Bio of Cancer Lecture #10: Enabling Characteristic: Tumor Promoting Inflammation – Flashcards
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Rudolf Virchow in the 19th century was the first to observe _____.
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leukocytes within the tissue of solid tumors
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What has Rudolf Virchow's observation led to?
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Since then our understanding of the relationship acute and chronic inflammation plays in tumorigenesis has greatly increased
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What is now evident with regard to a pro-inflammatory milieu?
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It is now evident that a pro-inflammatory milieu is a critical component in tumorigenesis- tumor growth
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Most tumors are not caused by _______ but instead come from accumulated mutations and environmental factors
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inherited mutations
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Where do most tumors come from?
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accumulated mutations and environmental factors
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Which factor from the tumor's environment pre-disposes you to tumor development?
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chronic inflammation
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Different inducers of _____ have been shown to promote tumorigenesis
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chronic inflammation
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What percentage of tumorigenesis is associated with chronic inflammation?
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20%
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What percentage of tumorigenesis is associated with Smoking/Inhaled pollutants?
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30%
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What percentage of tumorigenesis is associated with dietary factors?
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35%
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What percentage of tumorigenesis is associated with obesity?
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20%
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What are the four different types of inflammation?
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therapy-induced inflammation Chronic inflammation due to autoimmunity or infection tumor-associated inflammation inflammation caused by environmental factors
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What is infection induced chronic inflammation caused by?
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Several pathogens have the ability to directly or indirectly induce tumorigenesis
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What causes direct tumorigenesis?
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retrovirus by inserting themselves into promoters and into genes and effectively kill that gene
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How much of our genome is retroviral?
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about 5% and has been picked up over the last millennia
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What causes indirect tumorigenesis?
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Helicobacter pylori
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How does H. pylori work?
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infects the lining of the stomach and survives the extremely low pH by finding a corner to hide in and produce urea so it can raise the pH in a niche and then stays there long enough to cause a chronic infection like gastro-intestic ulcers
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What kind of infection is H. pylori?
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chronic; you pick it up and have it mostly for the rest of your life
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How can H. pylori be described?
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Class 1 carcinogen and the number one cause of gastric adenocarcinoma and MALT lymphomas
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What does MALT stand for?
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Mucoid Associated Lymphatic Tissue
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Why is H. pylori classified as indirect?
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H. pylori is not changing DNA to shut down tumor suppressors
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What is another disease that leads to infection induced chronic inflammation?
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Hepatitis B
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What does hepatitis b cause?
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liver cancer
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Hep B chronic infection occurs in a _____.
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small percentage of those infected
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A small portion of those with Hep B will become _____. Why?
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asymptomatic carriers because they are chronically infected
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What do Hep B patients develop over time?
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cirrhosis
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What percent of Hep B patients eventually become cirrhotic?
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20%
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What can cirrhotic Hep B patients eventually develop?
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Hepatocellular carcinoma or HCC Hep B is one of the most common causes of HCC.
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HBV carriers are _____ to develop HCC than non carriers.
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300x more likely
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What are the tumor stats associated with HCC?
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Most common liver tumor and 4th most common tumor overall
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When does HCC appear?
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appears about 5 years following cirrhosis
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_____ can trigger chronic inflammation
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Inhaled particulates
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While tobacco smoke is _____ the inhalation of particulates can _____ induce cancer by causing chronic inflammation.
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directly carcinogenic indirectly
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_____ and _____ particles give rise to cancer but are not directly carcinogenic.
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Asbestos and silica
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What can cause irritant induced chronic inflammation?
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Any chronically inhaled particles can cause this -coal, steel dust while black smithing
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How do inhaled particle trigger inflammation?
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These inhaled particles trigger inflammation by pro-IL-1B interactions with the inflammasome
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What is the inflammasome similar in function to?
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the apoptosome
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What is the inflammasome?
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a central regulator of several inflammatory pathways
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What does the inflammasome cause?
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it causes a broad and aggressive activation of the inflammatory pathways
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Obesity can increase cancer risk by _____
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1.6 fold.
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What do adipocytes express?
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pattern recognition receptors (PRRs) such as Toll-like Receptors (TLRs) on their surface
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What are pattern recognition receptors a part of and what do they do?
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part of the innate immune system and recognize patterns the are non-self
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What do PRR's recognize?
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Damage Associated Molecular Patterns (DAMPs) or Pathogen Associated Molecular Patterns (PAMPs).
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What are the two most important TLR's?
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TLR 2 and TLR4 are two of the most important TLRs
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What do TLR 2 and TLR 4 recognize and activate?
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TLR 2/4 recognize bacterial components and activate the immune signaling pathways which lead to activation of the transcription factors NFKB or AP-1 or IRF3
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What transcription factors are activated by the immune signaling pathway?
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NFKB AP-1 IRF3
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What does activation of transcription factors lead to?
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Activation of these transcription factors leads to IL-6 and TNF-alpha by cells that have recognized non self molecular patterns
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What do TLR 2/4 on the surface of the adipocyte recognize and bind to?
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diet derived saturated fatty acids
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What does this lead to?
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This leads to expression of IL-6 and TNF-a
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What kind of exposure to adipocytes will lead to chronic inflammation?
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If there is a constant exposure to the adipocytes then a low level, chronic inflammation will occur
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How does a tumor cause inflammation?
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the tumor it self will cause localized inflammation as the immune system struggles to eradicate the neoplastic cells
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How do tumors create a pro-inflammatory/pro-tumorgenesis milleu?
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tumors will work with stromal cells to recruit immune cells to the area
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We have already discussed how several types of immune cells play different roles in the process of _____.
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transformation
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All of the major immune cells have been shown to create an inflammation that is _____.
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tumorigenic
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What immune cells have we studied this far and that create immune environment good for cancer? What are their roles?
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Macrophages - TAMs : VEGF, angiogenesis CD8+ Cells : immunoediting (build stronger tumor) CD4+ Th1 Cells : produce IFNy (good and bad for tumor) Tregs: Lyse CTLs, activated DCs, supress anti-tumor immune system
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The ability of tumor cells to promote a tumorigenic environment is due to _____.
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the cytokines they release
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What four cytokines all promote tumor growth?
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IL-6, IL-17, IL-23, TNF-alpha
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Activation of ______ are particularly pro-tumor growth.
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NFKB, AP-1, STAT3
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What do activated immune cells produce and release?
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ROS and reactive nitrogen intermediates (RNIs)
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What will also cause an uptick in ROS/RNI release?
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Release of TNF-a
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What do ROS/RNI induce and increase?
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ROS/RNI induce DNA damage directly and increase the possibility of oncogene mutation
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ROS damage mismatch _____, increasing the likelihood of oncogene mutation
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repair enzymes
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What do mismatch repair enzymes increase?
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the likelihood of oncogene mutation
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Upregulation and Expression of AID
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Activation induced cytidine deaminase
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What is AID used in?
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AID is used in B cells as a critical enzyme in B cell class switching
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What does AID deaminate cytosine into?
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AID deaminates cytosine to a uracil
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What is the uracil now recognized as?
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This uracil is recognized as a thymine
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What happens when it is replicated?
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When replicated this causes a C:G to be replaced by a T:A
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Where is AID over expressed?
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in cancers
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What is AID induced by?
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NFKB dependent cytokines
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AID induces increased _____.
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genomic instability
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AID contributes to the development of _____.
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lymphomas and liver/gastric cancers
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Transcriptional silencing of tumor supressors such as _____ increases the rate of _____.
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INK4 tumor development
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Inflammation causes an increase in _____ of many genes, including these tumor suppressors.
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epigenetic silencing
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_____ is one of the best understood epigenetic changes
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DNA methylation
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Cytosines found in CpG islands within the promoter can be methylated by _____.
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DNA methyltransferases
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This methylation leads to _____.
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decreased transcription of the gene the promoter controls
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Histone deacetylases remove the _____.
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acetyl groups found on the histone tails of the nucleosome
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Acetyl groups on the histone tails supports a more _____, thereby increasing transcription.
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euchromatin arrangement
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Cytokines released by inflammatory cells have been shown to push _____.
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pre-neoplastic cells into full development
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What heavily influences hepatocellular carcinoma?
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IL-6
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IL-6 knockout mice are resistant to _____.
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HCC
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HCC is more common in _____.
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males
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Who produces more IL-6?
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males than females
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Chronic lymphocytic leukemia is thought to be induced by _____.
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repeated antigenic stimulation due to chronic pathogen infection
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What are some chronic pathogen infections?
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H. pylori, C. psisttacii, B. burgdoferi
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What do repeated stimulations cause?
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the release of cytokines such as IL-4 and VEGF that interact with bone marrow stromal cells to suppress apoptosis by upregulating BCL-2
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_____, _____, and _____ all induce inflammation.
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Surgery, chemotherapy and radiation
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How does chemotherapy kill cells?
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necrosis
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What does chemotherapy cause?
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This causes a large release of DAMPs that the TLRs can recognize (ATP, nucleic acids, heat shock proteins)
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What is a possibility for necrotic signals after chemotherapy?
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It is possible that the necrotic signals following chemotherapy create a pro tumor growth environment.
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Necrotic cell death can cause TLR4 to release _____ which is _____.
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IL-1B which is critical to anti-tumor immune function
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What appears to play a large role in the efficacy of chemotherapy?
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It appears that the patients particular TLR4 polymorphism plays a large role in the efficacy of chemo
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What are some current and possible anti-inflammatory cancer treatments?
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NSAIDs such as aspirin Inhibition of NKFB and STAT3 activity Anti IL-6 or TNF-a drugs
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Which cancers have NSAID's affected?
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These have been shown to help reduce the incidence of breast cancer, colon cancer and prostate cancer
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What can inhibition of NKFB and STAT3 activity lead to?
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May lead to immunosuppression
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What can be said about Anti IL-6 or TNF-a drugs
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These do exist and are prescribed for non-cancerous diseases but are not currently in use against cancers
