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Carcinogenesis

Carcinogenesis

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Carcinogenesis

  1. 1. Faculty of Medicine caa NEOPLSIA 2021 Carcinogenesis King Abdulaziz University Rabigh Branch
  2. 2. CARCINOGENESIS IS A MULTISTEP PROCESS
  3. 3. Cancer is a disease of the cell cycle Do you agree
  4. 4. What Is the Connection Among Cancer, the Cell Cycle, and Genetics? Cells either grow and divide with control ...or not! All kinds of malignant growth that the term "cancer" represents, all have one lethal attribute in common: The cells of the malignancy go through the cell cycle without control. These cells disobey control mechanisms that lie with them.
  5. 5. What Is the Connection Among Cancer, the Cell Cycle, and Genetics?  Many protein molecules involved in the cell cycle, each is the product of a single gene.  When there is a mutation in one of these genes, it can:  increase the likelihood that a cell will become cancerous and eventually, through repeated, unrestrained division, overtake the normal cells, become malignant;  possibly spread, or metastasise throughout the body
  6. 6. What Is the Connection Among Cancer, the Cell Cycle, and Genetics? Cancer can develop at almost any stage in life. Some forms of cancer develop very early, such as retinoblastoma (a cancer of the eye) Others tend to develop in childhood, such as various forms of leukaemia, a cancer of the blood There are many forms that develop during adulthood. In each case, cancer is the result of a mutated gene, or a series of mutated genes, that lead to unregulated cell growth and haphazard controls over cell proliferation.
  7. 7. MALIGNANT NEOPLASM (CANCER) • Is multifactorial disease (genetic, environmental) – Types of genes which may mutate to cause cancer: (tumour suppressor genes, oncogenes, DNA repair genes, telomerase, p53) – Environmental agents associated with cancer such as viruses, tobacco smoke, food, radiation, chemicals, pollution
  8. 8. • Cancer is considered as a genetic disease; occurs sporadically (somatic mutations), or as a hereditary trait. • Genes in which mutations cause cancer fall into two distinct categories: – Oncogenes – Tumor suppressor genes (TSGs) fall into two types Gatekeepers and Caretakers GENETIC BASIS OF CANCER
  9. 9. • Oncogene is a mutant allele of a proto-oncogene, whose altered function or expression results in abnormal stimulation of cell division and proliferation. – Proto-oncogene is normal gene that has physiologic function via its protein that regulate cell growth (proliferation & apoptosis) and differentiation ONCOGENES
  10. 10. ONCOGENES • Oncogenes facilitate malignant transformation by stimulating proliferation or inhibiting apoptosis. • Oncogenes have a dominant effect at the cellular level – when it is activated or overexpressed, a single mutant allele is sufficient to initiate the change in phenotype of a cell from normal to malignant.
  11. 11. ONCOGENES • The mutation can be an activating gain-of- function mutation in the coding sequence of the oncogene itself, a mutation in its regulatory elements, or an increase in its genomic copy number, leading to unregulated ectopic function of the oncogene product.
  12. 12. ONCOGENES • Activated oncogenes encode proteins such as: – proteins in signaling transduction pathways for cell proliferation (K-Ras, H-Ras, N-Ras) – receptors and cytoplasmic proteins that transduce signals – transcription factors that respond to the transduced signals and control the expression of growth-promoting genes (myc) – inhibitors of programmed cell death machinery
  13. 13. Proto-oncogene activation
  14. 14. Proto-oncogene activation • Point mutation: Ras oncogene point mutation results in decreased GTPase activity. – GTPase: enzyme that hydrolyze guanosine triphosphate. • Chromosomal rearrangement: (translocation and inversion) Philadelphia chromosomes, Burkitt’s lymphoma gene arrangement • Gene amplification
  15. 15. • Fig 16-3. Mechanisms of tumorigenesis by oncogenes of various classes. Unregulated growth factor signaling may be due to mutations in genes encoding growth factors themselves (1), their receptors (2), or intracellular signaling pathways (3). Downstream targets of growth factors include transcription factors (4), whose expression may become unregulated. Both telomerase (5) and antiapoptotic proteins that act at the mitochondria (6) may interfere with cell death and lead to tumorigenesis.
  16. 16. • TSGs are normal genes and their normal function is to regulate cell division, so can suppress the development of cancer – TSGs encode a proteins which are part of the system that regulates cell division (keeping cell division in check). • When mutated, TSGs lose their function, and as a result uncontrolled cell growth may occur – This may contribute to the development of a cancer • Both alleles need to be mutated or removed in order to lose the gene activity. – The first mutation may be inherited or somatic. – The second mutation will often be a gross event leading to loss of heterozygosity TUMOR SUPPRESSOR GENES (TSGS)
  17. 17. Knudsen’s “two hit” hypothesis explain why certain tumors can occur in both hereditary and sporadic forms
  18. 18. The Two-Hit Origin of Cancer • For example, it was suggested that the hereditary form of the childhood cancer retinoblastoma might be initiated when a cell in a person heterozygous for a germline mutation in a tumor-suppressor retinoblastoma gene, required to prevent the development of the cancer, undergoes a second, somatic event that inactivates the other allele.
  19. 19. The Two-Hit Origin of Cancer • As a consequence of this second somatic event, the cell loses function of both alleles, giving rise to a tumor. The second hit is most often a somatic mutation, although loss of function without mutation, such as occurs with transcriptional silencing (epigenetic changes), has also been observed in some cancer cells.
  20. 20. The Two-Hit Origin of Cancer • In the sporadic form of retinoblastoma, both alleles are also inactivated (two somatic events occurring in the same cell). • familial polyposis coli, familial breast cancer, neurofibromatosis type 1 (NF1), hereditary nonpolyposis colon carcinoma, and a rare form of familial cancer known as Li-Fraumeni syndrome.
  21. 21. • Gatekeeper TSGs regulate the cell cycle and control cell growth directly – they block tumor development by regulating the transition of cells through checkpoints ("gates") in the cell cycle or by promoting apoptosis and, thereby, controlling cell division and survival. – loss-of-function mutations of gatekeeper genes lead to uncontrolled cell proliferation. TUMOR SUPPRESSOR GENES (TSGS)
  22. 22. TUMOR SUPPRESSOR GENES (TSGS) • Gatekeeper TSGs encode: – regulators of various cell-cycle checkpoints – mediators of programmed cell death
  23. 23. • Caretaker TSGs are involved in repairing DNA damage and maintaining genomic integrity. – Loss of function of caretaker genes permits mutations to accumulate in proto-oncogenes and gatekeeper genes, which, in concert, go on to initiate and promote cancer. TUMOR SUPPRESSOR GENES (TSGS)
  24. 24. • Caretaker TSGs encode: – proteins responsible for detecting and repairing mutations – proteins involved in normal chromosome disjunction during mitosis – components of programmed cell death machinery TUMOR SUPPRESSOR GENES (TSGS)
  25. 25. • Loss of both alleles of genes that are involved in repairing DNA damage or chromosome breakage leads to cancer indirectly by allowing additional secondary mutations to accumulate either in proto-oncogenes or in other TSGs. TUMOR SUPPRESSOR GENES (TSGS)
  26. 26. Gene Gene product and possible function sporadic DISORDERS IN WHICH THE GENE IS AFFECTED Gatekeepers Familial Sporadic RB1 p110 Cell cycle regulation Retinoblasto ma Retinoblastoma, small cell lung carcinomas, breast cancer TP53 p53 Cell cycle regulation Li-Fraumeni syndrome Lung cancer, breast cancer, many others Selected Tumor-Suppressor Genes Caretakers Familial Sporadic BRCA1, BRCA2 Brca1, Brca2 Chromosome repair in response to double- stranded DNA breaks Transcriptional regulation and DNA repair Familial breast and ovarian cancer Breast cancer, ovarian cancer MLH1, MSH2 Mlh1, Msh2 Repair nucleotide mismatches between strands of DNA (Microsatellite instability, a marker of DNA mismatch repair) Hereditary nonpolyposis colon cancer Colorectal cancer
  27. 27. • The p53 protein is a DNA-binding protein that appears to be an important component of the cellular response to DNA damage. • In addition to being a transcription factor that activates the transcription of genes that stop cell division and allow repair of DNA damage, p53 also appears to be involved in inducing apoptosis in cells that have experienced irreparable DNA damage. TP53
  28. 28. TP53 • Loss of p53 function, therefore, allows cells with damaged DNA to survive and divide, thereby propagating potentially oncogenic mutations. The TP53 gene can therefore be considered to also be a gatekeeper TSG.
  29. 29. • Different types of genetic alterations are responsible for initiating cancer. These include mutations such as: – activating or gain-of-function mutations, including gene amplification, point mutations, and promoter mutations, that turn one allele of a proto-oncogene into an oncogene – chromosome translocations that cause misexpression of genes or create chimeric genes encoding proteins with novel functional properties – loss of function of both alleles, or a dominant negative mutation of one allele, of TSGs. Tumor Initiation & Progression
  30. 30. • Once initiated, a cancer progresses by accumulating additional genetic damage, through mutations or epigenetic silencing, of caretaker genes that encode the cellular machinery that repairs damaged DNA and maintains cytogenetic normality. • A further consequence of genetic damage is altered expression of genes that promote vascularization and the spread of the tumor through local invasion and distant metastasis. Tumor Initiation & Progression
  31. 31. • Stages in the evolution of cancer. Increasing degrees of abnormality are associated with sequential loss of tumor- suppressor genes from several chromosomes and activation of proto-oncogenes, with or without a concomitant defect in DNA repair. • Multiple lineages carrying somewhat different mutational spectra and epigenetic changes are likely, particularly once metastatic disease appears.
  32. 32. Transformation is a multistep process
  33. 33. • Some tumor-suppressor genes directly regulate proto-oncogene function (gatekeepers); others act more indirectly by maintaining genome integrity and correcting mutations during DNA replication and cell division (caretakers). Activation of an antiapoptotic gene allows excessive accumulation of cells, whereas loss of function of apoptotic genes has the same effect. • Activation of oncogenes or antiapoptotic genes is dominant. Mutations in tumor-suppressor genes are recessive; when both alleles are mutated or inactivated, cell growth is unregulated or genomic integrity is compromised. Loss of pro-apoptotic genes may occur through loss of both alleles or through a dominant negative mutation in one allele.
  34. 34. Tumor Initiation & Progression • The development of cancer (oncogenesis) results from mutations in one or more of the vast array of genes that regulate cell growth and programmed cell death.
  35. 35. Tumor Initiation & Progression • When cancer occurs as part of a hereditary cancer syndrome, the initial cancer-causing mutation is inherited through the germline and is therefore already present in every cell of the body. • Most cancers, however, are sporadic because the mutations occur in a single somatic cell, which then divides and proceeds to develop into the cancer.
  36. 36. Micro-RNA Genes • The catalogue of genes involved in cancer also includes genes that are transcribed into noncoding RNAs from which regulatory microRNAs (miRNAs) are generated. • There are at least 250 miRNAs in the human genome that carry out RNA-mediated inhibition of the expression of their target protein-coding genes, either by inducing the degradation of their targets' mRNAs or by blocking their translation.
  37. 37. Micro-RNA Genes • Approximately 10% of miRNAs have been found to be either greatly overexpressed or down- regulated in various tumors, and are referred to as oncomirs. • One example is the 100-fold overexpression of the miRNA miR-21 in glioblastoma multiforme, a highly malignant form of brain cancer.
  38. 38. Micro-RNA Genes • Overexpression of some miRNAs can suppress the expression of tumor-suppressor gene targets, whereas loss of function of other miRNAs may allow overexpression of the oncogenes they regulate. • Since each miRNA may regulate as many as 200 different gene targets, overexpression or loss of function of miRNAs may have widespread oncogenic effects because many genes will be dysregulated.

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