Exosomes are 30–100 nm microvesicles which contain complex cellular signals of RNA, protein and lipids. Because of this, exosomes are implicated as having limitless therapeutic potential for the treatment of cancer, pregnancy complications, infections, and autoimmune diseases. To date we know a considerable amount about exosome biogenesis and secretion, but there is a paucity of data regarding the uptake of exosomes by immune and non-immune cell types (e.g., cancer cells) and the internal signalling pathways by which these exosomes elicit a cellular response. Answering these questions is of paramount importance.

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response—(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

Objective. The aim of this study was to investigate the effect of endogenous matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) on the invasive characteristics of RA synovial fibroblasts. Methods. Synovial fibroblasts isolated from patients with RA or OA were treated with MMP small interfering RNA (siRNA), inhibitors and recombinant proteins or TNF-α, with or without cartilage explants. Cell viability and proliferation were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and 5-bromo-2-deoxyuridine (BrdU) proliferation assays, respectively; apoptosis by an in situ cell death detection kit; migration and invasion by CytoSelect invasion assay, scratch migration and collagen gel assays; cartilage degradation by 1,9-dimethylmethylene blue assay; and inflammatory mediators and MMPs by ELISA, western blot and zymography. Results. MMP-2 was expressed by both OA and RA synovial fibroblasts, whereas only RA synovial fibroblasts expressed MMP-9. Suppressing MMP-2 or MMP-9 reduced RA synovial fibroblast proliferation equally. However, MMP-9 siRNA had greater effects compared with MMP-2 siRNA on promoting apoptosis and suppressing RA synovial fibroblast viability, migration and invasion. Suppression/inhibition of MMP-9 also decreased the production of IL-1β, IL-6, IL-8 and TNF-α, inactivated nuclear factor κB (NF-κB), extracellular signal-regulated kinase (ERK) and c-Jun NH₂-terminal kinase (JNK) and suppressed RA synovial fibroblast-mediated cartilage degradation. In contrast, suppression/inhibition of MMP-2 stimulated TNF-α and IL-17 secretion and activated NF-κB, while recombinant MMP-2 (rMMP-2) inactivated NF-κB and suppressed RA synovial fibroblast-mediated cartilage degradation. Results using specific inhibitors and rMMPs provided supportive evidence for the siRNA results. Conclusion. Endogenous MMP-2 or MMP-9 contribute to RA synovial fibroblast survival, proliferation, migration and invasion, with MMP-9 having more potent effects. Additionally, MMP-9 stimulates RA synovial fibroblast-mediated inflammation and degradation of cartilage, whereas MMP-2 inhibits these parameters. Overall, our data indicate that MMP-9 derived from RA synovial fibroblasts may directly contribute to joint destruction in RA.

In this work, we brought together two existing clinical techniques used in cancer treatment—X-ray radiation and photodynamic therapy (PDT), whose combination termed X-PDT uniquely allows PDT to be therapeutically effective in deep tissue. To this end, we developed mitochondrially targeted biodegradable polymer poly(lactic-co-glycolic acid) nanocarriers incorporating a photosensitizer verteporfin, ultrasmall (2–5 nm) gold nanoparticles as radiation enhancers, and triphenylphosphonium acting as the mitochondrial targeting moiety. The average size of the nanocarriers was about 160 nm. Upon X-ray radiation our nanocarriers generated cytotoxic amounts of singlet oxygen within the mitochondria, triggering the loss of membrane potential and mitochondria-related apoptosis of cancer cells. Our X-PDT strategy effectively controlled tumor growth with only a fraction of radiotherapy dose (4 Gy) and improved the survival rate of a mouse model bearing colorectal cancer cells. In vivo data indicate that our X-PDT treatment is cytoreductive, antiproliferative, and profibrotic. The nanocarriers induce radiosensitization effectively, which makes it possible to amplify the effects of radiation. A radiation dose of 4 Gy combined with our nanocarriers allows equivalent control of tumor growth as 12 Gy of radiation, but with greatly reduced radiation side effects (significant weight loss and resultant death).

As the cornerstone of high-grade glioma (HGG) treatment, radiotherapy temporarily controls tumor cells via inducing oxidative stress and subsequent DNA breaks. However, almost all HGGs recur within months. Therefore, it is important to understand the underlying mechanisms of radioresistance, so that novel strategies can be developed to improve the effectiveness of radiotherapy. While currently poorly understood, radioresistance appears to be predominantly driven by altered metabolism and hypoxia. Glucose is a central macronutrient, and its metabolism is rewired in HGG cells, increasing glycolytic flux to produce energy and essential metabolic intermediates, known as the Warburg effect. This altered metabolism in HGG cells not only supports cell proliferation and invasiveness, but it also contributes significantly to radioresistance. Several metabolic drugs have been used as a novel approach to improve the radiosensitivity of HGGs, including dichloroacetate (DCA), a small molecule used to treat children with congenital mitochondrial disorders. DCA reverses the Warburg effect by inhibiting pyruvate dehydrogenase kinases, which subsequently activates mitochondrial oxidative phosphorylation at the expense of glycolysis. This effect is thought to block the growth advantage of HGGs and improve the radiosensitivity of HGG cells. This review highlights the main features of altered glucose metabolism in HGG cells as a contributor to radioresistance and describes the mechanism of action of DCA. Furthermore, we will summarize recent advances in DCA’s pre-clinical and clinical studies as a radiosensitizer and address how these scientific findings can be translated into clinical practice to improve the management of HGG patients.

Glioblastoma (GBM) is the most aggressive adult glioma with a median survival of 14 months. While standard treatments (safe maximal resection, radiation, and temozolomide chemotherapy) have increased the median survival in favorable O(6)-methylguanine-DNA methyltransferase (MGMT)-methylated GBM (~21 months), a large proportion of patients experience a highly debilitating and rapidly fatal disease. This study examined GBM cellular energetic pathways and blockade using repurposed drugs: the glycolytic inhibitor, namely dicholoroacetate (DCA), and the partial fatty acid oxidation (FAO) inhibitor, namely ranolazine (Rano). Gene expression data show that GBM subtypes have similar glucose and FAO pathways, and GBM tumors have significant upregulation of enzymes in both pathways, compared to normal brain tissue (p < 0.01). DCA and the DCA/Rano combination showed reduced colony-forming activity of GBM and increased oxidative stress, DNA damage, autophagy, and apoptosis in vitro. In the orthotopic Gl261 and CT2A syngeneic murine models of GBM, DCA, Rano, and DCA/Rano increased median survival and induced focal tumor necrosis and hemorrhage. In conclusion, dual targeting of glycolytic and FAO metabolic pathways provides a viable treatment that warrants further investigation concurrently or as an adjuvant to standard chemoradiation for GBM.