Lipopolysaccharide increases the release of VEGF-C that enhances cell motility and promotes lymphangiogenesis and lymphatic metastasis through the TLR4- NF-κB/JNK pathways in colorectal cancer

Abstract

Lipopolysaccharide (LPS) exists in the outer membrane of Gram-negative bacteria. Colorectal normal epithelium and colorectal cancer cells in situ are continuously exposed to LPS from intestinal bacteria, while little is known about the influence of LPS on colorectal cancer progression and metastasis. In this study, we investigated the potential role of LPS on colorectal cancer progression and metastasis as well as the underlying mechanisms. We measured higher LPS concentration in colorectal cancer tissues and even higher LPS concentration in colorectal cancer tissues with lymph node metastasis. LPS significantly enhanced cancer cell motility and promoted human dermal lymphatic endothelial cells' (HDLECs') capacity of tube-like formation in vitro, as well as accelerates lymphangiogenesis and lymph node metastasis in nude mice. Furthermore, we demonstrated LPS notably increased the expression of VEGF-C in a time-dependent and concentration-dependent manner. VEGF-C is a key regulator for lymphangiogenesis and lymph node metastasis. By constructing lentivirus-mediated shVEGF-C cells, VEGF-C down-regulation suppressed LPS' promotive effect on cancer cell motility and HDLEC tube-like formation capacity. In addition, we found TLR4- NF-κB/JNK signal pathways were important for LPS to increase VEGF-C expression. All these result suggested a critical role for LPS in migration, invasion, lymphangiogenesis and lymph node metastasis of colorectal cancer, providing evidence that LPS increased VEGF-C secretion to promote cell motility and lymphangiogenesis via TLR4- NF-κB/JNK signaling.

Tumor necrosis factor superfamily 15 promotes lymphatic metastasis via upregulation of vascular endothelial growth factor‐C in a mouse model of lung cancer

“…Activation of NF‐κB can be directly linked to VEGFC upregulation, because VEGFC upregulation, which is induced by TNFSF15, can be inhibited when treated with either NF‐κB inhibitor PDTC or NF‐κB subunit p65 siRNA in A549 cells. Our finding is consistent with previous studies on ovarian or colon cancer that NF‐κB activation can induce the production of VEGFC …”

“…Our finding is consistent with previous studies on ovarian or colon cancer that NF-κB activation can induce the production of VEGFC. 10,12,30 In summary, this study indicates that cytokine TNFSF15 pro- F I G U R E 6 Tumor necrosis factor superfamily 15 (TNFSF15) facilitates vascular endothelial growth factor-C (VEGFC)-stimulated lymphatic endothelial cell (LEC) migration and proliferation. A, Changes in VEGFC protein levels following TNFSF15 treatment in the presence or absence of VEGFC shRNA.…”

Lipopolysaccharide (LPS) enhances prostate cancer metastasis potentially through NF‐κB activation and recurrent dexamethasone administration fails to suppress it in vivo

“…Despite certain unexpected results, our in vivo study has for the first‐time provided the evidence that systemic administration of LPS could activate NF‐κB in PCa cells (Figures A and B) and enhance PCa cells metastasis in a cell line dependent manner (Figure A). We believe that, this effect could be through both direct and indirect methods of LPS‐mediated NF‐κB activation in PCa cells . No metastasis was observed in our DU145 orthotopic tumor model that confirms previously reported less metastatic nature of these cells .…”

“…14,19 LPS-mediated local inflammation and/or tissue damage in organs like lung favours metastasis to these sites. 20 Together, LPS could promote cancer cells' metastasis through its direct 18,[21][22][23][24][25][26][27] and/ or indirect effect 14,20,[28][29][30][31][32][33][34] on cancer cells.…”

Three‐dimensional nanofibrous polystyrene scaffolds modify macrophage phenotypes and activate macrophage angiogenic potential

“…Although VEGF-C mRNA levels were not increased in the macrophages cultured on NPS substrates, they were increased in pro-inflammatory (m1) media on both substrate types. This finding is consistent with the recently published reports stating that THP-1derived macrophages stimulated by LPSs (common proinflammatory compounds) react by increasing VEGF-C expression (Zhang et al, 2014;Zhu et al, 2016).…”