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Cancer Development Schematic Development of Metastatic Cancer What is Cancer? Cancer or malignant neoplasm is the name given to a collection of related diseases, including but not limited to breast cancer, lung cancer, prostate cancer, leukemia (cancer in the blood), etc. In all types of cancer, the main similarity is that some of the body’s cells begin to divide without stopping and spread into surrounding tissues. Due to its large spectrum of diseases, the chances of an individual having cancer is high; one in two men and one in three women are diagnosed with cancer. It is a result of a long process that begins when one of the cells in an organ or tissue becomes damaged or altered in a way that causes it to break free from the normal controls that allow our cells to work together in harmony. There are many aspects to cancer; When cancer develops cells become more and more abnormal, old or damaged cells survive when they should die, and new cells form when they are not needed. These extra cells can divide without stopping and may form growths called tumors. Many cancers form solid tumors, which are masses of tissue. Cancers of the blood, such as leukemia, generally do not form solid tumors. Not all tumors are cancerous, only malignant tumors are. A malignant tumor has the ability to spread into, or invade, nearby tissues while a benign tumor does not have these abilities. Benign tumors can sometimes be quite large, however. When removed, they usually don’t grow back, whereas malignant tumors sometimes do. Mutation • Metastatic Cancer: A cancer that has spread from the primary site to other distant or local parts of the body. • Occurs when cancer cells break away from a tumor and travel to other areas of the body through the bloodstream or the lymph system. • EMT, Epithelial Mesenchymal Transition: Transition that epithelial cells undergo in order to migrate away from the primary site. • EMT induces a decrease in cell contact inhibition and in adhesive characteristics of the malignant epithelial cell. • The reduced adhesiveness of cancer cells also results in morphological and cytoskeletal alterations • “Many tumor cells are rounder than normal, in part because they are less firmly attached to either the extracellular matrix or neighboring cells” (Cooper GM, 2016). • Different types of EMT exist: • Type 1 is “associated with implantation, embryo formation, and organ development” • Type 2 is “associated with wound healing, tissue regeneration, and organ fibrosis,” • “Type 3 EMT’s occur in neoplastic cells that have previously undergone genetic and epigenetic changes” (Kalluri, 2009). • The transition that cancerous epithelial cells undergo to become mesenchymal cells is type 3 EMT • During type 3 EMT which cell adhesion molecule E-cadherin expression is decreased and N-cadherin and vimentin expression is increased. • When a cell becomes malignant TGF-β becomes and oncogene and promotes EMT and metastasis Non-cancerous conditions Normal Cell division is monitored at three checkpoints during the cell division process: G1 Checkpoint G2 Checkpoint M checkpoint Every phase in the cell cycle is also regulated by various proteins at the checkpoints. Cyclin dependent kinases, CDKs, along with various cyclins, are the key proteins that regulate the cell cycle. When Cyclins bind to CDKs, the CDKs become activated, allowing them to phosphorylate other molecules and the process to proceed. 1. 2. Current Treatments • Surgery: Cryosurgery Lasers Hyperthermia Photodynamic Therapy • Radiation Therapy: External Beam Radiation Therapy Internal Radiation Therapy • • Immunotherapy: Monoclonal antibodies Adoptive cell transfer Cytokines Treatment Vaccines BCG • Targeted Therapy: Small-molecule drugs Monoclonal antibodies • Hormone Therapy • Stem Cell Transplant: Autologous Allogeneic Syngeneic Chemotherapy Density dependent inhibition 14. Presence of adhesion molecules such as ECadherin 13. 4. Transmission electron microscopy of mesenchymal (MES) and epithelial (E) cells Future Treatments Autocrine Growth Stimulation 3. Contact Inhibition 9. 8. 3. 3. 6. Immunohistochemistry of E-cadherin and vimentin expression Immunohistochemistry of E-cadherin and N-Cadherin expression Causes of Cancer • Precision Medicine • Immunotherapy: White Blood Cell Armies • Cell-Based Therapy: “Living Drugs” • Epigenetic Therapy • Research into Metastasis 14. Knudsen's Hypothesis, also known as the “Two-Hit Hypothesis”: The Two Hit Hypothesis states that cancer is developed due to multiple mutations at different times. “ Hits” can be: • Acquired mutations • External Mutations from : • Carcinogens • Radiation • Viruses 10. A- Strong E-Cadherin C- Negative N-Cadherin B- Benign Tumor D- Strong E-cadherin Immune system’s role against cancer 5. 15. Cancerous Conditions • • • • • • • • Cell cycle checkpoints stop working Loss of density dependent inhibition Loss of contact inhibition Uncontrollable cell division and proliferation Loss of tumor suppressor genes and proto-oncogenes Increase in oncogenes Autocrine growth stimulation Reduced expression of cell surface adhesion molecules like ECadherin References The Body’s response against cancer utilizes the process of immunoediting. Immunoediting is a three step process: 1. Elimination 2. Equilibrium 3. Escape Contact Inhibition 3. Density dependent inhibition 3. 13. 1. 2. 3. https://www.goconqr.com/en/p/64884-dna-and-cell-division-notes http://gleesonbiology.pbworks.com/f/1159269703/Cell%20cycle%20check%20points.jpg Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. The Development and Causes of Cancer. Available from: http://www.ncbi.nlm.nih.gov/books/NBK9963/ 4. Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120(11):1351–83. 5. Johansson J, Tabor V, Wikell A, Jalkanen S and Fuxe J (2015) TGF-β1-induced epithelial– mesenchymal transition promotes monocyte/macrophage properties in breast cancer cells. Front. Oncol. 5:3. doi: 10.3389/fonc.2015.00003 6. W.W. Minuth, L. Denk (2014). Advanced fixation for transmission electron microscopy unveils special extracellular matrix within the renal stem/progenitor cell niche. Methods Mol Biol. 7. http://www.nature.com/nri/journal/v6/n11/fig_tab/nri1961_F1.html 8. http://www.riversideonline.com/source/images/image_popup/c7_cells.jpg 9. https://www.premedhq.com/loss-of-cell-cycle-control-in-cancer-cells 10. Imaging, Diagnosis, Prognosis:A Switch from E-Cadherin to N-Cadherin Expression Indicates Epithelial to Mesenchymal Transition and Is of Strong and Independent Importance for the Progress of Prostate Cancer; Karsten Gravdal,Ole J. Halvorsen, Svein A. Haukaas, and Lars A. Akslen; Clin Cancer Res December 1, 2007 13:7003-7011; doi:10.1158/1078-0432.CCR-07-1263 11. http://www.cancer.gov/about-cancer/treatment/types 12. https://www.mskcc.org/blog/future-five-reasons-optimism The process of immunoediting uses the bodies immune system to fight against the neoplastic cells. Neoplastic cells are cells that have been mutated and are beginning to grow abnormally. 13. http://www.moderncancerhospital.com/cancer-treatments/biological-immunotherapy/ 14. Chen, Q.W., Zhu, X.Y., Li, Y.Y., & Meng, Z.Q. (2014). Epigenetic regulation and cancer (Review). Oncology Reports, 31, 523-532. http://dx.doi.org/10.3892/or.2013.2913 15. http://www.carlagoldenwellness.com/2015/08/17/how-to-disease-proof-your-health/ 16. Chakraborty, S., & Rahman, T. (2012). The difficulties in cancer treatment.Ecancermedicalscience, 6, ed16. http://doi.org/10.3332/ecancer.2012.ed16 17. Escamilla, J. (2012, December 11). How immune cells can promote cancer progression - Sanguine Bio Researcher Blog. Retrieved January 20, 2016, from http://technical.sanguinebio.com/how-immunecells-can-promote-cancer-progression/ 18. Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial-mesenchymal transition. The Journal of Clinical Investigation, 119(6), 1420–1428. http://doi.org/10.1172/JCI39104 19. Paul, S., Kuo, A., Schalch, T., Vogel, H., Joshua-Tor, L., McCombie, W. R., … Mills, A. A. (2013). Chd5 Requires PHD-mediated Histone 3 Binding for Tumor Suppression. Cell Reports, 3(1), 92–102. http://doi.org/10.1016/j.celrep.2012.12.009 20. Snook, A. E., & Waldman, S. A. (2013). Advances in Cancer Immunotherapy.Discovery Medicine, 15(81), 120–125. 21. The Genetics of Cancer. (2012, March 26). Retrieved January 20, 2016, from http://www.cancer.net/navigating-cancer-care/cancer-basics/genetics/genetics cancer 22. "Understanding Genetics." Understanding Genetics. The Tech Museum of Innovation, n.d. Web.23 Jan. 2016. 13. "What Is Cancer?" What Is Cancer? Cancer Center, 01 Jan. 0001. Web. 23 Jan. 2016. Acknowledgements 3. 7. 8. 9. SUNY Old Westbury Honors College Honors College Mentor : Dr. Anthony Deluca Biology Mentor: Dr. Shilpi Paul