Send the link below via email or IMCopy
Present to your audienceStart remote presentation
- Invited audience members will follow you as you navigate and present
- People invited to a presentation do not need a Prezi account
- This link expires 10 minutes after you close the presentation
- A maximum of 30 users can follow your presentation
- Learn more about this feature in our knowledge base article
Do you really want to delete this prezi?
Neither you, nor the coeditors you shared it with will be able to recover it again.
Make your likes visible on Facebook?
You can change this under Settings & Account at any time.
Life Threatening Cancer: Inflammatory Contribution
Transcript of Life Threatening Cancer: Inflammatory Contribution
Responsible for 90% of cancer deaths
Cancers exhibit patterns of metastasis due to factors discussed later.
Cascade of invasion-metastasis occurs when primary cancer cells acquire mobility, moves and arrests in microvessels of another organ, and grows into another tumor. Evading growth suppressors Life Threatening Cancer:
Inflammatory Contribution The A Team: Michael Talanian, Nicholas Mehfoud, John Hylton, Joe Moore, Scott McAlister, Max Girshevitsky Avoiding immune destruction Enabling Replicative Immortality Tumor-promoting inflammation Activating invasion & metastasis Inducing Angiogenesis Genome instability & mutation Resisting cell death Deregulation of cellular energetics Sustaining proliferative signaling What is Inflammation? Can Be Beneficial Can Be Detrimental Chronic Inflammation - unresolved inflammatory response
Dysfunciton of regulatory mechanisms such as IL-10 and Treg cells
Cause of a wide range of human diseases such as diabetes, atherosclerosis, metabolic syndrome, allergies, heart disease and cancer
Favors pro-inflammatory M1 macrophage population
Key players in chronic inflammation
Release of Free Radicals
Used to combat microbial infections but it can also damage our DNA which can lead to hallmark development
Examples: reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI)
Pro-inflammatory cytokines and suppression of regulatory mechanisms Angiogenesis Inflammatory Contributions Evasion of Apoptosis Apoptosis - programmed pathway of cell death
eliminates dangerous cells -CANCER CELLS
important in normal development of limbs, organs etc.
cell shrinkage and rounding Function of immune system
surface presentation of phosphatidyl serine causes phagocytosis of cell
Two Pathways - redundancy
Extrinsic Pathway - cytoplasmic pathway via Fas Death Receptor
Intrinsic Pathway - mitochondrial release of Cytochrome C Cancer can defeat both pathways at their junction - Death Receptors 4 & 5
Cancer recruits inflammation cells because they can recruit immune cells thus preventing an immune response to the cancer.
Inflammatory cells and matrix promote growth and ignore apoptosis in wound healing which can lead to cancer development. Inflammatory Contributions The Growth Suppressors Inflammatory Contributions Inflammatory Contribution Inflammatory Response Inflammatory Contribution Inflammatory Contributions Inflammatory Contributions Metastasis and Invasion Inflammation promotes the mesenchymal phenotype by causing EMT (Epithelial-Mesenchymal Transition) in secondary epithelial cells via signaling by TNF-α.
Some of these changes are mediated by matricelluar proteins, which regulate adhesion and migration in extracellular matrix.
Chemokines induce migratory behavior and control patterns of metastasis in cancer cells The Mesenchymal phenotype - increases mobility and metastasis
Up-regulation of transcription factors Snai1, Twist and expression of metalloproteases
Down-regulation of tumor suppressor E-Cadherin and metastasis suppressor Kiss1 Expressed under inflammatory conditions, such as tissue repair, in an attempt to normalize the environment
Often help cancers metastasize
Attracts T-Cells and monocytes to sites of inflammation
Malignant cells adhere to T-Cells and monocytes and are transported throughout the body
Another way that OPN promotes metastasis in the inflammatory microenvironment is through the urokinase plasimogen activator (uPA) and matrix metalloproteases (MMPs), which involves the translocation of neoplastic cells across tissue boundaries and then into the extracellular matrix and then throughout the body. Kushiro K, Nunez N (2011) Ob/ob serum
promotes a mesenchymal phenotype in B16BL6 melanoma cells. Springer Science: 877-885
Kushiro K, Nunez N (2012) Adipocytes Promote B16BL6 melanoma cell Invasion
and the Epithelial-to-Mesenchymal Transition. Springer Science: 74-81
Müller, Anja, Homey, Bernhard, Soto, Hortensia, Ge Nianfeng, Catron, Daniel, Buchanan, Matthew, E., McClanahan, Terri, Murphy, Erin, Yuan, Wei, Stephan N. Wagner, Stephen N., Barrera, Jose Luis, Mohar, Alejandro, Verástegui, Emma, Zlotnik, Albert. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50-56 (1 March 2001) | doi:10.1038/35065016; Received 15 May 2000; Accepted 17 January 2001. http://www.nature.com/nature/journal/v410/n6824/full/410050a0.html Finkielstien, Carla, Ph.D. “Programmed Cell Death” Slide 4-5. Febuary 22nd, 2013 Integrated Cellular Response Laboratory. Matricellular Proteins Chemotaxis Chemokines are inflammatory molecules responsible for direction of chemotaxis
chemotaxis is the intentional movement of cells following a chemical gradient
Example: Breast Cancer Metastatic Pattern
Breast cancer tends to metastasize to bone marrow, the lungs, the liver and lymph nodes in the area.
Breast cancer cells often exhibit chemokine receptors CXCR4 and CCR7.
These receptors are sensitive to chemokines XCL12/SDF-1 and CCL21/6Ckine, which are highly expressed in the areas where breast cancer metastasizes
Ligation of these chemokines with their receptors has been shown to induce the formation of pseudopodia in breast cancer cells Enabling Replicative Immortality Overexpression of telomerase
Studies have shown that telomerase is involved in the inflammatory response by activating NF-kB
Loss of Function of p53
Studies have shown that loss of Function of p53 in intestinal epithelial cells leads to a myeloid cell-dominated microenvironment associated with NF-κB activation facilitating Epithelial-mesenchymal transition and invasion. The Emerging Hallmark: Avoiding Immune Destruction NF-kB and STAT3 are important transcription factors in inflammation responses in many cancers, especially in hepatocellular carcinoma.
Mainly NF-kB pathway is responsible for tumor promoting inflammation. This pathway regulates IL-6, which is involved in the activation of STAT3 transcription factor which is responsible for survival and proliferation of genes in premalignant cells. Theoretically, cancer cells should be detected and eliminated by immune surveillance.
If this were true - cancerous tumors would not form.
Upon re-examination, Hanahan and Weinberg have added it to the hallmarks of cancer as an "emerging hallmark"
Immune system normally protects against cancer in two ways
Adaptive immunity "NF-κB in Kupffer cells and STAT3 in hepatocytes contribute to the development of hepatocellular carcinoma ." - Michael Karin Individuals who are immuno-compromised have a higher incidence of cancers induced by viruses.
Indicates that the main defense against virus-induced cancers is reduction of viral load by the immune system Goubin He, Michael Karin. "NF-κB and STAT3 – Key Players in Liver Inflammation and Cancer." Cell Research. Nature Publishing Group, 28 Dec. 2010. Web. 21 Apr. 2013.
Michael Karin. "NF-κB as a Critical Link Between Inflammation and Cancer." NF-κB as a Critical Link Between Inflammation and Cancer. Cold Spring Harbor Perspective Biology, 2009. Web. 21 Apr. 2013.
David R. Hodge, Elaine M. Hurt, and William L. Farrar. "The Role of IL-6 and STAT3 in Inflammation and Cancer." Science Direct. SciVerse, Nov. 2005. Web. 27 Apr. 2013.
Hema Rangaswami, Anuradha Bulbule, and Gopal C. Kundu. "Osteopontin: Role in Cell Signaling and Cancer Progression." Science Direct. SciVerse, Feb. 2006. Web. 26 Apr. 2013.
http://www.sciencedirect.com/science/article/pii/S0962892405003132 Smyth, M., Hayakawa, Y., Takeda, K., Yagita, H. (Nov. 2002). New aspects of natural-killer-cell surveillance and therapy of cancer. Nature.com. Nature Publishing Group. Nature Reviews Cancer 2, 850-861. http://www.nature.com/nrc/journal/v2/n11/fig_tab/nrc928_F3.html
Hanahan, D., Weinberg, R. (4 Mar. 2011). Hallmarks of cancer: the next generation. Cell. Elsevier Inc. Volume 144, Issue 5, 646-674. 14 Apr. 2013 http://www.cell.com/abstract/S0092-8674(11)00127-9#Summary
Subbiah, E., (2013). Cancer related inflammation - guest lecture to inflammation biology. Associate Professor. Virology. Fralin Life Science Institute. -image - Inflammatory Contribution and next frame
Li, L., (2013). Lecture 16 - complement activation. Professor of Biological Sciences. Inflammation Biology. Virginia Tech Biological Sciences. A continuous process of blood vessel proliferation that occurs at a rapid rate in the young, and a low constant rate in adults
The process is induced by tumors in order to gain nutrients, oxygen, and undergo metastasis.
The resulting blood vessels are leaky and more susceptible to penetration by cancer cells Neovascularization Differs from angiogenesis in that angiogenesis is the outgrowth and extension of pre-existing blood vessels, whereas neovascularization is the generation of completely new blood vessels.
Also promoted by tumor microenvironment. Innate Immunity cytotoxic innate immune cells
Natural Killer Cells (NK)
Complement activation and construction of a membrane attack complex via the alternative pathway.
Alternative pathway utilizes background levels of C3b to start complement activation at the cleavage of C5. Adaptive Immunity Cytotoxic T Lymphocytes (CTL)
require education and activation
Antigen presentation by antigen presenting cells (APC) using MHC1 interaction with T-cell receptors (TCR)
Complement activation - classical pathway
C1 complex binds constant chains of multiple antigen bound antibodies
can lead to opsonization and enhanced phagocytosis by macrophages
cleavage of successive proteins results in C#a and C#b segments
C#b product used directly in complement activation and construction of membrane attack complex
C#a acts as an inflammatory modulator via GPCRs Cancer cells have the ability to change and adjust their energy metabolism to ensure sufficient energy sources for unlimited cell growth and division.
Cancer cells increase gycolysis and lactate fermentation and decrease oxidative phosphorylation, regardless that it is a less efficient energy process. This is known as the Warburg Effect. Background information The IL-6 Cytokine IL-6 cytokine is responsible for the prevention of apoptosis in the cell when an inflammatory response is initiated.
The ability of the IL-6 cytokine to keep the cell from dying when the inflammatory reaction is initiated is also responsible for the tumor cells from dying in the same environment.
Estrogen, interestingly enough, inhibits the IL-6 cytokine which in turn protects female mice from hepatocellular carcinoma. This illustration shows the part of the NF-kB pathway which promotes inflammatory cells as well as inhibitors for its own transcription. Ghosh, A., Saginc, G., Leow, S., Khattar, E., Shin, E. M., Yan, T. D., Wong, M., Zhang, Z., Li,
G., Sung, W., Zhou, J., Chng, W. J., Li, S., Liu, E., & Tergaonkar, V. (2012). Telomerase directly regulates NF-κB-dependent transcription. Nature Cell Biology, 14, 1270–1281. doi: 10.1038
Goodman, W. A., & Jain, M. K. (2011). Length does not matter: A new take on telomerase
reverse transcriptase. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 235-236. doi: 10.1161
Schwitalla, S., Ziegler, P. K., Horst, D., Becker, V., Kerle, I., Begus-Nahrmann., Y.,Lechel, A.,
Rudolph, K. L., Langer, R., Slotta-Huspenina, J., Bader, F. G., Prazeres da Costa, O.,Neurath, M. F., Meining, A., Kirchner, T., Greten, F. R. (2013). Loss of p53 in enterocytesgenerates an inflammatory microenvironment enabling invasion and lymph node metastasisof carcinogen-induced colorectal tumors. Cancer Cell, 23(1), 93-106. doi: 10.1016 This diagram shows how NF-kB is involved in activating anti and pro tumor inflammatory mediator. The Warburg Effect Oxidative stress within the cancer cell can lead to the recruitment of TAMs (tumor associated macrophages) and CAFs (cancer associated fibroblasts).
TAMs can secrete proinflammatory cytokines, which coordinate a inflammatory response, leading to cancer cell dissemination. Inflammatory macrophages release cytokines such as TNF-alpha, this upregulates adhesion molecules ICAM-1 and VCAM-1.
Ang-2 sensitizes the endothelial tissue to TNF-alpha, causing them to upregulate ICAM-1 and VCAM-1, even when the amount of TNF-alpha would not normally have an effect. Maldonado, J. Deregulation of cancer metabolism. How
Cancer Works. University of Texas at Austin.
Fiaschi, T., Chiarugi, F. Oxadative stress, tumor
microenvironment, and metabolic reprogramming: a
diabolic liaison. (2012). International Journal
of Cell Biology, volume 2012, article 762825 This illustration shows the NF-kB transcription factor and its pathway's involvement in the production of anti and pro cancer inflammatory mediators. When following the intrinsic pathway, which includes STAT3, we can see that it produces pro-cancer inflammatory mediators. Inflammation for cancer Inflammation that is caused by disease is meant to fight the disease using specific immune cells, cytokines, and transcription factors.
Here we take a look at the inflammatory responses that our body produces which helps as well as suppreses tumorgenesis and metastasis.
The transcription factors NF-kB and STAT3 have been identified as some of the key players in tumorgenesis.
The transforming growth factor beta (TGF-B) has been associated with tumor suppression by inhibit epithelial cell cycle progression and promoting apoptosis. Inflammatory Mediators Alterations due to Cancer The Tie-2 Receptor Ang-1 and Ang-2 compete over the Tie-2 receptor.
When Ang-1 activates the Tie-2 receptor it downregulates NF-κB, and thus ICAM-1 and VCAM-1
It also promotes blood vessel stabilization. Ang-1 and Ang-2 When Ang-1 binds to the Tie-2 receptor, it downregulates inflammation.
When Ang-2 binds to Tie-2, inflammation is upregulated.
Ang-2 also sensitizes the endothelial tissue to the Vascular endothelial growth factor (VEGF) In a tumor microenvironment the ratio of Ang-1:Ang-2 is heavily skewed toward Ang-2.
The amount of VEGF present is also abnormally high.
This results in the continual growth of unstable and immature blood vessels in the tumor microenvironment.
The constant high levels of Ang-2 also continue to promote inflammation.
The alteration of NF-κB expression increases the expression of VEGF. Mechanisms As the tumor begins to develop, many recruit inflammatory macrophages and other inflammatory cells.
The recruited inflammatory cells confer several advantages to the tumor. They can use their cytokines to alter the immune response to suit the needs of the tumor.
One of the major advantages is that the constant inflammation means that Ang-2 will continue to be upregulated, destabilizing nearby vascular tissue.
The increase in VEGF causes the vascular tissue to grow toward and into the tumor. Angelo, L. S., & Kurzrock, R. (2007). Vascular endothelial growth factors and its relationship to inflammatory mediators. Clinical Cancer Research.
May 4, 2013. http://clincancerres.aacrjournals.org/content/13/10/2825.full
Hata, K., Nakayama, K., Fujiwaka, R., Katabuchi, H., Okamura, H., & Miyazaki, K.
(2004). Expression of the angopoietin-1, angopoietin-2, tie-2, and vascular endothelial growth factor gene in epithelial ovarian cancer. Gynecologic Oncology, 93(1), 215-222. http://europepmc.org/abstract/MED/15047239
Imhof, B., & Aurrand-Lions, M. (2006). Angiogenesis and inflammation face off. Nature, 12, 171-172.
http://www.nature.com/nm/journal/v12/n2/full/nm0206-171.html Activation Pathways Membrane Attack Complex (MAC) Cytokines Suppressing Immune Response A poly C9 complex
Perforates cell membrane resulting in cell lysis and death TGF-β
Binds TβRI and TβRII to activate SMADs 2, 3 and 4
Results in immune suppression via increase Treg action
Binds IL-10RI and IL-10RII activating JAK1 and TYK2
Activation of STAT3 resulting in general down-regulation of immune and inflammatory response to disease Proinflammatory stimuli, including oxidized low-density lipoprotein, tumor necrosis factor α, and lipopolysaccharide, signal to primary macrophages, inducing activation and translocation of NF-κB. NF-κB–mediated transcription of telomerase reverse transcriptase (tert) leads to the effects seen in the green block. Inflammation is physically characterized by:
Redness - recruitment of immune cells
Swelling - increased blood flow for delivery of key players in the bloodstream
Warmth - fever response to inhibit microbes
Pain - protect from further injury
Monitors and responds to physical challenges
Physical/biological stressors - temperature changes or injury
Rogue host cells such as cancer cells NF-κB-dependent gene transcription regulates proliferation, resistance to apoptosis, and innate immune responses in normal cells.
This pathway is rapidly turned off because of feedback mechanisms such as synthesis of IκB proteins and the action of phosphatases and de-ubiquitinases. In cancer cells, NF-κB target genes like Telomerase reverse transcriptase have enhanced activity.
hTERT will stabilize p65 on promoters that will increase the expression of NF-κB target genes.
This will lead to invasion, cellular proliferation, and resistance to apoptosis.
Another effect is that theses cancer cells will release chemokines that will attract macrophages to produce more NF-κB activating cytokines. Acute inflammatory response
Rapid response to challenge, followed shortly by elimination of the challenge and resolution of the inflammation
Recruitment of immune cells to fight infection
Induction of angiogenesis via factors such as vascular endothelial growth factor (VEGF) for product delivery
Delivery of growth factors for tissue healing Inflammation is the normal response, designed to help an injury heal. When a tissue is damaged many of its cells are dead or damaged. In order to heal from these injuries rapidly inflammatory leukocytes release growth factors to quickly replace lost cells.
In many cases the growth signaling from inflammatory leukocytes can deregulate the normal checkpoints that are normally required. Key Players of Inflammation Typical Tissues
Epithelial and endothelial cells as sentries and a first line of defense
Specialized Immune Cells
Innate Immune Cells - no programming required
Rapid yet specific response utilizing Pathogen Associated Molecular Patterns (PAMPs) - Natural Killer (NK) cells
Adaptive Immune Cells - require education and provide memory for subsequent attacks
Slower response utilizing antibodies - enhance macrophage action, B cell antibody production, T cells etc. Mediating Molecules and Associated Receptors Can act as autocrine, paracrine and endocrine signals
Cytokines - intercellular messengers
Pro-inflammatory and anti-inflammatory classes along with the ability to internalize sensitive receptors provides regulation
Modulate patterns of division and metabolism with effects on transcription factors such as NF-κB
Names based on what cells produce them: Interleukins (IL) produced by and act on leukocytes
Chemokines - specific class of cytokines responsible for chemotaxis
Influence and regulate cell migration and recruitment Growth suppressors are specific proteins or transcription factors that monitor and halt the cell cycles.
Some of the key players that govern the decisions of cell proliferation or, alternatively, activate senescence and apoptosis are RB (retinoblastoma-associated) and TP53 proteins.
RB works through signals that originate outside the cell while TP53 receives inputs that originate inside the cell. Li, L., (2013). Lectures 1 & 2 - introduction to inflammation and cytokines
Professor of Biological Sciences. Inflammation Biology. Virginia Tech Biological Sciences.
Luo, M. X. (April 9, 2013). Inflammation and disease. Assistant Professor
of Immunology. Virginia-Maryland Regional College of Veterinary Medicine. Department of Biomedical Sciences and Pathobiology. Inflammatory Deregulation of TP53 Cancerous Growth Sources of Inflammation In cancer what should be a temporary deregulation of proliferation for the purposes of healing becomes a constant state, as the macrophages send out cytokines that are necessary for tumor development, as well as increasing the degree of inflammation.
Pro-growth chemokines also play a large role in subverting the Ras proliferation pathway and causing continual proliferation.
These functions are all provided to the tumor via, Tumor-Associated Macrophages (TAMs) Environmental
Air and water pollution
Drinking, smoking and high fat diet
Obesity - production of lipokines and dysfunction of adipose tissue
Latent viral infections
Frequent infections Cytokines Cytokines are local, small signaling molecules that can effect many functions, such as proliferation and cell death.
TAMs can kill neoplastic cells through activation of the apoptosis pathway by activating cytokines IL-2, IFM, and IL-12. However these are also required for tumor progression.
The transforming growth factors, which are highly associated with cancer, are all cytokines. Many of these are either released by or altered by inflammation. TP53 receives inputs from stress and abnormality detectors
TP53 can stop the cell cycle until the conditions return to normal.
If the damage is too severe.
If the levels of DNA related building blocks are abnormal.
AID (activation-induced cytidine deaminase) is an enzyme which promotes immunoglobulin gene by deamination of cytosine in DNA.
Inflammation related transcription factors NF-κB and TGF-B induce the overexpression of AID which promotes genomic instability which in turn induces mutations in the TP53 gene.
This domino effect prevents TP53 from stopping the tumor cell cycle. Effect of AID on TP53 This figure depicts the effects of the overexpression of AID on P53. When P53 is compromised DNA repair, cell cycle arrest, and apoptosis are compromised as well. Rakoff-Nahoum, S. (2007). Why cancer and
inflammation?. Yale Journal of Biology and Medicine, 79(3), 123-130. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994795/ TAMs -Tumor Associated Macrophages Macrophages can be grouped into M1 and M2 macrophages
M1 macrophages are signaled by things such as bacterial LPS and are tumor suppressing
TAMs are overwhelmingly M2 macrophages
M2 polarization can be triggered by cytokines from the tumor such as IL-10, TGF-β or IL-4 depending on the cancer.
M2 macrophages promote functions such as tissue remodeling, angiogenesis, scavenging and matrix remodeling.
M2a, M2b and M2c depending on cytokines present in the tumor microenvironment.
IL-4 and IL-13 = M2a polarization, resulting in Th2 responses, allergy and killing encapsulated parasites.
IC+TLR/IL-1R = M2b polarization and results in Th2 response and immunoregulation.
FIL-10 = M2c polarization and creates an immunoregulatory response along with matrix decomposition and tissue remodeling.
Higher the concentration of TAMs relate to a more grim the prognosis. The important pathway in this figure is the cytokines --> AID --> p53. The specific cytokine which upregulates AID is TNF, which in turn causes p53 to disfunction which results in chromosomal instability. The Warburg Effect A mutation with p53 produces the Warburg Effect, which is when cancer cells produce intermediates and energy at a high rate of aerobic glycolysis for use in cell division. A mutated p53 decreases the use of the TCA cycle and leads to compromised oxidative phosphorylation chains. The effect also causes mitochondrial dysfunction, where the mitochondria can not keep up with the high level of glycolysis, leading to raised levels of lactate in the cell. Grivennikov, S. I., Greten, F. R., & Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140(6), 883-899. http://www.sciencedirect.com/science/article/pii/S0092867410000607
Serpi, R. (2003). Mechanism of benzo (a) pyrene-induced accumulation of p53 tumour suppressor protein in mouse. Oulun yliopisto. http://herkules.oulu.fi/isbn9514270398/html/x243.html
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646-674.
Colotta, F., Allavena, P., Sica, A., Garlanda, C., & Mantovani, A. (2009). Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 30(7), 1073-1081.
http://carcin.oxfordjournals.org/content/30/7/1073.full.pdf+html Inflammation plays a large role in nitrative and oxidative DNA damage.
Infectious and noninfectious foreign agents induce an inflammatory response.
iNOS-dependent formation 8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) in cancer and precancerous tissues
Results in DNA base damage, which may lead to double strand breaks and other mutations. Chronic inflammation leads to dysregulation of mitotic checkpoint proteins
They become unable to halt cell division for DNA repair to commence.
Nitric oxide and certain pro-inflammatory cytokines can suppress TP53, there by protecting the tumor cells from going through apoptosis.
Allows mutations to persist in a cell that would normally die
Inflammatory cytokines, such as IL-6, can promote DNA methyltransferase, resulting in hypermethylation of tumor genomes.
Hypermethylation turns gene transcription down or off
Detrimental effects if it affects a tumor suppressor
Hypomethylation - turns gene transcription up
Detrimental effects if it affects an oncogene or tumor promoter Genome Instability & Mutations Genomic instability is an enabling characteristic that leads directly to the other hallmarks
Allows for the accumulation of mutations
Cancer cells are more susceptible to mutagens because they lack the ability to repair damage
Mediators involved in DNA repair can have a DNA malfunction
This can cause in a cascade of improper DNA repair mechanisms as more and more mediators are affected. Activation- induced cytidine deaminase (AID)
One of the only human enzymes known to induce DNA mutation in the human genome.
Theoretically this enzyme induces C/G to T/A mutations causing dimers.
Core Proteins such as H. Pylori and HCV cause prolonged inflammation and ,enhance NF-κB activity.
AID expression is upregulated by NF-κB along epithelial linings, causing more frequent mutations.
Leading to certain liver cancers and colon cancers. The Big Influence Shimizu, T., Marusawa, H., Endo, Y., & Chiba, T. (2012).
Inflammation‐mediated genomic instability: roles of activation‐induced cytidine deaminase in carcinogenesis. Cancer Science, 103(7), 1201-1206.
http://www.ncbi.nlm.nih.gov/pubmed/22469133 Gorgoulis, V. G. (2012). Genomic Instability, Inflammation, and Cancer.
Journal of Biomedicine and Biotechnology, 2012. http://www.hindawi.com/journals/bmri/2012/308043/ Closing Statement Inflammation alone is not sufficient for tumorigenesis. Caner cells must acquire all of the hallmarks of cancer in order to form a life threatening tumor of significant size with the ability to metastasize. Tumor promoting inflammation has been deemed an enabling factor and, as research continues to elucidate its role, it may become a hallmark in its own right. We would certainly argue that it is its own hallmark because it is involved in promotion and acquisition of the others. Inflammation may not be a stand alone hallmark, but without it a cell may not be able to acquire the traits necessary for full blown cancer. Hopefully as we learn more about the inflammatory imbalances that lead to cancer, they will provide us with novel new therapies, using our own defense systems to fight cancer. Inflammatory Gene Regulation