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Biology of Cancer and Tumor Spread

Biology of Cancer and Tumor Spread. Chapter 9. First Medial Description :Egyptian Text@ 2500BC-Imhotep. Mastectomy: Johannes Scultetus (1595-1645)- fire, acid, leather binding. Tumor – 1922 “it is tissue overgrowth that is independent of the laws governing the remainder of the body”

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Biology of Cancer and Tumor Spread

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  1. Biology of Cancer and Tumor Spread Chapter 9

  2. First Medial Description :Egyptian Text@ 2500BC-Imhotep

  3. Mastectomy: Johannes Scultetus (1595-1645)-fire, acid, leather binding

  4. Tumor – 1922 “it is tissue overgrowth that is independent of the laws governing the remainder of the body” “neoplastic overgrowth serves no useful purpose to the organism”

  5. Cancer • Modern: “uncontrolled clonal proliferation of cells that can arise from virtually any cell type in the body” • Derived from the Greek word for crab karkinoma – Hippocrates (460 – 370 BC) • Malignant tumors • Tumor • Also referred to as a neoplasm – new growth

  6. Clonal Proliferation of a Single Cell“Storm Troopers: Star Wars”

  7. Benign vs. Malignant Tumors

  8. Classification & Nomenclature • Benign • Named according to the tissue from which they arise, and includes the suffix - “oma” • Lipoma • Glioma • Leiomyoma • Chondroma

  9. Classification & Nomenclature • Malignant tumors • Named according to the cell type from which they arise • Epithelial tissue – carcinoma • Ductal or glandular epithelium – adenocarcinoma Example: mammary adenocarcinoma • Connective tissue – sarcoma Example: rhabdomyosarcoma • Lymphatics – lymphomas • Blood forming cells – leukemia

  10. Classification & Nomenclature • Carcinoma in situ (CIS) • Preinvasiveepithelial malignant tumors of glandular or squamous cellorigin that have not broken through the basement membrane or invaded the surround stroma • Cervix, skin, oral cavity, esophagus and bronchus (epithelium) • Stomach, endometrium, breast, large bowel (glandular)

  11. Stages of Cancer Spread “important component to diagnosis and treatment” • Physical findings • Laboratory tests – histological/biochemical/genetic • Imaging studies

  12. Breast Cancer

  13. Cancer Cells • Transformation • Autonomy • Cancer cells: independent from normal cellular controls • Anaplasia • Loss of differentiation (specialization and organization) • “without form” - pleomorphic

  14. Cancer and Stem Cells • Stem cells self-renew • Cell divisions create new stem cells • Stem cells are pluripotent • Ability to differentiate into multiple different cell types

  15. Stem Cell

  16. Cancer…a genetic disease • DNA RNA Proteins(workhorse of the cell) • “normal regulated growth” • DNA** RNA** Proteins** • 1. Plasma membrane ** • 2. Intracellular enzyme system** • 3. Hormones/Growth factors** “unregulated growth…colonal proliferation ** multiple mutations- how many?

  17. Cancer…a genetic disease • DNA** RNA** Proteins**(antigen) • Example: • EarlyCDT-Lung (Oncoimmune)-blood test • 6 cancer associated antigens (p53, +5) • Autoantibodies…against abnormal proteins** Medscape Medical News Sept 20,2010

  18. Tumor Markers (DNA…RNA…Proteins) • Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found on tumor plasma cell membranes, in the blood, CSF, or urine • Hormones • Enzymes • Genes • Antigens • Antibodies

  19. Tumor Markers Table 9-2 • Used • Screen and identify individuals at high risk for cancer(CA-125, PSA, CEA, Bense Jones protein) • Diagnose specific types of tumors • Observe clinical course of cancer

  20. Types of Genetic Lesions in Cancer • Point mutation • Subtle alterations (insertions, deletions, translocation) • Chromosome changes (aneuploidy and loss of heterozygosity) • Amplification • Gene silencing • Exogenous sequences (tumor viruses)

  21. Genetic Basis of Cancer • Cancer-causing mutations • Disease of aging (more mutation over time) • Clonal proliferation or expansion Mutation leads to a Darwinian Survival advantage (↑ growth or ↓ apoptosis) • Multiple mutationsare required before cancer can develop (how many?)

  22. Oncogenes and Tumor-Suppressor Genes • Proto-oncogene/Oncogenes • Mutant genes that in their non-mutant state direct protein synthesis and cellular growth (acceleration-pedal to the metal) • Tumor-suppressor genes • Encoded proteins that in their normal state negatively regulate proliferation • Also referred to as antioncogenes (put the brakes on)

  23. Types of Mutated Gene:” 7 mechanisms” • Secretion of growth factors (autocrine stimulation) • Increased growth factor receptors (HER2/neu) • Signal from cell-surface receptors is mutated to the “on” position • Mutation in therasintracellular signaling protein – (cell growth without growth factors) : “kinase” “all lead to increase growth”

  24. Types of Mutated Genes

  25. Types of Mutated Genes:”7 mechanisms” • Inactivation of Rb tumor suppressor(tumorsuppression) inherited • Activation of protein kinase* that drive the cell cycle (oncogene) • Mutation in the p53 gene (# apoptosis)-tumor suppressiongene 17p13.1 • *-PO4: activates and amplifies enzymatic processes over and over…

  26. Types of Mutated Genes:Bowel Cancer

  27. Question: How many mutations does it take to cause cancer? • “Cancer Genome Atlas”-breast cancer 127 mutations • Driver mutations: 11-15 (average=13)-directly cause growth and survival of the cancer; hit oncogenes/tumor suppression genes; limited number exist • Bystander/passenger mutations: accidental copying of DNA; no impact on the biology of cancer

  28. Driver Mutations • “Core metabolic pathway leads to dysregulation of any tumor” • One or more proto-oncogene/tumor suppression gene may skip mutation, but others mutations activate the core pathway CANCER

  29. Angiogenesis (core pathway) • Growth of new blood vessels • Advanced cancers can secrete angiogenic factors (VEGF)

  30. Telomeres and Immortality: core • Body cells are not immortal and can only divide a limited number of times (double about 50 times -Hayflick Limit: 1961) • Telomeres are protective cap on each chromosome and are held in place by telomerase (germ cells & stem cells) enzyme • Telomeres become smaller and smaller with each cell division- “somatic cells” – quit dividing/die • Telomerase enzyme: rebuilds telomeres • Nobel Prize 2009:Blackburn, Greider, Szostak

  31. Telomeres and Immortality

  32. Mutations of Normal Genes→ Cancer Genes • Point mutation (most common) • Change of one or a few nucleotide base pairs • ras gene (pancreatic, colon) • Chromosome translocation • A piece on one chromosome is transferred to another • t(8;14) Burkitt Lymphoma • t(9;22) chronic myeloid leukemia (Philadelphia chromosome – 1960)

  33. Mutations of Normal Genes → Cancer Genes • Chromosome amplification • Duplication of a small piece of chromosome (DNA) over and over • Result in ↑ expression of an oncogene • N-myc oncogene @ 25% amplification

  34. Mutation of Normal Genes

  35. Oncogenes and Tumor-Suppressor Genes • Oncogenes • Mutant genes that in their non-mutant state direct protein synthesis and cellular growth (jammed acceleration) • Tumor-suppressor genes • Encoded proteins that in their normal state negatively regulate proliferation • Also referred to as antioncogenes (put the brakes on)

  36. Mutations of Normal Genes →Cancer Genes • Tumor-suppression genes(“inherited”) • Unregulated cellular growth (put on the brakes) Rb gene (inactivated) → retinoblastoma, lung, breast, bone • Two hits or mutationsto inactivate the genes(Rb) • Childhood retinoblastomas: 2 forms-inherited(2-6 mo.)/sporadic(2-4 yrs) • De Gouvea(1872)-Brazilian Ophthmol. :young boy & his 2 daughters= cancer can be inherited

  37. Mutations of Normal Genes → Cancer Genes • Loss of heterozygosity • Loss of a chromosome region in one chromosome • Unmasks mutation in the other locus of a tumor suppression gene

  38. Mutation of Normal Genes: Tumor Suppression Genes

  39. Mutations of Normal Genes → Cancer Genes • Gene silencing • No mutation or change in DNA sequence • Whole regions of chromosomes are shut off while the same regions in other cells remain active • Shuts off critical tumor suppression genes

  40. Mutations of Normal Genes → Cancer Genes • Caretaker genes(“inherited”) • Encode for proteins that are involved in repairing damaged DNA (UV or ionizing radiation, chemicals and drugs) • Loss lead to increase mutation rates • Chromosome instability • Increase in malignant cells • Results in chromosome loss, loss of heterozygosity and chromosome amplification • Loss of tumor suppression genes with overexpression of oncogenes

  41. Genetics and Cancer-Prone Families • Somatic cells – most cancers • Exposure to mutagen • Defect in DNA repair • Not inherited • Germ line cells (sperms and eggs) • Vertical transmission of cancer causing genes • Tumor suppression and caretaker genes • One mutant allele (mom or dad), loss of heterozygosity in some cells → tumors

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