BioSci 145A Lecture 15 - Oncogenes and Cancer
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1 BioSci 145A Lecture 15 - Oncogenes and Cancer Topics we will cover today Introduction to normal and cancer cells Characteristics of cells in culture Cancerous changes in cells Viruses can harbor transforming genes DNA from tumor cells can transform normal cultured cells Oncogenes and cell growth tumor suppressor genes Last year s final exam is posted Don t forget that the next two lectures will be held in the Beckman Laser Institute Library No office hours on the following dates (I will be out of town) 3/1 3/6 Office hours for 3/8 will be held on 3/9 from 2-3 BioSci 145A lecture 15 page 1
2 Introduction to normal and cancer cells Most cells in the organism have a finite lifetime majority of differentiated cells are postmitotic stem cells can divide nearly endlessly other cell types that typically divide skin lining of gut hematopoeitic stem cells hair follicles liver cells can dedifferentiate, re-enter the cell cycle cell growth and division are tightly controlled most cells that can divide are only capable of a finite number of cell divisions so-called Hayflick limit cancer cells are a notable exception Cancer cells have lost their ability to regulate their own growth or to respond to normal growth regulatory cues or to sense their proper location in the organism each of these characteristics of cancer cells contributes to disease progression a variety of genetic events are responsible generally speaking, different genetic events can be associated with characteristics of the developing tumor. BioSci 145A lecture 15 page 2
3 Introduction to normal and cancer cells (contd) Three types of changes occur as a cell becomes tumorigenic immortalization - cells retain the ability to divide endlessly not necessarily detrimental to organism telomerase transformation - cells stop responding to normal growth controls do not need growth factors and/or do not respond to growth inhibitors transformed cells typically form tumors in situ metastasis - cells gain the ability to move from their normal location and invade other tissues very dangerous feature of cancer cells aberrant regulation of extracellular matrix proteases BioSci 145A lecture 15 page 3
4 Cells in culture growth characteristics of normal and tumor cells differ normal cells do not grow well, in vitro, typical cancer cells grow very well primary cells are the immediate descendents of cells taken directly from a tissue. such cells divide a small number of times and then stop growing - senescence subsequently, most cells will die. Lewin calls this the crisis stage if the cells are kept and fed for a long time, a small number may begin to grow cell lines are cells that successfully pass through crisis and gain the ability to divide indefinitely many, if not most, overexpress telomerase Fundamental rule - Cells (even primary cells) change their phenotype almost immediately when they are placed in culture degree of difference depends on the similarity of their microenvironment to their usual environment extracellular matrix type and density of surrounding cells change usually comes after several cell divisions. primary cells that stop dividing will maintain more of their phenotype than those that divide BioSci 145A lecture 15 page 4
5 Cells in culture (contd) Characteristics of cells in culture - most cells grow as a monolayer for the following reasons: anchorage dependence - cells require a substrate to grow on solid or semi solid medium serum dependence - cells require substances in serum to grow commonly called growth factors but in reality there are two different types mitotic factors - required for cells to grow and divide» typically peptide growth factors, e.g. FGF, EGF, PDGF, etc survival factors - not strictly required for cell division, but required for cells to survive in culture» typically lipids or other small molecules, e.g. retinol, 14-hydroxy retroretinol density-dependent inhibition (contact inhibition) - cells only grow until confluence surface is completely covered at this time cells go into G0 and exit the cell cycle cytoskeletal organization - cells are flat and extended on the surface BioSci 145A lecture 15 page 5
6 Cells in culture (contd) illustrates morphological differences flat vs rounded up contact inhibition transformed cells pile up on plates and cluster in 3D nuclear morphology note strong staining in transformed cells, a higher resolution picture would show multinucleate cells and mitotic figures BioSci 145A lecture 15 page 6
7 Cells in culture (contd) How does one judge the normalcy of cultured cells? much can be surmised from morphology what is the chromosomal constitution of the cells? chromosomal duplications, deletions and translocations are common in culture cells that have changed from normal, diploid state are aneuploid are the cells anchorage dependent? most normal cells (except blood cells) are anchorage dependent many transformed cells can grow in soft agar are the cells serum dependent? many abnormal cells are serum independent but many normal cell lines can be adapted to low or serum-free conditions do the cells express normal protein complement? do the cells form tumors if injected into animals? if not, they are not transformed cells originating from tumors are typically transformed reduced serum dependence reduced anchorage independence reduced contact inhibition - cells grow in foci will cause tumors if injected into animals typically use nude mice (lack significant part of immune system). somewhat cheating BioSci 145A lecture 15 page 7
8 Cancerous changes in cells benign vs malignant tumors benign tumors contain cells that look and function like normal cells express normal complement of proteins typically remain localized to appropriate tissues often surrounded by a fibrous capsule of connective tissues can become problematic if: their size interferes with normal function of the tissue (e.g. brain tumor) they secrete excessive amounts of biologically active substances such as hormones (e.g. pituitary tumor) malignant tumors look qualitatively different from normal tissues of origin close enough to determine tissue of origin but not identical to normal tissue express only a subset of normal proteins many grow and divide more rapidly than normal can remain encapsulated in situ for a time (e.g. carcinoma in situ) later become invasive and metastatic (definition of malignant) many tumors produce growth factors that increase the local blood supply BioSci 145A lecture 15 page 8
9 Cancerous changes in cells (contd) Induction of tumors discovery of oncogenes led to the model that genetic changes could cause cancer tumor incidence increases with age -> a series of events is required to cause a tumor believed that 6-7 discrete genetic events are required to get a cancer agents that increase frequency of cell transformation are called carcinogens can be classified according to properties tumor initiators cause tumors typically cause DNA damage (e.g. benzapyrene-diol-epoxide) tumor promoters aid in the growth of transformed cells, typically by inhibiting growth control (e.g. phorbol esters) BioSci 145A lecture 15 page 9
10 Cancerous changes in cells (contd) two classes of genes are targets of mutations that cause transformation oncogenes encode proteins that can transform cells or cause cancer in animals most are dominant gain of function mutations - three basic types point mutations that cause constitutively active protein products gene amplification that leads to overexpression translocations that result in inappropriate expression (Dr. La Morte) tumor suppressor genes are recessive, loss-offunction mutations that inactivate cellular genes that regulate growth or cell cycle five classes of tumor suppressor genes intracellular proteins that regulate or inhibit progression through the cell cycle receptors for secreted hormones that should inhibit cell proliferation (e.g. TGF-beta) checkpoint control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal proteins that promote apoptosis (programmed cell death) enzymes that participate in DNA repair BioSci 145A lecture 15 page 10
11 Viruses can harbor transforming genes Peyton Rous (1911) took chicken fibrosarcomas, ground them up, filtered out all cells, cellular debris and things as small as bacteria injected this filtrate into other chickens -> fibrosarcomas Rous sarcoma virus remains one of the most virulent tumor viruses ever discovered received the Nobel Prize in 1966 (55 years later) when it was finally discovered that a virus was the cause of the cancer RSV contains an oncogene v-src that was demonstrated to be required for cancer induction RSV is a retrovirus with only 4 genes so this was relatively easy to demonstrate Bishop and Varmus (1977) showed that normal cells from chickens and other species contained a cellular homolog of v-src. This c-src (cellular src) was the first proto-oncogene fundamental discovery that revolutionized the field (and got them a Nobel prize) was that cancer may be induced by the action of normal, or nearly normal cellular genes that were incorporated into transducing viruses turns out that c-src is a protein tyrosine kinase that is constitutively active when mutated BioSci 145A lecture 15 page 11
12 Viral oncogenes (contd) many acutely transforming retroviruses exist affect a variety of species impact many cellular signaling pathways fundamental mechanism is transduction of cellular gene and later mutation due to inaccurate viral reverse transcriptases BioSci 145A lecture 15 page 12
13 Viral oncogenes (contd) oncogenes may be involved in many types of cancers same c-onc (cellular oncogene) may be represented as v-onc (viral oncogenes) in a variety of cancers sis in both simian and feline sarcoma viruses viruses may contain related v-onc genes Harvey and Kirsten sarcoma viruses contain v- ras genes derived from two different members of the c-ras family evidence exists directly linking oncogenes from acutely transforming retroviruses with cancer first obtained from RSV using temperature sensitive mutations in v-src that allowed the phenotype to be reverted and regained identification of dominant oncogenes from acutely transforming retroviruses led to the model that single gene changes could cause cancers major opponent to this idea was Peter Duesberg who later became somewhat infamous for his criticism of the involvement of HIV in AIDS in this case, Duesberg was correct although the data linking acutely transforming retroviruses with cancer are strong, this mechanism is considered to be a relatively minor cause of cancer in humans BioSci 145A lecture 15 page 13
14 Viral oncogenes (contd) most acutely transforming retroviruses require normal retroviruses to get packaged into infective particles growth-promoting genes transduced by retroviruses confer a selective advantage because they increase the proliferation of infected tissues retroviruses cannot replicate unless cell is proliferating viruses can be transferred laterally from one organism to another, carrying the cancer potential along viruses can also be transferred to offspring BioSci 145A lecture 15 page 14
15 Viral oncogenes (contd) Not all viruses are acutely carcinogenic slow-acting retroviruses cause cancers by integrating near cellular protooncogenes and activating them inappropriately act slowly because integration into cellular protooncogenes is a rare event and other mutations may be required various DNA viruses oncogenic potential resides in a single function or group of related functions that are activated early in viral lytic cycle many oncogenes act by inactivating tumor suppressor genes polyoma T antigens papilloma virus E6,7 antigens and cervical cancer adenovirus E1A,B BioSci 145A lecture 15 page 15
16 Viral oncogenes (contd) Models for differences in properties between c-onc and v-onc quantitative model viral genes are functionally indistinguishable from normal cellular genes oncogenesis comes from overexpression expression in inappropriate cell types failure to turn expression off qualitative model c-onc genes are not intrinsically oncogenic mutations can convert into oncogenes that acquire new properties or lose old properties as usual, both models are correct mos, sis and myc genes can confer oncogenesis without significant mutation ras and src are changed by point mutations into dominant transforming oncogenes BioSci 145A lecture 15 page 16
17 Tumor cell DNA can transform cultured cells DNA from any of a variety of tumors can be transfected into cultured cells (typically NIH 3T3 cells) a small number take up DNA and form foci of transformed cells DNA is extracted from these foci and re-transfected into fresh cells to enrich for the specific human sequence genomic library is prepared and human clones selected by hybridizing with repetitive DNA (Alu) oncogene responsible is isolated and characterized BioSci 145A lecture 15 page 17
18 Tumor cell DNA can transform cultured cells (contd) Using such methods, a variety of human oncongenes were identified two important properties were identified in oncogenes isolated in this way many have closely related sequences in the DNA of normal cells this argues that the transformation was caused by mutation of a normal cellular gene (proto-oncogene) could be a point mutation or reorganization of genomic DNA many have counterparts in the oncogenes carried by acutely transforming retroviruses e.g.mutations were found in human bladder cancer DNA that corresponded those in the Ha-ras gene from harvey sarcoma virus. oncogenes found in this manner frequently do not cause tumors when introduced into normal cells NIH-3T3 cells already have a mutation in a tumor suppressor gene that, in combination with the introduced oncogene, could lead to transformation It is important to note that DNA with transforming activity can only be isolated from tumorigenic cells not present in normal DNA in general, this is not such a great way to identify oncogenes BioSci 145A lecture 15 page 18
19 Oncogenes and cell growth Seven classes of proteins control cell growth Collectively, these genes comprise the known set of genes involved in tumor formation BioSci 145A lecture 15 page 19
20 Oncogenes and cell growth (contd) Dominant transforming oncogenes are frequently created from proteins involved in regulating cell growth Growth factors Growth factor receptors Intracellular transducers of above Transcription factors that mediate the terminal effects of extracellular signaling BioSci 145A lecture 15 page 20
21 Oncogenes and cell growth (contd) Growth factors - proteins secreted by one cell that act on another cell (eg sis, wnt, int) oncoprotein growth factors can only transform cells that harbor the specific receptor Growth factor receptors - transmembrane proteins that are activated by binding to extracellular ligand (protein) very frequently protein tyrosine kinases oncogenicity usually results from constitutive (ligand-independent) activation Intracellular transducers - several classes protein tyrosine kinases, e.g. src G-protein signal transduction pathways - primary effectors of activated growth factors (e.g. ras) protein serine/threonine kinases (e.g. mos, raf) Transcription factors - these regulate gene expression directly myc - HLH protein fos, jun - b-zip proteins erba - nuclear receptor common feature among these is that each type of protein can trigger general changes in cell phenotypes by: initiating changes that lead to cell growth respond to signals that cause cell growth altering gene expression directly BioSci 145A lecture 15 page 21
22 Oncogenes and cell growth (contd) One example signaling pathway - MAPK (Bardwell lab) growth factor receptor tyrosine kinase ras kinase cascase (serine/threonine) transcription factors since the signal passes from one component to the next, inappropriate activation of one element in the cascade canl lead to widespread changes in gene expression these pathways are not strictly linear but branch and interact with many other signaling pathways can cause wider effects may require mutations in parallel pathways to get oncogenesis central importance of this pathway is illustrated by the number of components that can be mutated into oncogenes aberrant activation of mitogenic pathways can contribute to oncogenicity BioSci 145A lecture 15 page 22
23 Oncogenes and cell growth (contd) Growth factor receptors are ligand modulated dimers EGF receptor (v-erbb) is the prototype member EGF binding stimulates dimerization and activates tyrosine kinase cascade one oncogenic variant can dimerize in the absence of ligand and signals constitutively another lacks an internal regulatory domain resulting in constitutive signaling activated kinase domain autophosphorylates and can then interact with src family proteins BioSci 145A lecture 15 page 23
24 Oncogenes and cell growth (contd) transforming activity of src-family kinases is related to kinase activity autophosphorylation controls activity Y 416 -> active Y 527 -> weak, normally suppresses phosphorylation of Y 416 some oncoproteins activate src by interfering with phosphorylation of Y 527 BioSci 145A lecture 15 page 24
25 Oncogenes and cell growth (contd) modulation of transcription factor activity is important for oncogenesis can t cause cancer without altering gene expression! BioSci 145A lecture 15 page 25
26 Oncogenes and cell growth (contd) transcription factors and cancer several prominent families of oncogenes are transcription factors - rel, jun, fos, erba, myc, myb actions may be quantitative or qualitative effects may be to increase activity of the oncoprotein increased expression could upregulate target genes and influence growth, e.g. AP- 1 alternatively, the mutations could make the oncoprotein a dominant negative inhibitor of other cellular transcription factors (e.g. v-erba) many members are immediate early genes transcription is immediately upregulated without the requirement for new protein synthesis when cells are treated with mitogens likely to be involved with initiating or promoting growth increased activity would be expected to increase oncogenesis and it does with some but not others BioSci 145A lecture 15 page 26
27 Tumor suppressor genes oncogenesis is not typically dominant. A growing number of tumor suppressor genes have been identified that confer a genetic predisposition to cancers several types of genes are involved apoptosis proteins (eg p53) cell-cycle control proteins (RB) DNA-repair proteins (p53) classic examples are RB (retinoblastoma) and p53 loss of tumor suppressor genes is implicated in several infrequent cancers of childhood retinoblastoma Wilm s tumor BioSci 145A lecture 15 page 27
28 Tumor suppressor genes (contd) RB is a nuclear phosphoprotein that influences the cell cycle unphosphorylated RB prevents cell proliferation by binding to E2F and blocking G1/S transition phosphorylation of RB inhibits binding to E2F and releases block some oncogenes (e.g. SV40 T-antigen, E1A) function by sequestering RB and removing block to cell growth similar effects by loss of both alleles in human disease BioSci 145A lecture 15 page 28
29 Tumor suppressor genes (contd) A variety of other cell-cycle control proteins are tumor suppressor genes p16, p21 and D cyclins shown by identification of inactivating mutations in a variety of human tumors in quiescent cells RB is not phosphorylated D cyclin levels are low or absent p16, p21 and p27 prevent activity of cdk-cyclin complexes cdc2, cdk2 and cdk4,6 interact with cyclins and promote cell cycle this is blocked by tumor suppressor genes BioSci 145A lecture 15 page 29
30 Tumor suppressor genes (contd) P53 suppresses cell growth or triggers apoptosis more than 50% of human tumors have lost p53 protein or harbor mutations in the gene a variety of mutations are possible recessive mutations cause loss of p53 function allowing unrestrained growth (eg. ko mice) others are dominant negative p53 mutants that interfere with normal p53 subunits in cells and allow unrestrained growth (eg rare cancers) BioSci 145A lecture 15 page 30
31 Tumor suppressor genes (contd) p53 has dual functions cells normally have low levels of p53 DNA damage induces large increase in p53 levels increased p53 leads to growth arrest until DNA is repaired if cells are in G1 cells in S-phase or later are triggered to become apoptotic p53 is a transcription factor that typically activates one target is p21 -> cell cycle arrest another is GADD45 - a DNA repair protein role in inducing apoptosis is unknown at present apoptosis is an important pathway in preventing tumor formation - blocking it is a common strategy BioSci 145A lecture 15 page 31
32 Cancer - putting it all together BioSci 145A lecture 15 page 32
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