed. We have now discovered that small extracellular vesicles (sEVs, exosomes) derived from CRC can be specifically targeted to liver tissue and induce liver macrophage polarization toward an interleukin-6 (IL-6)-secreting pro-inflammatory phenotype. More importantly, we found that microRNA-21-5p (miR-21) was highly enriched in CRC-derived sEVs and was essential for creating a liver pro-inflammatory phenotype and liver metastasis of CRC. Silencing either miR-21 in CRC-sEVs or Toll-like receptor 7 (TLR7) in macrophages, to which miR-21 binds, abolished CRC-sEVs' induction of pro-inflammatory macrophages. Furthermore, miR-21 expression in plasma-derived sEVs was positively correlated with liver metastasis in CRC patients. Collectively, our data demonstrate a pivotal role of CRC-sEVs in promoting liver metastasis by inducing an inflammatory pre-metastatic niche through the miR-21-TLR7-IL6 axis. Thus, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis.

Scope Nobiletin (NBT) is a major citrus flavonoid with various health benefits. Herein, we investigated the colon cancer chemopreventive effects of NBT and its colonic metabolites in a colitis-associated colon carcinogenesis mouse model as well as in human colon cancer cell models. Methods and results In azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice, oral administration of NBT effectively decreased both incidence and multiplicity of colonic tumors. NBT showed significant anti-proliferative, pro-apoptotic and anti-inflammatory effects in the mouse colon. HPLC analysis revealed that oral administration of NBT resulted in high levels of metabolites, i.e. 3′-demethylnobiletin (M1), 4′-demethylnobiletin (M2), and 3′, 4′-didemethylnobiletin (M3) in the colonic mucosa. In contrast, the colonic level of NBT was about 20-fold lower than the total colonic level of three metabolites. Cell culture studies demonstrated that the colonic metabolites of NBT significantly inhibited the growth of human colon cancer cells, caused cell cycle arrest, induced apoptosis, and profoundly modulated signaling proteins related with cell proliferation and cell death. All of these effects were much stronger than those produced by NBT alone. Conclusions Our results demonstrated that oral administration of NBT significantly inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly associated with its colonic metabolites.

Exosomes are extracellular vesicles with diameters ranging from 30 to 150 nm. They can be secreted by all cell types and transfer information in the form of their contents, which include proteins, lipids and nucleic acids, to other cells throughout the body. They have roles in normal physiological processes as well as in disease development. Here, we review recent findings regarding tumor-derived exosomes, including methods for their extraction and preservation. We also describe the actions of exosomes in tumorigenesis. The exosomal antigen-presenting effect during antitumor immune responses and its suppressive function in immune tolerance are discussed. Finally, we describe the potential application of exosomes to cancer therapy and liquid biopsy.

Typically, tumor-associated macrophages (TaMs), an abundant population of leukocytes in lung cancer, are affected by tumor microenvironment (TMe) and shift towards either a pro-tumor (M2-like) or an anti-tumor phenotype (M1-like). M2-polarized macrophages, are one of the primary tumor-infiltrating immune cells and were reported to be associated with the promotion of cancer cell growth, invasion, metastasis, and angiogenesis. TaMs are considered a potential target for adjuvant anticancer therapies, and recent therapeutic approaches targeting the M2 polarization of TaMs have shown encouraging results. The present review discusses recent developments in the role of TaMs in cancer, in particular TaMs functions, clinical implication and prospective therapeutic strategies in lung cancer. Contents 1. introduction 2. Macrophage plasticity in lung cancer development 3. Functional aspects of macrophages in lung cancer 4. clinical implications of TaMs in lung cancer 5. TaM-targeted therapeutics 6. conclusions