Dr. D. Browning
Mechanisms of Disease, Lecture 16a
March 7th, 2006
- Inflammation and the Immune Response
- Cellular Mediators of Inflammation
- Cancer and Tumor Progression
- Inflammation and Cancer
- Tumor Progression
- Myeloid stem cells produce most of the inflammatory apparatus.
- Macrophages are the major effector cell in inflammation
- Macrophages bear a large complement of "Toll-like" receptors, including receptors for bacterial components such as peptidoglycan, and for compounds released by dying cells.
- When macrophages encounter invading organisms such as bacteria, they release cytokines (IL-1β and TNF-α) which recruit leukocytes to the area.
- Another chemokine, IL-8, is important in allowing extravasation of inflammatory leukocytes, by encouraging them to bind to endothelium and roll along it.
- Activated inflammatory leukocytes degranulate, secreting cytokines, producing reactive oxygen species, and become chemotactic and phagocytic.
- Cells involved in wound healing are, in usual order of recruitment, platelets, neutrophils, macrophages, and lymphocytes, which finally induce actual healing by fibroblasts and capillaries.
- Early in inflammation, pro-inflammatory cytokines escalate immune responses.
- Later in inflammation, anti-inflammatory cytokines reduce and stop the inflammatory response.
- Tissue-resident macrophages detect invading organisms or cell debris and become activated.
- Macrophage-derived cytokines and chemokines orchestrate the recruitment and activation of other leukocytes to the area.
- Activated phagocytes, mainly neutrophils aggressively fight the infection with ROSs and enzymes.
- Near inflammatory resolution, growth factors contribute to granulation, or tissue regeneration by attracting fibroblasts and endothelium to the wound site.
- Anti-inflammatory cytokines stop the reaction when it is no longer necessary.
- Tumor initiation often involves genes which regulate apoptosis, or genes which are involved in growth factor signal transduction.
- Pro-apoptotic genes are called tumor suppressors.
- Mutations in growth factors and components of their signal cascades, such as ras, can allow cells to become less dependent on external signals for their own growth.
- In colorectal cancer, a well-defined pathway exists for tumor formation.
- An APC mutation produces a hyperproliferative phenotype (aberrant crypts).
- A second "hit", often in ras, destabilizes the genome and gives the cells even more of a propensity to divide (early and intermediate adenoma).
- Mutations in Smad2/4 and p53 are usually necessary to allow tumor formation from the adenoma, since they are involved in apoptosis, and cells with such mutations can become immune to cell death (late adenoma and carcinoma).
- Metastatic tumors require mutations in E-cadherin and other adherence-modulating genes to allow them to easily detach and roam throughout the body, displaying a macrophage-like or amoeboid phenotype.
- Reactive nitrogen species (RNSs), especially large concentrations (high micromolar levels) of nitric oxide produced by macrophages, can be mutagenic.
- Simple inflammatory responses, especially if prolonged, can precipitate cancer, due to large amounts of RNSs produced.
- Peroxynitrite (a free-radical form of nitric oxide) is a specific DNA-damaging compound capable of inducing base changes, such as cytosine deamination to produce uracil.
- Macrophages and neutrophils (producing RNSs and ROSs, respectively) coming together in an inflammatory response can produce peroxynitrite, possibly inducing carcinogenesis.
- Nitrosylation of proteins can produce other dysfunctions, often inhibiting DNA repair enzymes.
- Hyperplasia can only progress to the size of a millimetre or so until they need their own blood supply.
- If angiogenesis doesn't occur, cells in the centre of the tumor will necrose (since they likely are already incapable of apoptosis), bringing an inflammatory response to bear.
- This inflammatory response provides growth factors to the cancer cells, as well as stimulating angiogenesis.
- Many tumor cells secrete chemokines for neutrophils, overriding the need for a necrotic state to initiate inflammatory angiogenesis.
- Cells need multiple mutations to block suppressors and activate oncogenes for tumor initiation.
- Inflammation is associated with high RNS concentrations which damage DNA by deamination of cytosine.
- Protein nitrosylation can block apoptosis and stimulate proliferation, as well as inhibiting DNA repair to make mutations permanent.
- Tumor promotion and progression require proliferation and neovascularization.
- Tumors recruit inflammatory leukocytes by internal necrosis or by secretion of cytockines.
- Tumor-resident macrophages secrete angiogenic and growth-promoting factors.
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