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Sonic hedgehog (Shh)-driven medulloblastoma (Shh MB) cells are dependent on constitutive Shh signaling, but targeted treatment of Shh MB has been ineffective due to drug resistance. The purpose of this study was to address the critical role of signal transducer and activator of transcription 3 (STAT3) in Shh signaling and drug resistance in Shh MB cells. Herein, we show that STAT3 is required for Smoothened (Smo)-dependent Shh signaling and, in turn, is reciprocally regulated by Shh signaling, and demonstrate that STAT3 activity is critical for expression of HCK proto-oncogene, Src family tyrosine kinase (Hck) in Shh MB. We also demonstrate that maintained STAT3 activity suppresses p21 expression and promotes colony formation of Shh MB cells, whereas dual treatment with inhibitors of both Smo and STAT3 results in marked synergistic killing and overcomes drug resistance in vitro of Smo-antagonist-resistant Shh MB cells. Finally, STAT3 inhibitor treatment significantly prevents in vivo tumor formation in genetically engineered Shh MB mice. Collectively, we show that STAT3 is necessary to maintain Shh signaling, and thus is a potential therapeutic target to treat Shh MB and overcome anti-Smo drug resistance.

Purpose To investigate the ability of radiation to stimulate exosome release from melanoma cells and to characterize the resulting exosome-containing vesicle preparations for their ability to promote a host antitumor immune response. Materials and Methods Cultured B16F10 murine melanoma cells or tumors were irradiated, and secreted extracellular vesicles were isolated and characterized. The exosome-containing vesicle preparations were injected into fresh tumors in syngeneic mice, and tumor growth and infiltrating T cells and natural killer (NK) cells were characterized. Results Irradiation stimulated exosome release from B16F10 murine melanoma cells. Exosome preparations from irradiated cell culture supernatants were biologically active, as demonstrated by uptake into recipient cells and by the ability to induce dendritic cell maturation and activation in vitro. Intratumoral injection significantly delayed tumor growth in vivo, whereas injection of similar preparations from non irradiated cells had no effect. The antitumor effect was correlated to an increase in interferon gamma–producing tumor-infiltrating NK cells. Pretreatment of the host mice with anti-NK cell antibodies abolished the effect, whereas pretreatment with anti-CD8+ T-cell antibodies did not. Conclusion Exosomes from irradiated cells, or synthetic mimics, might provide an effective strategy for potentiation of NK cell–mediated host antitumor immunity.

Participants in deep space missions face protracted exposure to galactic cosmic radiation (GCR). In this setting, lung cancer is a significant component of the overall risk of radiation-exposure induced death. Here we investigate persistent effects of GCR exposure on DNA repair capacity in lung-derived epithelial cells, using an enzyme-stimulated chromosomal rearrangement as an endpoint. Replicate cell cultures were irradiated with energetic 48Ti ions (a GCR component) or reference γ-rays. After a six-day recovery, they were challenged by expression of a Cas9/sgRNA pair that creates double-strand breaks simultaneously in the EML4 and ALK loci, misjoining of which creates an EML4-ALK fusion oncogene. Misjoining was significantly elevated in 48Ti-irradiated populations, relative to the baseline rate in mock-irradiated controls. The effect was not seen in γ-ray irradiated populations exposed to equal or higher radiation doses. Sequence analysis of the EML4-ALK joints from 48Ti-irradiated cultures showed that they were far more likely to contain deletions, sometimes flanked by short microhomologies, than equivalent samples from mock-irradiated cultures, consistent with a shift toward error-prone alternative nonhomologous end joining repair. Results suggest a potential mechanism by which a persistent physiological effect of GCR exposure may increase lung cancer risk.

Worldwide, HCC is considered as one of the major cancer-related deaths. Tumor-derived exosomes play a potential role in HCC by mediating intracellular communication, immune responses, and antigen presentation. Exosomes communicate between the cells using proteins, mRNA, miRNA, lipids, and DNA present in their cargo. Increased understanding of exosomes and their role in cancer could lead to a powerful strategy for the treatment of HCC. In this chapter, we summarize the role of exosomes in cancer initiation, progression, and metastasis and in NF-κB through its miRNA. MiRNA derived from exosomes of HCC cells can enhance and modulate TAK1 and downstream signaling in recipient cells. Exosomes have a greater potential in the near future making it as prognostic biomarkers; they can serve in anticancer drug resistance and immunotherapy in the near future.

The transcription factor STAT3 important for regulating factors that involve in the modulation of gene expression. The factors such as growth factors and cytokines regulate homeostasis of both epithelial and stromal cells. Deregulation of STAT3 activation is important in the initiation of transformation of various cancers that are epithelial in origin. This chapter mainly focuses on STAT3 activation in gastric cancer and its progression with the activation of cytokines; it also discusses how STAT3 associated with progression of gastric cancer. The studies have shown the association of deregulated JAK/STAT in the development of solid cancers especially in gastric cancer. Therapeutic use of STAT3 may prevent the development of gastric cancer. Inhibitors of STAT3 are emerging as a potent drug in treatment options. STAT3 inhibitors are under evaluation in various clinical trials, showing promising results for the treatment.

Lung malignancy is the foremost cause of cancer-related deaths globally and is frequently related to long-term tobacco smoking. Recent studies reveal that the expression of matrix metalloproteinases (MMPs) is extremely high in lung tumors compared with non-malignant lung tissue. MMPs are zinc-dependent proteases and are involved in the degradation of extracellular matrix (ECM). Several investigations have shown that MMPs manipulate the activity of non-ECM molecules, including cytokines, growth factors and receptors that control the tumor microenvironment. In this review, we have summarized and critically reviewed the published works on the role of MMPs in non-small-cell lung cancer. We have also explored the structure of MMPs, their various types and roles in lung cancer metastasis including invasion, migration and angiogenesis.

e21535Background: The abscopal (literally, “out of field”) effect is seen when radiotherapy targeted to one tumor site causes regression of distant metastases. The abscopal effect may be the clinic...