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Inflammation and Cancer Pin Ling (凌 斌), Ph.D. ext 5632; [email protected] References: 1. “Hallmarks of Cancer: The Next Generation” (Cell, 2011) 2. “Paradoxical roles of immune system during cancer development” (Nat Rev. Cancer, 2006) 3. Insight Review on Inflammation (Nature, 2008, July) Outline 1. Roles of the immune system in cancer development 2. Overview of Inflammation 3. Inflammation, The NF-kB pathway, and Cancer Development 4. Tumor microenvironment and Tumor-Associated Macrophages Cancer development & Microenvironment 1. Cancers are not only autonomous masses of mutant cells. => Composed of other cell types? => fibroblasts, epithelial cells, “immune cells”, cells forming blood & lymphatic vessels, & mesenchymal cells. 2.Here “Tissue is maintained by coordinated we homeostasis” focus on the relationship between interactions these diverse cell types. the immune between cells and cancers. => How about cancer? => Cancerous cells hijack the normal physiological process to favour their own survival. 3. Most cancers found in clinical are already the outcome of hijacking microenvironment by malignant cells Paradoxical roles of the immune system in cancer development 1. The key functions of the mammalian immune system: (1) Protect from infectious pathogens (2) Monitor tissue homeostasis => Eliminate damaged cells or tumor cells 2. Mechanisms against cancer development: (1) Cellular immunity- T, NK, & Other innate immune cells (2) Humoral immunity- Cytokines, Abs, ..etc 3. Mechanisms promoting cancer development: (1) Inflammation => Angiogenesis & Tissue remodelling (2) Enhance survival pathways (NF-kB) (3) Suppression of anti-tumor immune responses Cancers display the signs of inflammation -infiltration of immune cells HE Stain Most cancers outplay the immune system CD45 Stain (all immune cells) => Escape from cytotoxic T cell attacks => Make other immune cells help their survival The complex relationship between the immune system and cancers-I 1. Adaptive and innate immune cells regulate tissue homeostasis and efficient wound healing 2. Altered interactions between adaptive and innate immune cells can lead to “chronic inflammatory disorders”. 3. Chronic inflammatory conditions enhance a predisposition to cancer development. 4. In cancers, an abundance of infiltrating innate immune cells (e.g. macrophages, mast cells, and neutrophils) correlates with increased angiogenesis and/or poor prognosis. The complex relationship between the immune system and cancers-II 5. Long-term usage of non-steroidal anti-inflammatory drugs and selective cyclooxygenase 2 (COX2) inhibitors reduces cancer incidence. 6. In cancers, an abundance of infiltrating lymphocytes correlates with favourable prognosis. 7. Activation of anti-tumour adaptive immune responses can suppress tumour growth 8. Polymorphisms in genes that regulate immune balance influence cancer risk. 9. Genetic elimination or depletion of immune cells alters cancer progression in experimental models. Outline 1. Roles of the immune system in cancer development 2. Overview of Inflammation 3. Inflammation, The NF-kB pathway, and Cancer Development 4. Tumor microenvironment and Tumor-Associated Macrophages Key Concepts about Inflammation-I 1. Inflammation- A physiological process whereby tissues respond to infectious & non-infectious insults (also called sterile inflammation, including toxic, traumatic, or autoimmune insults). 2. Four key signs: (1) Redness (2)Swelling (3) Heat (4)Pain 3. This process includes several phases: (1) Initial phase-Changes in local blood flow & accumulation of inflammatory cells (neutrophiles, macrophages, DCs, & lymphocytes) (2) Middle phase-Resolution of initial insults (3) Final phase-Termination of inflammation & tissue repair Causes & Outcomes of Inflammation The Inflammatory Pathway Inflammation in innate and adaptive immunity Inflammatory cells, cytokines, & chemokines are major effectors in this process. PRRs for sensing infectious & endogenous stimuli 1. PRRs (Pattern Recognition Receptor) for: (1) PAMPs from pathogens (2) DAMPs (Danger Associated Molecular Patterns) from host cells 2. Deregulated immune responses to these stimuli leading to • Infectious diseases • Autoimmune disorders • Allergy • “Cancer development” An infection case of inflammation Macrophages release cytokines and initiate an inflammation response during infection Leukocytes transmigrate to infection sites Trafficking molecules in the multi-step adhesion cascade An overview of leukocyte migration at sites of inflammation Inflammatory cytokines secreted by macrophages (IL-8) Resolution of acute inflammation Lipid mediator class switching: PGE2, Leukotrienes => Lipoxins Lipid mediators in Pro- & Antiinflammatory responses Role of macrophages in resolution of inflammation Key Concepts about Inflammation-II 4. Dysregulation of any step in the inflammation process leads to diseases. 5. While acute inflammation is a part of the defense response, chronic inflammation leads to inflammatory disorders, diabetes, atherosclerosis, & “Cancer.” 6. Malignant cells actively turn the inflammation process to become the chronic status. 7. Chronic inflammation creates a microenvironment for cancer progression. Outline 1. Roles of the immune system in cancer development 2. Overview of Inflammation 3. Inflammation, The NF-kB pathway, and Cancer Development 4. Tumor microenvironment and Tumor-Associated Macrophages Question Q: Whether all the inflammation is the same? Role of chronic inflammation in promoting cancer development Pathways connecting inflammation & cancers Oncogenes & Cancer-related Inflammation Hallmarks of Cancer-2000 Inflammation Inflammation Inflammation Inflammation is the 7th hallmark of cancer Mantovani, A., Nature, 20091 Hallmarks of Cancer-2011 Hanahan, D. & Weunberg, RA, Cell , 2011 Inflammatory network in cancer The NF-kB pathway is the key underlying pathway promoting cancer The NF-kB Pathway 1. Inflammation 2. Innate immune responses 3. Survival NF-kB induces cytokines to promote tumor survival Association of inflammation with cancers Outline 1. Roles of the immune system in cancer development 2. Overview of Inflammation 3. Inflammation, The NF-kB pathway, and Cancer Development 4. Tumor microenvironment and Tumor-Associated Macrophages The Cells of the Tumor Microenvironment R. A. Weinberg, Cell 2011 Signaling Network in the Tumor Microenvironment A model of innate & adaptive immune cells in cancer development Cancer cell necrosis promotes tumor progression by recruiting macrophages Macrophage polarization during tumor progression Tumor-associated macrophages in promoting cancer Tumor-associated macrophages in promoting cancer Targeting of Hallmarks of Cancer Hanahan, D. & Weunberg, RA, Cell , 2011 The End & Thank You Figure 1 Source: Cell , Volume 144, Issue 5, Pages 646-674 (DOI:10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Lipid mediators in Pro- & Antiinflammatory responses