Lecture 8 Neoplasia II. Dr. Nabila Hamdi MD, PhD

Transcription

1 Lecture 8 Neoplasia II Dr. Nabila Hamdi MD, PhD

2 ILOs Understand the definition of neoplasia. List the classification of neoplasia. Describe the general characters of benign tumors. Understand the nomenclature of benign and malignant tumors. Recall the most important epidemiological aspects of cancer. Discuss the etiology of malignant tumors. Recognize the definition, microscopic changes and types of dysplasia. Understand the pathogenesis of tumor formation. Describe general characters of malignant tumors. Understand the methods of grading and staging of malignant neoplasms. Understand the definition of Carcinoma in-situ Explain the molecular basis of cancer Discuss the methods of spread of malignant tumors. Discuss the laboratory diagnosis of malignant tumors. Be aware of the effects of tumors on the host.

3 Outline 1. Overview 2. Nomenclature 3. Characteristics of Benign and Malignant Tumors 4. Epidemiology 5. Carcinogenesis: The Molecular Basis of Cancer Self-Sufficiency in Growth Signals Insensitivity to Growth-Inhibitory Signals Evasion of Apoptosis Limitless Replicative Potential Sustained Angiogenesis Invasion and Metastasis Role of DNA Repair Genes 6. Etiology of Cancer: Carcinogenic Agents 7. Host Defense Against Tumors: Tumor Immunity 8. Clinical Aspects of Neoplasia Neoplasia 2 Neoplasia 3 3

4 Overview Genetic Hypothesis of Cancer Nonlethal genetic damage (mutation, translocation, amplification, deletion..) lies at the heart of carcinogenesis Acquired (chemicals, radiation, or viruses) Inherited (in the germ line) Tumors are monoclonal A tumor mass results from the clonal expansion of a single progenitor cell that has incurred genetic damage 4

5 Overview Four classes of normal regulatory genes Protooncogenes (Growth-promoting) mutation Oncogenes dominant Cancer autonomous cell growth (transformed phenotype) Tumor suppressor genes (Growth-inhibiting) recessive Cells refractory to cell inhibition Genes that regulate apoptosis dominant recessive Down regulation of pro-apoptotic genes Up regulation of anti-apoptotic genes Genes that regulate repair of damaged DNA Mostly recessive Widespread mutation in the genome

6 Flow chart depicting a simplified scheme of the molecular basis of cancer 6

7 Overview More aggressive Less responsive to treatment Tumor progression and generation of heterogeneity New subclones arise from the descendants of the original transformed cell by multiple mutations. With progression, the tumor mass becomes enriched for variants that are more adept at evading host defenses and are likely to be more aggressive. 7

8 Six hallmarks of cancer. Most cancer cells acquire these properties during their development, typically by mutations in the relevant genes. 8

9 Self-Sufficiency in Growth Signals 9

10 Self-Sufficiency in Growth Signals Growth Factors In normal cells, most soluble growth factors are made by one cell type and act on a neighboring cell to stimulate proliferation (paracrine action). Cancer cells acquire growth self-sufficiency by: Synthesizing the same growth factors to which they are responsive (autocrine loop): Glioblastomas secrete platelet-derived growth factor (PDGF) and express the PDGF receptor. Sarcomas make both transforming growth factor-α (TGF-α) and its receptor. Interacting with stroma: in some cases, tumor cells send signals to activate normal cells in the supporting stroma, which in turn produce growth factors that promote tumor growth. 10

11 Self-Sufficiency in Growth Signals Growth Factor Receptors Mutant receptor proteins deliver continuous mitogenic signals to cells, even in the absence of the growth factor in the environment. Overexpression of growth factor receptors is more common than mutations: cancer cells are hyper-responsive to levels of the growth factor that would not normally trigger proliferation. Example: epidermal growth factor (EGF) receptors ERBB1 is overexpressed in 80% of squamous cell carcinomas of the lung, 50% of glioblastoma and 80 to 100% of epithelial tumors of head and neck HER2/NEU (ERBB2), is amplified in 25% to 30% of breast cancers and adenocarcinomas of the lung, ovary, and salivary glands. High level of HER2 protein in breast cancer cells is a harbinger of poor prognosis!! 11

12 Self-Sufficiency in Growth Signals Growth Factor Receptors "bench to bedside" medicine What is the significance of HER2 in the pathogenesis of breast cancers? The clinical benefit derives from blocking the extracellular domain of this receptor with anti-her2 antibodies: Treatment of breast cancer with anti-her2 antibody 12

13 Self-Sufficiency in Growth Signals Signal-Transducing Proteins: RAS Intrinsic GTPase activity GTPase-activating proteins (molecular brakes) Approximately 30% of all human tumors contain mutated versions of the RAS gene 13

14 Self-Sufficiency in Growth Signals Signal-Transducing Proteins: RAS Normal RAS proteins flip back and forth between an excited signal-transmitting state and a quiescent state RAS proteins are inactive when bound to GDP; stimulation of cells by growth factors leads to exchange of GDP for GTP and subsequent conformational changes that generates active RAS The activated RAS in turn stimulates down-stream regulators of proliferation, such as the RAF-mitogen-activated protein (MAP) kinase mitogenic cascade, which floods the nucleus with signals for cell proliferation. 14

15 Self-Sufficiency in Growth Signals Signal-Transducing Proteins: RAS The excited signal-emitting stage of the normal RAS protein is short-lived, because its intrinsic guanosine triphosphatase (GTPase) activity hydrolyzes GTP to GDP. The GTPase activity of activated RAS protein is magnified dramatically by a family of GTPase-activating proteins (GAPs), which act as molecular brakes that prevent uncontrolled RAS activation by favoring hydrolysis. The mutant RAS protein (point mutations) is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. RAS is thus trapped in its activated GTP-bound form, and the cell is forced into a continuously proliferating state. 15

16 Self-Sufficiency in Growth Signals Signal-Transducing Proteins: ABL (non-receptor-associated tyrosine kinase) The ABL proto-oncogene has tyrosine kinase activity that is dampened by internal negative regulatory domains. The BCR-ABL hybrid protein has potent, unregulated tyrosine kinase activity, which activates several pathways, including the RAS-RAF cascade In chronic myeloid leukemia (CML) and certain acute leukemias, this activity is unleashed because the ABL gene is translocated from its normal location on chromosome 9 to chromosome 22, where it fuses with part of the breakpoint cluster region (BCR) gene 16

17 Self-Sufficiency in Growth Signals Signal-Transducing Proteins: ABL A cell with BCR-ABL fusion gene is dysregulated by inappropriate tyrosine kinase activity that leads to growth autonomy. The crucial role of BCR-ABL in transformation has been confirmed by the dramatic clinical response of patients with chronic myeloid leukemia after therapy with an inhibitor of the BCR-ABL fusion kinase called imatinib mesylate (Gleevec, STI571) Mechanism of action of STI571: it Inhibits growth by inhibiting the kinase activity. 17

18 Self-Sufficiency in Growth Signals Nuclear Transcription Factors Growth autonomy may thus occur as a consequence of mutations affecting genes that regulate transcription of DNA: MYC, MYB, JUN, FOS, and REL oncogenes regulate the expression of growth-promoting genes, such as cyclins. The MYC gene is involved most commonly in human tumors. The MYC proto-oncogene is expressed in virtually all cells, and the MYC protein is induced rapidly when quiescent cells receive a signal to divide. 18

19 Self-Sufficiency in Growth Signals Nuclear Transcription Factors Cell cycle activation Cyclins, CDKs + _ CDKIs Betrayed by Nature: The War on Cancer, Dr. Robin Hesketh In normal cells, MYC levels decline to near basal level when the cell cycle begins. Oncogenic versions of the MYC gene are associated with persistent expression or overexpression, contributing to sustained proliferation. 19

20 Self-Sufficiency in Growth Signals Nuclear Transcription Factors Oncogenic MYC gene Increases expression of genes that promote progression through the cell cycle (cyclins, CDKs) Represses genes that slow or prevent progression through the cell cycle (CDKIs) Dysregulation of the MYC gene occurs in: Burkitt lymphoma, a B-cell tumor: translocation t(8;14) Breast cancer Colon cancer Lung cancer Neuroblastomas (develops from the tissues that form the sympathetic nervous system) Amplification 20

21 Self-Sufficiency in Growth Signals Cyclins & Cyclin- Dependent Kinases (S) DNA synthesis phase (G 2 ) Premitotic growth phase (M) Mitotic phase (G 1 ) Presynthetic growth phase All cancers appear to have genetic lesions that disable the G1-S checkpoint causing cells to continually reenter the S phase 21

22 Self-Sufficiency in Growth Signals Cyclins & Cyclin- Dependent Kinases Cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or more CDK Cyclin D genes: overexpressed in many cancers, including those affecting the breast, esophagus, liver, and a subset of lymphomas. CDK4 gene is amplified in melanomas, sarcomas, and glioblastomas. Cyclin B and cyclin E are mutated in some malignant neoplasms, but they are much less frequent than those affecting cyclin D/CDK4. CDKIs are disabled by mutation, gene silencing, deletions in many cancers. 22

23 Insensitivity to Growth-Inhibitory Signals Proto-Oncogenes + - Tumor suppressor genes Cell growth RB, p53, TGFβ Antigrowth signals can prevent cell proliferation by two complementary mechanisms: The signal may cause dividing cells to go into G 0 (quiescence) Cells may enter a postmitotic, differentiated pool and lose replicative potential. 23

24 Insensitivity to Growth-Inhibitory Signals Retinoblastoma Gene (RB) Two-hit hypothesis (Knudson, 1974) Two mutations (hits) of RB gene (chromosome 13q14) are required to produce retinoblastoma In familial cases (40%), children inherit one defective copy in the germ line; the other copy is normal. Retinoblastoma develops when the normal RB gene is lost in retinoblasts as a result of somatic mutation. In sporadic cases (60%), both normal RB alleles are lost by somatic mutation in one of the retinoblasts. 24

25 Insensitivity to Growth-Inhibitory Signals 25

26 Insensitivity to Growth-Inhibitory Signals Retinoblastoma Gene (RB) A cell heterozygous at the RB locus is not neoplastic. Tumors develop when the cell becomes homozygous for the mutant allele or, in other words, loses heterozygosity of the normal RB gene. it is now evident that homozygous loss of this gene is a fairly common event in several tumors: Breast cancer Small-cell cancer of the lung Bladder cancer 26

27 Insensitivity to Growth-Inhibitory Signals Retinoblastoma Gene (RB) When RB is phosphorylated by the cyclin D-CDK4/6 and cyclin E-CDK2 complexes, it releases E2F. E2F then activates transcription of S-phase genes. The phosphorylation of RB is inhibited by CDKIs, because they inactivate cyclin-cdk complexes Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits chromatin remodeling factors (histone deacetylases and histone methyltransferases), and inhibits transcription of genes whose products are required for the S phase of the cell cycle. Mutations in other genes that control RB phosphorylation can mimic the effect of RB loss (CDK4, cyclin D, CDKI) 27

28 Insensitivity to Growth-Inhibitory Signals In G 1, diverse signals are integrated to determine whether the cell should enter the cell cycle, exit the cell cycle and differentiate, or die RB is a key node In this decision Chromatin remodeling proteins The transition from G 1 to S is believed to be an extremely important checkpoint in the cell cycle clock 28

29 Insensitivity to Growth-Inhibitory Signals Transforming Growth Factor-β Pathway TGF-β is a potent inhibitor of proliferation Transcriptional activation of CDKIs Repression of growth-promoting genes (c-myc, CDK2, CDK4, cyclins A/E) In 100% of pancreatic cancers and 83% of colon cancers, at least one component of the TGF-β pathway is mutated! 29

30 Insensitivity to Growth-Inhibitory Signals p53: Guardian of the Genome p53 senses DNA damage and assists in DNA repair by causing G 1 arrest and inducing DNA repair genes. A cell with damaged DNA that cannot be repaired is directed by p53 to either enter senescence or undergo apoptosis. With homozygous loss of p53, DNA damage goes unrepaired, mutations become fixed in dividing cells, and the cell turns onto a oneway street leading to malignant transformation. 30

31 p53: Guardian of the Genome 31

32 References Cover image Basic Pathology 8th Edition, by Kumar, Cotran and Robbins Basic Pathology 9th Edition, by Kumar, Cotran and Robbins 32

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