Cancer A Disorder of Altered Cell Differentiation and Growth = Neoplasia (new growth)
Cancer • The second leading cause of death in the United States • Estimated 1.45 million diagnosed • 559,650 die each year • 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
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 also duplicated • Duplicated chromosomes are appropriately aligned for distribution between two genetically identical daughter cells • Process of specialization
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.
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
Cyclins and CDK’s • Two key classes of regulatory molecules, Cyclins and Cylin-Dependent Kinases (CDKs), determine a cell’s progress through the cell’s cycle
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.
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
Tumor Suppressor Genes • Tumor suppressor genes inhibit the proliferation of cells in a tumor • Inactivate genes and get unregulated growth • http://highered.mcgraw-hill.com/sites/9834092339/student_view0/chapter10/how_tumor_suppressor_genes_block_cell_division.html
Tumor Suppressor Genes • Retinoblastoma is a rare childhood cancer due to the inactivation of a specific tumor suppressor gene • Retinoblastoma (pRB) gene • Prevents cell division • Retinoblastoma tumor suppressor protein (pRB) • Phosphorylation of pRB causes progression of the cell into the S-phase • A point mutation renders the pRB pathway non-functional • Thought to occur in almost all human cancers
Tumor Suppressor Genes • p53 gene • Found on the small arm of chromosome 17 • Its protein product is in virtually all normal tissues • Controls p53 protein levels • p53 proteins increase with damage to DNA • Initiates apoptosis of DNA-damaged cells
p53 Gene • “Guardian of the genome” • Restricts uncontrolled cellular proliferation under circumstances in which cells with abnormal DNA might propagate • Deleted or mutated in 70% to 80% of cases of colorectal cancer, breast cancer, small cell carcinoma of the lung, hepatocellular carcinoma, astrocytoma and numerous other tumors
p53 • Acquired mutation in p53 is the most common genetic alteration found in human cancer • One p53 allele may be deleted while the other is mutated • Therapies are directed at re-establishing the p53 genes to cause massive apoptosis of cancer cells
Telomeres • http://www.youtube.com/watch?v=qQCecSuPa1w&feature=related
Telomerase • DNA polymerase can’t replicate the ends of chromosomes • 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
Oncogene • A gene that has the potential to cause cancer • Activated oncogenes can cause cells that ought to die to survive and proliferate instead
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
Types of Proto-Oncogenes • Examples of proto-oncogenes • RAS andMYC
RAS ONCOGENE • Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. • Normally, Ras binds GDP in its neutral state. • A message is passed from the receptor to Ras by guanine nucleotide exchange factors (GEFs) that expel this GDP, allowing GTP, which is more plentiful in the cytoplasm, to bind in its place.
Genetic Events Leading to Oncogene Formation • Ras proto-oncogene family • Signal relaying proteins that transmit growth signals 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, dysregulatedras signaling can ultimately lead to oncogenesis and cancer
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 is believed to regulate expression of 15% of all genes • A mutated version of Myc is found in many cancers • Myc is 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
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
Genetic and Molecular Basis of Cancer • Epigenetic factors • http://youtu.be/Xjq5eEslJhw • http://youtu.be/wFsxVkuChdU
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
Definitions • 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.
Tumor • An abnormal growth of tissue resulting from uncontrolled, progressive multiplication of cells and serving no physiological function- may look like swelling under the skin
Tumors • Named by adding the suffix -oma to the parenchymal tissue type from which the growth originated
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
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.
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
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).