Oral-gut pathogens are closely associated with pancreatic cancer, such as Campylobacter jejuni, Clostridium difficile, Enterococcus faecalis, Escherichia coli, Fusobacterium nucleatum, Helicobacter pylori, Porphyromonas gingivalis, and Vibrio cholera, but the related mechanisms remain not well understood. Phosphatase and tensin homolog (PTEN, a widely known tumor suppressor) play a key role in the anti-cancer immune system. Pancreatic cancer cells with PTEN loss are often in the immunosuppressive tumor microenvironment regulated by myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2 macrophages, which are regarded as the mechanism in the immune escape of cancers. The miR-21, as an oncogene in human cancers, plays an important role in pancreatic cancer progression, downregulates the levels of PTEN, and may promote cancer to evade host immune surveillance. Some oral-gut pathogens have been found to promote miR-21 expression and reduce PTEN expression. On the other hand, most gut pathogens infection is thought to produce reactive oxygen species (ROS) or activate inflammatory cytokines, which may also induce ROS-mediated miR-21 expression. These pathogens' infection is involved with the cell density of MDSCs, Tregs, and M2 macrophages. Therefore, it is quite reasonable to propose that oral-gut pathogens possibly promote pancreatic cancer escaping from host immune surveillance by activating the miR-21/PTEN axis and immune-suppressive cells. The present exploration suggests that an increased understanding of the pattern of the effects of gut pathogens on the miR-21/PTEN axis will lead to better insights into the specific mechanisms associated with the immune escape of pancreatic cancer caused by oral-gut microbiota.
Background:The effect and underlying mechanisms of endoglin on angiogenesis and immunity during tumour progression were investigated.Methods: Differences in the growth of established EO771 breast tumours between endoglin-knockout (Eng-iKO e ) and control mice were evaluated. The tumour tissues were harvested on the day 7th and 14th after engraftment, at which times the growth differences between the groups were significant. The expression of markers of angiogenesis (CD31), endoglin (CD105), tumour associated macrophages (TAMs) (F4/80) and M2 macrophages (CD206) and of interleukin-6 (IL-6), IL-10, and IL-6/Janus kinase 2 (JAK2)/ signal transducer and activators of transcription 3 (STAT3) proteins in tumour tissues of Eng-iKO e and control mice were evaluated.Results: We found that tumour angiogenesis and growth were both inhibited in the Eng-iKO e group relative to the control group on day 7, whereas, no significant between-group difference was observed on day 14. Moreover, in breast cancer tissues of the Eng-iKO e group, the numbers of M2 macrophages were significantly decreased on day 7 and increased on day 14, and the expression of IL-6 and IL-10 were lower on day 7 and higher on day 14. Positively strong correlations were found between the IL-6 level and the number of M2 macrophages both on days 7 (P=0.017, r=0.80) and 14 (P<0.01, r=0.94). However, there was just a moderate correlation between IL-10 expression and the number of M2 macrophages on day 14 (P=0.043, r=0.682), not day 7 (P=0.055). Furthermore, the protein levels of IL-6, p-JAK2, and p-STAT3 were significantly lower on day 7, and higher on day 14 in the Eng-iKO e group compared with the control group, which was in accordance with the changes of M2 macrophage numbers. Conclusions:The effect of endoglin-targeted anti-angiogenic therapy was weakened by affecting the infiltration of M2 macrophages in breast cancer through modulation of the IL-6 level. This indicated that IL-6 could not only predict the efficacy after anti-angiogenic therapies, but also acts as a potential target to improve efficacy of anti-angiogenic therapies.
Chemotherapy is the main method for controlling pancreatic cancer metastasis but the prevalent chemotherapy resistance limits its utilization. The response of oxidation and inflammation often promotes pancreatic cancer progression and chemo‐resistance. It is critical to explore the potential natural products with few side effects to control inflammatory responses and understand the related mechanisms. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti‐inflammatory properties, which may be associated with improvement of chemotherapy sensitivity during pancreatic cancer treatment. Quercetin may sensitize pancreatic cancer cells to the chemotherapeutic agents, including bromodomain and extraterminal domain inhibitors (BETI), daunorubicin, gemcitabine, sulforaphane, doxorubicin, and tumor necrosis factor‐related signaling apoptosis‐inducing ligand (TRAIL). Meanwhile, during the chemo‐resistance therapy, many signaling molecules are involved with toll‐like receptor 4 (TLR4)‐mediated oxidative and inflammatory pathway. The effects of quercetin on other oxidative and inflammatory pathways were also explored. Quercetin may exert antitumor activity during the prevention of pancreatic cancer progression by regulating oxidative and inflammatory networks, which can promote immune escape of cancer cells by inducing immunosuppressive cytokines. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo‐sensitivity. Practical applications Chemotherapy is the major way for treating pancreatic cancer metastasis but the prevalent chemotherapy resistance caused by oxidative and inflammatory responses limits its utilization. It is necessary to explore the potential natural products with few side effects to prevent the oxidative and inflammatory responses. Quercetin is a flavonoid widely found in numerous vegetables, fruits, and foods and is thought to have antioxidant and anti‐inflammatory properties, which may be associated with improvement of chemotherapy sensitivity of pancreatic cancer treatment by sensitizing pancreatic cancer cells to various chemotherapeutic agents via the regulation of oxidative and inflammatory networks. Studying these patterns will help us to better understand the functional role of quercetin in the improvement of pancreatic cancer chemo‐sensitivity.
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