Previous studies have demonstrated that senescent cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), unlike non-senescent CAFs from genetically stable carcinomas (GS-OSCC), promoted keratinocyte invasion in vitro in a paracrine manner. The mechanism by which this occurs is unclear. Previous work to characterise the senescent-associated secretory phenotype (SASP) has used antibody arrays, technology that is limited by the availability of suitable antibodies. To extend this work in an unbiased manner, we used 2D gel electrophoresis and mass spectroscopy for protein identification. Matrix metalloproteinases (MMPs) were investigated by gelatin zymography and western blotting. Neutralising antibodies were used to block key molecules in the functional assays of keratinocyte adhesion and invasion. Among a variety of proteins that were differentially expressed between CAFs from GU-OSCC and GS-OSCC, MMP-2 was a major constituent of senescent CAF-CM derived from GU-OSCC. The presence of active MMP-2 was confirmed by gelatine zymography. MMP-2 derived from senescent CAF-CM induced keratinocyte dis-cohesion and epithelial invasion into collagen gels in a TGF-β-dependent manner. Senescent CAFs from GU-OSCC promote a more aggressive oral cancer phenotype by production of active MMP-2, disruption of epithelial adhesion and induction of keratinocyte invasion.

Oral mucositis is a common and most debilitating complication associated with cancer therapy. Despite the significant clinical and economic impact of this condition, there is little to offer to patients with oral mucositis, and the medications used in its management are generally only palliative. Given that mucositis is ultimately a predictable and, therefore, potentially preventable condition, in this study we appraised the scientific literature to evaluate effective methods of prevention that have been tested in randomised controlled trials (RCTs). Published high-level evidence shows that multiple preventative methods are potentially effective in the prevention of oral mucositis induced by radiotherapy, chemotherapy, or both. Anti-inflammatory medications (including benzydamine), growth factors and cytokines (including palifermin), cryotherapy, laser-and-light therapy, herbal medicines and supplements, and mucoprotective agents (including oral pilocarpine) showed some degree of efficacy in preventing/reducing the severity of mucositis with most anticancer treatments. Allopurinol was potentially effective in the prevention of radiotherapy-induced oral mucositis; antimicrobial mouthwash and erythropoietin mouthwash were associated with a lower risk of development of severe oral mucositis induced by chemotherapy. The results of our review may assist in highlighting the efficacy and testing the effectiveness of low-cost, safe preventative measures for oral mucositis in cancer patients.

Hyaluronic acid (HA) receptor CD44 is widely used for identifying cancer stem cells and its activation promotes stemness. Recent evidence shows that overexpression of CD44 is associated with poor prognosis in most human cancers and mediates therapy resistance. For these reasons, in recent years, CD44 has become a treatment target in precision oncology, often via HA-conjugated antineoplastic drugs. Importantly, HA molecules of different sizes have a dual effect and, therefore, may enhance or attenuate the CD44-mediated signaling pathways, as they compete with endogenous HA for binding to the receptors. The magnitude of these effects could be crucial for cancer progression, as well as for driving the inflammatory response in the tumor microenvironment. The increasingly common use of HA-conjugated drugs in oncology, as well as HA-based compounds as adjuvants in cancer treatment, adds further complexity to the understanding of the net effect of hyaluronan-CD44 activation in cancers. In this review, I focus on the significance of CD44 in malignancy and discuss the dichotomous function of the hyaluronan/CD44 axis in cancer progression.