Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to ...damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.
Cancer development and its response to therapy are strongly influenced by innate and adaptive immunity, which either promote or attenuate tumorigenesis and can have opposing effects on therapeutic ...outcome. Chronic inflammation promotes tumor development, progression, and metastatic dissemination, as well as treatment resistance. However, cancer development and malignant progression are also associated with accumulation of genetic alterations and loss of normal regulatory processes, which cause expression of tumor-specific antigens and tumor-associated antigens (TAAs) that can activate antitumor immune responses. Although signals that trigger acute inflammatory reactions often stimulate dendritic cell maturation and antigen presentation, chronic inflammation can be immunosuppressive. This antagonism between inflammation and immunity also affects the outcome of cancer treatment and needs to be considered when designing new therapeutic approaches.
A potential link between inflammation and cancer has been suspected for over a century, but the exact molecular mechanisms connecting the two remained nebulous. We proposed that NF-κB transcription ...factors regulated via the IκB kinase （IKK） complex play a critical role in coupling inflammation and cancer and have set out to test this hypothesis in mouse models of cancer. Using mice bearing mutations in the genes coding for the IKKβ and IKKα catalytic subunits we obtained evidence supporting a critical role for IKKβ in tumor promotion and more recently identified the involvement of IKKα in metastatogenesis. Whereas the major pro-tumorigenic function of IKKβ is mediated via NF- κB, the proetastatic function of IKKα is NF-κB-independent. In addition to illustrating the critical roles of the two IKK molecules in linking inflammation and cancer and providing an explanation for increased cancer risk in response to persistent infections and inflammation, these results also identify new targets for development of novel anti-cancer therapies and preventive strategies. Instead of targeting the cancer cell itself, as done by conventional anti-cancer drugs, the new therapeutics will target processes that occur within inflammatory cells that are essential for cancer development and progression. Unlike cancer cells, inflammatory cells retain a normal and stable genome and therefore are unlikely to become genetically resistant to therapeutic intervention.
Highlights • The IL-6 family of cytokines includes IL-6, IL-11, IL-27, IL-31, LIF, OSM, CNTF, CT-1 and CLC. • The IL-6 family of cytokines regulates cell proliferation, survival, migration, invasion, ...metastasis, angiogenesis and inflammation via gp130. • The JAK-STAT3 pathway is the major pathway downstream of gp130 signaling. • IL-6 and IL-11 are highly up-regulated in many cancers and are important mediators linking inflammation and cancer. • IL-6 and IL-11 are potential therapeutic and preventive targets as well as prognostic factors in cancer.
The immune system has crucial roles in cancer development and treatment. Whereas adaptive immunity can prevent or constrain cancer through immunosurveillance, innate immunity and inflammation often ...promote tumorigenesis and malignant progression of nascent cancer. The past decade has witnessed the translation of knowledge derived from preclinical studies of antitumour immunity into clinically effective, approved immunotherapies for cancer. By contrast, the successful implementation of treatments that target cancer-associated inflammation is still awaited. Anti-inflammatory agents have the potential to not only prevent or delay cancer onset but also to improve the efficacy of conventional therapeutics and next-generation immunotherapies. Herein, we review the current clinical advances and experimental findings supporting the utility of an anti-inflammatory approach to the treatment of solid malignancies. Gaining a better mechanistic understanding of the mode of action of anti-inflammatory agents and designing more effective treatment combinations would advance the clinical application of this therapeutic approach.
Autophagy, a cellular waste disposal process, has well-established tumor-suppressive properties. New studies indicate that, in addition to its cell-autonomous anti-tumorigenic functions, autophagy ...inhibits cancer development by orchestrating inflammation and immunity. While attenuating tumor-promoting inflammation, autophagy enhances the processing and presentation of tumor antigens and thereby stimulates anti-tumor immunity. Although cancer cells can escape immunosurveillance by tuning down autophagy, certain chemotherapeutic agents with immunogenic properties may enhance anti-tumor immunity by inducing autophagic cell death. Understanding the intricate and complex relationships within this troika and how they are affected by autophagy enhancing drugs should improve the efficacy of cancer immunotherapy.
Understanding the complex relationships between autophagy, inflammation, and immunity, as well as the multiple ways they are affected by autophagy-enhancing drugs, may help to improve the efficacy of cancer immunotherapy.
Abstract
Nuclear factor erythroid 2‐related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation ...may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.
Basic and clinical studies have demonstrated the efficacy of immunotherapy, a technical and conceptual breakthrough that has revolutionised cancer treatment. Hepatocellular carcinoma (HCC), a deadly ...malignancy with aetiologic diversity and a chronic course, is strongly influenced by the immune system, and was recently found to partially benefit from immune-checkpoint inhibitor therapy. Notably, HCC onco-immunology depends on diverse genetic and environmental factors that together shape cancer-promoting inflammation and immune dysfunction – critical processes that control HCC malignant progression and response to therapy. Herein, we summarise the current understanding of liver and HCC onco-immunology obtained through basic studies with mouse models and clinical practice in humans. In particular, we discuss preclinical and clinical findings that implicate immunomodulation as a major factor in HCC development and explain the basis for HCC-targeting immunotherapy.
Adaptor proteins participate in selective autophagy, which is critical for cellular detoxification and stress relief. However, new evidence supports an autophagy-independent key role of the adaptor ...p62 (encoded by the gene Sqstm1) in signaling functions central to tumor initiation in the epithelium and suppression of tumor progression in the stroma.
New evidence supports an autophagy-independent key role of the adaptor p62 in cancer.
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