Cancer cells collectively invading as a cohesive and polarized group is termed collective invasion, which is a fundamental property of many types of cancers. In this multicellular unit, cancer cells are heterogeneous, consisting of two morphologically and functionally distinct subpopulations, leader cells and follower cells. Leader cells at the invasive front are responsible for exploring the microenvironment, paving the way, and transmitting information to follower cells. Here, in this review, we will describe the important role of leader cells in collective invasion and the emerging underlying mechanisms of leader cell formation including intrinsic properties and the support from neighboring cells. It will help us to elucidate the essence of collective invasion and provide new anticancer therapeutic clues.

High expression of δ-like ligand 4 (Dll4) is reportedly related to the invasion, metastasis, and clinical prognosis of various malignant tumours. Our previous study revealed that collective cell invasion was a common pattern in salivary adenoid cystic carcinoma (SACC). However, the roles of the Dll4/Notch1 signalling pathway in the collective invasion of SACC remain unclear. The present study revealed that Dll4 expression was higher at the invasive front of SACC, and that this upregulation was associated with solid tumour type, high TNM grade, and high rates of metastasis and recurrence. Furthermore, the expression levels of Notch1 and Dll4 were positively correlated at the invasive front, and a three-dimensional (3D) culture model revealed that leader cells showed high expression of Dll4, while follower cells showed high expression of Notch1. Moreover, silencing of Dll4 expression using small interfering RNA reduced the migration, invasion, and collective invasion of SACC cells, and these abilities were rescued by Notch1 overexpression. Finally, SACC collective invasion was increased via the Dll4/Notch1 signalling pathway in experiments that involved a stiff 3D gel, hypoxia and co-culture with human endothelial cells. These findings indicated that the Dll4/Notch1 signalling pathway may be involved in the collective invasion of SACC, which may help to provide possible targets for the treatment of SACC.

The activation of CXCL12/CXCR4 axis participated in the progression of multiple cancers, but potential effect in terms of perineural invasion (PNI) in SACC remained ambiguous. In this study, we identified that CXCL12 substantially expressed in nerve cells. CXCR4 strikingly expressed in tumour cells, and CXCR4 expression was closely associated with the level of EMT‐associated proteins and Schwann cell hallmarks at nerve invasion frontier in SACC. Activation of CXCL12/CXCR4 axis could promote PNI and up‐regulate relative genes of EMT and Schwann cell hallmarks both in vitro and in vivo, which could be inhibited by Twist silence. After overexpressing S100A4, the impaired PNI ability of SACC cells induced by Twist knockdown was significantly reversed, and pseudo foot was visualized frequently. Collectively, the results indicated that CXCL12/CXCR4 might promote PNI by provoking the tumour cell to differentiate towards Schwann‐like cell through Twist/S100A4 axis in SACC.

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BackgroundTumour vascular normalisation therapy advocates a balance between pro‐angiogenic factors and anti‐angiogenic factors in tumours. Artemisinin (ART), which is derived from traditional Chinese medicine, has been shown to inhibit tumour growth; however, the relationship between ART and tumour vascular normalisation in oral squamous cell carcinoma (OSCC) has not been previously reported.MethodsDifferent concentrations(0 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg)of ART were used to treat the xenograft nude mice model of OSCC. The effects of ART on migration and proliferation of OSCC and human umbilical vein endothelial cells (HUVEC) cells were detected by scratch assay and CCK‐8 assay. OSCC cells with macrophage migration inhibitory factor (MIF) silenced were constructed to explore the effect of MIF.ResultsTreatment with ART inhibited the growth and angiogenesis of OSCC xenografts in nude mice and downregulated vascular endothelial growth factor (VEGF), IL‐8, and MIF expression levels. ART reduced the proliferation, migration, and tube formation of HUVEC, as well as the expression of VEGFR1 and VEGFR2. When the dose of ART was 50 mg/kg, vascular normalisation of OSCC xenografts was induced. Moreover, VEGF and IL‐8 were needed in rhMIF restoring tumour growth and inhibit vascular normalisation after the addition of rhMIF to ART‐treated cells.ConclusionArtemisinin might induce vascular normalisation and inhibit tumour growth in OSCC through the MIF‐signalling pathway.