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
Cancer A Disorder of Altered Cell Differentiation and Growth = Neoplasia (new growth)
NormalTumor • Abnormal regulation of cell growth • Abnormal cell-cell interactions
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
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
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 cyclin-dependent kinases (CDKs), determine a cell's progress through the cell 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 = unregulated growth
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
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
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
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
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
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
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.
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
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.
Tumor • A swelling that can be caused by a number of conditions • Inflammation • Trauma • Mass of cells that arises because of overgrowth
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).
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
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
Characteristics of Malignant Neoplasms • Two categories • Solid tumors • Hematologic cancers
Solid Tumor • Cells detach from the original tumor mass • Invade surrounding tissue • Enter blood and lymph system • Metastasize
Hematologic Cancers • Cells normally found within the blood and lymph • Automatically metastasizes
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