Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop.

Inflammation is a component of tumour progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumours, but their regulation and functions in neoplasia are not understood. We recently demonstrated that pro-inflammatory IL-17-producing cells recruited blood neutrophils into the peritumoural stroma of hepatocellular carcinoma by epithelium-derived CXC chemokines. Here we show that a substantial population of neutrophils accumulates in the peritumoural stroma of hepatocellular, cervical, colorectal, and gastric carcinomas, and that this correlates with metastases in hepatocellular and gastric carcinomas. Exposure of neutrophils to culture supernatants from several types of solid tumour cells (TSN) resulted in sustained survival and pro-tumourigenic effects of cells. Kinetic experiments reveal that, shortly after exposure to TSN, neutrophils began to provoke activation and then produced significant inflammatory cytokines and expressed more anti-apoptotic Mcl-1 but less pro-apoptotic Bax. These long-lived neutrophils effectively enhanced the cancer cell motility via a contact-dependent mechanism; this effect, together with early activation and subsequent longevity of TSN-exposed neutrophils, could be reversed by blocking the activation of PI3K/Akt signalling in neutrophils. Moreover, we found that hyaluronan (HA) fragments constitute a common factor produced by various tumours that mimics the effect of TSN to induce long-lived neutrophils and subsequent malignant cell migration. The effects of TSN were inhibited by function blocking interactions between HA and its receptor TLR4 on neutrophils, suggesting that this is a key signalling pathway involved. These results indicate that HA derived from malignant cells educates neutrophils to adopt an activated phenotype, and in that way stimulates the metastasis of malignant cells, which represents a positive regulatory loop between tumours and their stroma during neoplastic progression.

Wu Y ，Zhao Q ，Peng C ，Sun L ，Li XF ，Kuang DM ... -  《-》

TLR4 through IFN-β promotes low molecular mass hyaluronan-induced neutrophil apoptosis.

Leu SW ，Shi L ，Xu C ，Zhao Y ，Liu B ，Li Y ，Shiedlin A ，Xiang C ，Shen H ，Quinn DA ，Hales CA ，Zhao H ... -  《-》

Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4.

Voelcker V ，Gebhardt C ，Averbeck M ，Saalbach A ，Wolf V ，Weih F ，Sleeman J ，Anderegg U ，Simon J ... -  《-》

Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization.

Shimada M ，Yanai Y ，Okazaki T ，Noma N ，Kawashima I ，Mori T ，Richards JS ... -  《DEVELOPMENT》

Fibroblast growth factor-2 stimulates directed migration of periodontal ligament cells via PI3K/AKT signaling and CD44/hyaluronan interaction.

Fibroblast growth factor-2 (FGF-2) regulates a variety of functions of the periodontal ligament (PDL) cell, which is a key player during tissue regeneration following periodontal tissue breakdown by periodontal disease. In this study, we investigated the effects of FGF-2 on the cell migration and related signaling pathways of MPDL22, a mouse PDL cell clone. FGF-2 activated the migration of MPDL22 cells and phosphorylation of phosphatidylinositol 3-kinase (PI3K) and akt. The P13K inhibitors, Wortmannin and LY294002, suppressed both cell migration and akt activation in MPDL22, suggesting that the PI3K/akt pathway is involved in FGF-2-stimulated migration of MPDL22 cells. Moreover, in response to FGF-2, MPDL22 showed increased CD44 expression, avidity to hyaluronan (HA) partly via CD44, HA production and mRNA expression of HA synthase (Has)-1, 2, and 3. However, the distribution of HA molecular mass produced by MPDL22 was not altered by FGF-2 stimulation. Treatment of transwell membrane with HA facilitated the migration of MPDL22 cells and an anti-CD44 neutralizing antibody inhibited it. Interestingly, the expression of CD44 was colocalized with HA on the migrating cells when stimulated with FGF-2. Furthermore, an anti-CD44 antibody and small interfering RNA for CD44 significantly decreased the FGF-2-induced migration of MPDL22 cells. Taken together, PI3K/akt and CD44/HA signaling pathways are responsible for FGF-2-mediated cell motility of PDL cells, suggesting that FGF-2 accelerates periodontal regeneration by regulating the cellular functions including migration, proliferation and modulation of extracellular matrix production.

Shimabukuro Y ，Terashima H ，Takedachi M ，Maeda K ，Nakamura T ，Sawada K ，Kobashi M ，Awata T ，Oohara H ，Kawahara T ，Iwayama T ，Hashikawa T ，Yanagita M ，Yamada S ，Murakami S ... -  《-》