Glioblastoma multiforme (GBM) are the most malignant among brain tumors. They are frequently refractory to chemotherapy and radiotherapy with mean patient survival of approximately 6 months, despite surgical intervention. The highly glycolytic nature of glioblastomas describes their propensity to metabolize glucose to lactic acid at an elevated rate. To survive, GBMs efflux lactic acid to the tumor microenvironment through transmembrane transporters denoted monocarboxylate transporters (MCTs). We hypothesized that inhibition of MCT function would impair the glycolytic metabolism and affect both glioma invasiveness and survival. We examined the effect on invasiveness with α-cyano-4-hydroxy-cinnamic acid (ACCA, 4CIN, CHCA), a small-molecule inhibitor of lactate transport, through Matrigel-based and organotypic (brain) slice culture invasive assays using U87-MG and U251-MG glioma cells. We then conducted studies in immunodeficient rats by stereotaxic intracranial implantation of the glioma cells followed by programmed orthotopic application of ACCA through osmotic pumps. Effect on the implanted tumor was monitored by small-animal magnetic resonance imaging. Our assays indicated that glioma invasion was markedly impaired when lactate efflux was inhibited. Convection-enhanced delivery of inhibitor to the tumor bed caused tumor necrosis, with 50% of the animals surviving beyond the experimental end points (3 months after inhibitor exhaustion). Most importantly, control animals did not display any adverse neurologic effects during orthotopic administration of ACCA to brain through programmed delivery. These results indicate the clinical potential of targeting lactate efflux in glioma through delivery of small-molecule inhibitors of MCTs either to the tumor bed or to the postsurgical resection cavity.

Head and neck squamous cell carcinoma (HNSCC) is one of the main malignant tumours affecting human health, mainly due to delayed diagnosis and high invasiveness. Extracellular vehicles (EVs) are membranous vesicles released by cells into the extracellular matrix that carry important signalling molecules and stably and widely exist in various body fluids, such as plasma, saliva, cerebrospinal fluid, breast milk, urine, semen, lymphatic fluid, synovial fluid, amniotic fluid, and sputum. EVs transport almost all types of bioactive molecules (DNA, mRNAs, microRNAs (miRNAs), proteins, metabolites, and even pharmacological compounds). These “cargoes” can act on recipient cells, reshaping the surrounding microenvironment and altering distant targets, ultimately affecting their biological behaviour. The extensive exploration of EVs has deepened our comprehensive understanding of HNSCC biology. In this review, we not only summarized the effect of HNSCC-derived EVs on the tumour microenvironment but also described the role of microenvironment-derived EVs in HNSCC and discussed how the “mutual dialogue” between the tumour and microenvironment mediates the growth, metastasis, angiogenesis, immune escape, and drug resistance of tumours. Finally, the clinical application of EVS in HNSCC was assessed.

Aberrant expression or mutation of the Septin gene family is closely associated with cancer progression, and septin 2 (SEPT2) exerts its tumor‐promoting effects in multiple cancers, but its role in regulating laryngeal squamous cell carcinoma (LSCC) progression and drug resistance has not been investigated. Based on the published data, the present study identified that SEPT2 promoted cancer progression and increased cisplatin‐resistance in LSCC, and a novel LncRNA FGD5‐AS1/miR‐497‐5p axis was crucial for this process. Mechanistically, SEPT2 tended to be enriched in LSCC tissues and cells, and knock‐down of SEPT2 inhibited cell proliferation, viability, migration, and tumorigenesis in LSCC cells in vitro and in vivo. Aside from that, SEPT2 overexpression increased cisplatin resistance in LSCC cells. Next, by conducting the dual‐luciferase reporter gene system assay, we identified that the LncRNA FGD5‐AS1/miR‐497‐5p axis regulated SEPT2 in LSCC. Specifically, LncRNA FGD5‐AS1 sponged miR‐497‐5p to upregulate SEPT2 in LSCC cells in a competing endogenous RNA (ceRNA) mechanisms‐dependent manner. Interestingly, upregulated LncRNA FGD5‐AS1 and downregulated miR‐497‐5p were observed in LSCC tissues and cells, and LncRNA FGD5‐AS1 ablation inhibited cancer progression. Also, LncRNA FGD5‐AS1 overexpression increased cisplatin‐resistance in LSCC by modulating the miR‐497‐5p/SEPT2 axis. Collectively, we conclude that targeting the LncRNA FGD5‐AS1/miR‐497‐5p/SEPT2 signaling cascade may be an alternative strategy to treat LSCC in the clinic.

The aim of the present study was to examine the potential role of human heparin-binding epidermal growth factor (HB-EGF) secreted by M2 macrophages in the development of radioresistance in head and neck squamous cell carcinoma (HNSCC). Immunohistochemistry was used to detect radiosensitivity in human papilloma virus (HPV)-positive and HPV-negative HNSCC tissues and immunohistochemical staining with specific antibodies for macrophage surface markers was used to assess the infiltration of M1 and M2 macrophages in HPV-positive and-negative HNSCC tissues. The expression of HB-EGF in HPV-positive and-negative HNSCC tissues was determined by multi-cytokine detection in order to determine the relationship between HB-EGF and radiosensitivity. M1 and M2 macrophages were co-cultured with the HNSCC cell line CAL27 and treated with HB-EGF and its neutralizing antibodies to assess radiation sensitivity. Finally, the major DNA double-strand break repair pathways required for the activation of HB-EGF and promotion of epidermal growth factor receptor (EGFR) were identified. The results revealed that radiosensitivity was higher in HPV-positive HNSCC compared with HPV-negative. There was a higher infiltration of M2 macrophages in HPV-negative HNSCC, which were revealed as the main source of HB-EGF secretion. Furthermore, it was determined that overexpression of HB-EGF induced radioresistance in HPV-negative HNSCC. HB-EGF promoted the activation of the non-homologous end-joining pathway by activating EGFR. To the best of our knowledge, this is the first study to demonstrate the association between HB-EGF and radiosensitivity in HNSCC. These results indicated that the secretion of HB-EGF by M2 macrophages could induce radioresistance of HPV-negative HNSCC.