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Nanoparticle-based anticancer medications were first approved for cancer treatment almost 2 decades ago. Patients benefit from these approaches because of the targeted-drug delivery and reduced toxicity, however, like other therapies, adverse reactions often limit their use. These reactions are linked to the interactions of nanoparticles with the immune system, including the activation of complement. This activation can cause well-characterized acute inflammatory reactions mediated by complement effectors. However, the long-term implications of chronic complement activation on the efficacy of drugs carried by nanoparticles remain obscured. The recent discovery of protumor roles of complement raises the possibility that nanoparticle-induced complement activation may actually reduce antitumor efficacy of drugs carried by nanoparticles. We discuss here the initial evidence supporting this notion. Better understanding of the complex interactions between nanoparticles, complement, and the tumor microenvironment appears to be critical for development of nanoparticle-based anticancer therapies that are safer and more efficacious. [ABSTRACT FROM AUTHOR]

Complement was initially discovered as an assembly of plasma proteins “complementing” the cytolytic activity of antibodies. However, our current knowledge places this complex system of several plasma proteins, receptors, and regulators in the center of innate immunity as a bridge between the initial innate responses and adaptive immune reactions. Consequently, complement appears to be pivotal for elimination of pathogens, not only as an early response defense, but by directing the subsequent adaptive immune response. The discovery of functional intracellular complement and its roles in cellular metabolism opened novel avenues for research and potential therapeutic implications. The recent studies demonstrating immunoregulatory functions of complement in the tumor microenvironment and the premetastatic niche shifted the paradigm on our understanding of functions of the complement system in regulating immunity. Several complement proteins, through their interaction with cells in the tumor microenvironment and in metastasis-targeted organs, contribute to modulating tumor growth, antitumor immunity, angiogenesis, and therefore, the overall progression of malignancy and, perhaps, responsiveness of cancer to different therapies. Here, we focus on recent progress in our understanding of immunostimulatory vs. immunoregulatory functions of complement and potential applications of these findings to the design of novel therapies for cancer patients. [ABSTRACT FROM AUTHOR]

The complement system is one of the key players in the defence against infections. Its activation during the innate immune response leads to the generation of several proteins that contribute to the lysis and opsonization of microorganisms, regulate inflammatory reactions and bridge innate immunity with the subsequent adaptive immune response. Complement is also activated in overwhelming bacterial infections that lead to sepsis, and its protective functions play a role in this frequently lethal disorder. However, despite its role in protection, complement can also contribute to the development of severe complications that significantly worsen the prognosis of septic patients. Therefore, an understanding of the mechanisms involved in the activation of complement during sepsis is essential to our efforts to introduce rational therapies targeting complement to the treatment of patients suffering from this condition. This review presents a current view of the mechanisms involved in the activation of complement in sepsis, in the context of the multiple interactions between complement and other biological systems that are involved in the pathogenesis of this disorder. [ABSTRACT FROM AUTHOR]

Abstract: The anatomic localization and unique vasculature of the liver, along with its cell properties, make this organ an efficient line of defense against blood-borne infections, either systemic or arising in the abdomen. Liver cells can modify the host immune response by releasing immunomodulatory molecules, interacting with cells of the immune system and acting as scavengers for inflammatory mediators. However, these defensive functions do not protect the liver itself from the severe injury that may be caused by pathogens, toxins or pollutant xenobiotics. Therefore, the mammalian liver has developed a unique adaptation in the form of an astonishing regenerative capability. The complexity of regeneration requires a well-orchestrated system to control this process. Growing evidence suggest the importance of immune mechanisms as a part of this system. It seems likely that the mechanisms that serve to eliminate infections (and may simultaneously cause liver injury) are also active in restoring the structural and functional integrity of the damaged liver. [Copyright &y& Elsevier]

The link of the complement system to angiogenesis has remained circumstantial and speculative for several years. Perhaps the most clinically relevant example of possible involvement of complement in pathological neovascularization is age-related macular degeneration. Recent studies, however, provide more direct and experimental evidence that indeed the complement system regulates physiological and pathological angiogenesis in models of wound healing, retinal regeneration, age-related macular degeneration, and cancer. Interestingly, complement-dependent mechanisms involved in angiogenesis are very much context dependent, including anti- and proangiogenic functions. Here, we discuss these new developments that place complement among other important regulators of homeostatic and pathological angiogenesis, and we provide the perspective on how these newly discovered complement functions can be targeted for therapy. [ABSTRACT FROM AUTHOR]