ABSTRACT
High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.
Subject(s)
Extracellular Matrix/metabolism , Animals , Cell Line , Cell Surface Display Techniques , Contrast Media/metabolism , Female , Ferric Compounds/metabolism , Gadolinium/metabolism , Heterocyclic Compounds/metabolism , Humans , Male , Mice , Nanoparticles/metabolism , Organometallic Compounds/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Tumour necrosis factor alpha (TNF-alpha) is an inflammatory cytokine primarily produced by macrophages. It is a unique protein with contradictive properties; it has the ability to induce cellular death by apoptosis and oncosis, but can also induce cellular regeneration and growth. Genetic polymorphisms in TNFA have been associated with poor outcome in some surgical patients and this may provide a useful tool to screen for high-risk patients. Manipulating TNF-alpha levels in vivo may influence the progression of several pathological conditions. TNF-alpha has anti-cancer properties and has been used to treat cancer patients. Treatment with anti-TNF-alpha drugs and antibodies has been successful in rheumatoid arthritis and other autoimmune diseases, but disappointing in the management of patients with sepsis. This review article focuses on the biological activities, genetic polymorphism of TNFA and the role of TNF-alpha and anti-TNF-alpha treatments, based on animal experiments and clinical trials.
Subject(s)
Inflammation/metabolism , Inflammation/surgery , Tumor Necrosis Factor-alpha/metabolism , Animals , Biomarkers/metabolism , DNA/genetics , Humans , Macrophages/metabolism , Polymorphism, Genetic , Tumor Necrosis Factor-alpha/geneticsABSTRACT
The restoration of blood flow to ischemic tissues causes additional damage, which is termed reperfusion injury. All tissues are susceptible to reperfusion injury, but this susceptibility varies between tissues. Reperfusion has wide clinical relevance. It influences the outcome of patients after myocardial infarction, stroke, organ transplantation, and cardiovascular surgery. Advances in the treatment of reperfusion injury have created an opportunity for plastic surgeons to apply these treatments to flaps and reimplanted tissues. The main putative mechanisms identified in animal models involve leukocyte-endothelium interactions, reactive oxygen species, and the complement system. However, it has become evident that these fundamental biological systems are controlled by many interrelated pathways. Attempts to bypass this complexity have led to a search for the early "upstream" initiating events, rather than the "downstream" cascading events. This contrasts with current clinical efforts that are directed toward hypothermia, intraarterial flushing, and preconditioning. This article outlines the molecular and cellular events that occur during reperfusion injury and then reviews the efforts that have been made to exploit this knowledge for clinical advantage.
