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Neoplasia. Cancer. Cancer. The second leading cause of death in the United States Estimated 1.45 million diagnosed 559,650 died Prostate is the most common cancer for men Breast is the most common cancer for women Excluding skin cancer

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  1. Neoplasia Cancer

  2. Cancer • The second leading cause of death in the United States • Estimated 1.45 million diagnosed • 559,650 died • Prostate is the most common cancer for men • Breast is the most common cancer for women • Excluding skin cancer • Lung cancer is the leading cause of death in both men and women

  3. Cancer A Disorder of Altered Cell Differentiation and Growth = Neoplasia (new growth)

  4. NormalTumor • Abnormal regulation of cell growth • Abnormal cell-cell interactions

  5. Neoplasia • Growth is uncoordinated and relatively autonomous • Lacks normal regulatory controls over cell growth and division • Tends to increase in size and grow after stimulus ceases or needs of organism are met

  6. Cell Cycle • Cell proliferation • Process of cell division • Inherent adaptive mechanism for replacing body cells • Sequence of events that occurs as a cell duplicates • Genetic information is duplicated • Duplicated chromosomes are appropriately aligned for distribution between two genetically identical daughter cells • Process of specialization

  7. Interphase • G1 (gap 1) • From the end of the M phase until the beginning of DNA synthesis • Growth Phase • The cell determines its readiness to commit to DNA synthesis • S (DNA Synthesis) • DNA replication • G2 (gap 2) • DNA replication is assessed and errors are corrected • the gap between DNA synthesis and mitosis, the cell will continue to grow.

  8. Cell Cycle • M-Phase (Mitotic Phase) • the replicated chromosomes are separated and packaged into two new nuclei by mitosis • The cytoplasm is divided between the two daughter cells by cytokinesis • Prophase • Metaphase • Anaphase • Telophase

  9. Cyclins and CDK’s • Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle

  10. Cell Cycle • Cyclins are proteins that control the entry and progression of cells through the cell cycle • Cyclins bind to cyclin-dependent kinases (CDK), which are enzymes that phosphorylate proteins • Cyclin-dependent kinase inhibitors-regulates cell cycle checkpoints to prevent DNA replication mistakes.

  11. Cyclins and CDK’s • Progression from one phase of the cell cycle to the next is controlled by the orderly activation of cyclin dependent kinases • Cyclin proteins bind to CDK’s to cause phosphorylation and activation

  12. Tumor Suppressor Genes • Tumor suppressor genes inhibit the proliferation of cells in a tumor • Inactivate genes = unregulated growth

  13. Genes That Control Cell Growth and Replication • Tumor suppressor genes • Retinoblastoma (pRB) gene • Prevents cell division • Retinoblastoma tumor suppressor protein (pRB) • Phosphorylation of pRB causes progression of the cell into the S-phase • Genetic lesions that render the pRB pathway non-function are thought to occur in almost all human cancers

  14. Tumor Suppressor Genes • p53 gene • “Guardian of the genome” • Controls p53 protein levels • p53 proteins increase with damage to DNA • Initiates apoptosis of DNA-damaged cells

  15. p53 • Acquired mutation in p53 is the most common genetic alteration found in human cancer • On chromosome 17p • One p53 allele may be deleted while the other is mutated • Mutations of p53 are implicated in lung, breast and colon cancer • Therapies are directed at re-establishing the p53 genes to cause massive apoptosis of cancer cells

  16. Telomerase • DNA polymerase can’t replicate the ends of chromosomes • Loss of ends of chromosomes called telomeres • Telomeres • 15 to 20 kilobase pairs long • Cut off with each cell division • If pRB and p53 are nonfunctional, cells bypass non-growth function to become cancerous • Cancer cells can reactivate Telomerase

  17. Oncogene • A gene that has the potential to cause cancer • Activated oncogenes can cause cells that ought to die to survive and proliferate instead

  18. Proto-oncogenes • A normal gene that can become an oncogene due to mutations or increased expression • Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. • Proto-oncogenes are often involved in signal transduction

  19. Types of Proto-Oncogenes • Examples of proto-oncogenes • RAS andMYC

  20. Genetic Events Leading to Oncogene Formation • Ras proto-oncogene family • Signal relaying proteins that transmit growth signals to the nucleus • Ras communicates signals from outside the cell to the nucleus • Mutations in ras genes can permanently activate it and cause inappropriate transmission inside the cell, even in the absence of extracellular signals. • These signals result in cell growth and division, dysregulated Ras signaling can ultimately lead to oncogenesis and cancer

  21. Genetic Events Leading to Oncogene Formation • Myc proto-oncogene • Encodes for growth signal proteins • Myc (c-Myc) codes for a transcription factor that is located on chromosome 8 in humans and is believed to regulate expression of 15% of all genes • A mutated version of Myc is found in many cancers • Myc to be persistently expressed. This leads to the unregulated expression of many genes some of which are involved in cell proliferation and results in the formation of cancer.

  22. Epigenetics • Involves changes of gene expression without a change in the DNA • “silence” genes such as tumor suppressor genes • Methylation of the promoter region • Prevents transcription to cause gene inactivity • Can be inherited

  23. Genetic and Molecular Basis of Cancer • Epigenetic factors • http://youtu.be/Xjq5eEslJhw • http://youtu.be/wFsxVkuChdU

  24. Definitions • Neoplasia • uncontrolled growth of cells that is not under physiologic control. • Tumor or "mass lesion” • a "growth" or "enlargement" which may not be neoplastic (such as a granuloma). • Cancer • implies malignancy • neoplasms can be subclassified as either benign or malignant.

  25. Tumor • A swelling that can be caused by a number of conditions • Inflammation • Trauma • Mass of cells that arises because of overgrowth

  26. Tumors • Named by adding the suffix -oma to the parenchymal tissue type from which the growth originated

  27. Types of Tumors • Adenoma:benign tumor of glandular epithelial tissue • Adenocarcinoma:malignant tumor of glandular epithelial tissue • Carcinoma:malignant tumor of epithelial tissue • Osteoma:benign tumor of bone tissue • Sarcoma:malignant tumors of mesenchymal origin • Papilloma:benign microscopic or macroscopic fingerlike projection growing on a surface

  28. Tissue evidence of carcinogenic factors at work • The two forms of cellular transformation that are potentially reversible, but may be steps toward a neoplasm, are: • Metaplasia: the exchange of normal epithelium for another type of epithelium. • Metaplasia is reversible when the stimulus for it is taken away. • Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated.

  29. Characteristics of Benign Neoplasms • Grow by expansion • Remain localized to the site of origin • Inability to metastasize to distant sites • Develop a surrounding rim of connective tissue • Fibrous Capsule • Helps with better surgical removal

  30. Benign characteristics include: • Slow growth • Resemblance to tissue of origin (well differentiated) • Lack of invasion • Absence of metastases • Benign neoplasms usually arise in a solitary manner (e.g., lipoma of colon, meningioma of brain), but may be multiple (e.g., leiomyomata of uterus). • Though benign, they may cause problems through mass effect, particularly in tight quarters (pituitary adenoma in the sellaturcica).

  31. Characteristics of Malignant Neoplasms • Tend to grow rapidly • Invades and infiltrates nearby tissue • Spreads widely • Lack of defined capsule • Margins are not clearly separated from normal surrounding tissue • Have the potential to kill regardless of their original location

  32. Characteristics of Malignant Neoplasms • Tend to compress blood vessels and outgrow their blood supply, causing ischemia and tissue necrosis • Rob normal tissues of essential nutrients • Secretes hormones and/or cytokines, liberates enzymes and toxins that destroy tumor tissue and normal tissue

  33. Characteristics of Malignant Neoplasms • Two categories • Solid tumors • Hematologic cancers

  34. Solid Tumor • Cells detach from the original tumor mass • Invade surrounding tissue • Enter blood and lymph system • Metastasize

  35. Hematologic Cancers • Cells normally found within the blood and lymph • Automatically metastasizes

  36. Malignant Neoplasm • Characteristics of malignant neoplasms include: • More rapid increase in size • Less differentiation (or lack of differentiation, called anaplasia • Tendency to invade surrounding tissues • Ability to metastasize to distant tissue

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