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

Abstract

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.

Effect of radiotherapy on expression of hyaluronan and EGFR and presence of mast cells in squamous cell carcinoma of the head and neck

“…Changes in the staining patterns induced by radiotherapy (RT). an abundance of mast cells, in accordance with animal studies demonstrating an influx of mast cells during RT (33,34). There is an established correlation between chronic inflammation and cancer (35) and mast cells are known to contribute to pre-malignant progression (36)(37)(38)(39).…”

“…Irradiation is known to induce structural alterations of HA such as degradation (33) and cause alteration of the physical properties; however, to which extent, is yet unknown. HA fragments are further released by most solid tumour cells and activate inflammatory cell signalling, promoting tumour motility (34). In the present study, however, we did not detect any changes in HA expression in normal epithelium or in the one sample with viable tumour cells following RT.…”

PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression

“…We previously showed that environmental hyaluronan (HA) fragments from hepatoma cells induced protumorigenic myeloid cells via TLR4 activation ( 23 ) . D, CD40L plus CpG ODN, anti-human IgM, or anti-IgM, IgA, and IgG cocktail used as combined stimuli triggered IL10 production in blood CD38 hi CD24 hi Bregs but not in CD5 hi CD27 hi/ + tumor B cells.…”

“…Proteins from cells were extracted as previously described ( 23 ). The antibodies used are listed in Supplementary Table S5.…”

Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma

“…[14][15][16] Neutrophils are the most abundant leukocytes and serve as essential effector cells in the first line of host defense against invading microorganisms. 17,18 In addition to direct bactericidal activities, neutrophils can actively regulate angiogenesis and tissue remodeling by releasing multiple proteases.…”