Neoplasia II Lecture Notes PDF

PATHOLOGY | TRANS #3B LE Neoplasia II JOSELLI RUEDA-CU, RN, LLB, DTM&H, MHA, MPH, MD, FPSP | 09/20/2024 | Version 1...

PATHOLOGY | TRANS #3B LE Neoplasia II JOSELLI RUEDA-CU, RN, LLB, DTM&H, MHA, MPH, MD, FPSP | 09/20/2024 | Version 1 02 OUTLINE I. BIOLOGY OF NEOPLASIA I. Biology of Neoplasia VIII. Chemical Carcinogenesis Non-lethal damage lies at the heart of carcinogenesis A. Molecular Basis of A. Initiation of Carcinogenic (acquired mutation) Neoplasia Event Tumor is formed by the clonal expansion of a single B. Cellular and Molecular B. Promotion precursor cell (monoclonal) that has incurred genetic Hallmarks of Cancer IX. Cellular Transformation damage II. Causes of Neoplasia A. Characteristics of A. Theories of Origin Transformed (Neoplastic) Four classes of normal regulatory genes: III. Genomic Changes in Cells → Proto-oncogenes Tumors X. Clonality → Suppressor genes: growth inhibiting genes A. Point Mutations XI. Tumor Growth ▪ In most cases, both alleles must be damaged before B. Chromosomal Structural A. Cell Kill Theory transformation occurs Mutations B. Tumor Burden → Apoptosis regulation: regulation of programmed cell IV. DNA Alterations and C. Growth Fraction death Oncogenesis D. Cell Cycle → DNA repair A. Proto-oncogenes XII. Epidemiology of Neoplasia B. Tumor Suppressor Genes A. Key Concepts ▪ Principal targets of cancer causing mutation impairing C. DNA Repair Genes B. Effects of Neoplasia on the ability to recognize and repair non-lethal genetic D. Apoptotic Genes Body damage → mutator phenotype marked by genomic V. Telomere Shortening XIII. Diagnosis of Neoplasia instability VI. Hallmarks of Cancer A. Cytology A. Limitless Replicative B. Biopsy A. MOLECULAR BASIS OF NEOPLASIA Potential C. Autopsy ROLE OF GENETIC AND EPIGENETIC ALTERATIONS B. Angiogenesis D. Limitations of Diagnosis Carcinogenesis results from accumulation of C. Invasion and Metastasis E. Adjuncts to Histologic D. Evasion of Host Diagnosis complementary mutations in a stepwise function over time Defenses XIV. Molecular and Cytogenetic Driver Mutation E. Genomic Instability as Diagnosis → Mutations that contribute to the development of the Enabler of Malignancy XV. Treatment of Neoplasia malignant phenotype F. Cancer Enabling Effects A. Surgery Loss of function mutations in genes that maintain integrity of Inflammatory Cells and B. Radiation → Early step into malignancy in solid tumors Resident Stromal Cells C. Chemotherapy Once established, tumors evolve genetically during their G. Dysregulation of Cancer D. Immunotherapy outgrowth and progression under the pressure of Associated Genes E. Physical Agents VII. Tissue Evidence of F. Gene Therapy Darwinian selection (survival of the fittest) Carcinogenic Factors at XVI. Review Questions → Explains the natural history of cancer and changes in Work XVII.Reference tumor behavior following therapy A. Metaplasia XVIII. Formative Quiz B. Dysplasia XIX. Appendix C. Molecular Basis of Multistep Carcinogenesis Must Lecturer Book Previous Youtube ❗️ 💬 📖 📋 🔺 Know Trans Video SUMMARY OF ABBREVIATIONS Figure 1. Development of a cancer through stepwise ALL Acute Lymphoblastic Leukemia acquisition of complementary mutations[Lecture] CA Cancer CCS Cell cycle specific drugs → Figure 1 shows the order in which various driver CCNS Cell cycle non specific drugs mutations occur in initiated precursor cells varies from CML Chronic Myelogenous Leukemia tumor to tumor EBV Epstein-Barr Virus 1. Initiating mutation 2. Acquisition Of Genomic Instability ECM Extracellular Matrix 3. Acquisition Of Cancer Hallmarks EGFR Epidermal Growth Factor Receptor 4. Further Genetic Evolution HBV Hepatitis B virus HCV Hepatitis C virus GENETIC MODIFICATIONS HNPC Hereditary Nonpolyposis Cancer Change in expression and function of key genes HPV Human Papillomavirus Mutations → genomic instability → driver mutations → HSR Homologous Staining Region innumerable acquired mutations MHC Major Histocompatibility Complex Driver mutations: contribute to the development of the RB Retinoblastoma malignant phenotype TNF Tumor Necrosis Factor → First driver mutation: initiating mutation maintained in all of the cells of the subsequent cancer. This may TP53 Tumor Protein 53 preexist years before the malignancy is diagnosed. LE TG 1 | L. Nuesa, J. Obispo, J. Olivares, J. Oliveros, H. TE | P. Roces, JB. Ricafort AVPAA | A. Perez PAGE 1 of 27 TRANS 1 Ong, A. Opetina, J. Orduña, K. Orge, J. Oro, J. Patawaran VPAA | D. Patajo PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP → Consistent with the idea of cancer stem cell, which has Acquisition of genetic and epigenetic alterations that cause the capacity for self renewal and long-term persistence the above changes may be accelerated by: Phenotypic cancer hallmarks due to genomic alterations: → Genomic instability → Excessive growth → Cancer promoting inflammation → Local invasiveness II. CAUSES OF NEOPLASIA → Ability to form distant metastases The origin for many neoplasia is obscure EPIGENETIC MODIFICATIONS → Carcinogen Epigenetic modifications are usually passed on to daughter ▪ Any substance that can initiate tumor formation cells → Carcinogenic Potentially reversible by drugs inhibiting DNA or histone ▪ How cancer evolves from a certain substance modifying factors (man-made chemicals, drugs, and natural compounds) DNA METHYLATION ▪ Created by DNA methyltransferases A. THEORIES OF ORIGIN Tends to silence gene expression ENVIRONMENTAL Local DNA hypermethylation → silencing of tumor Dominant risk factor for most cancers suppressor genes → cell transformation Man-made chemicals (e.g. aniline dyes, bladder cancer) Changes in DNA methylation occur throughout the genome Drugs (eg. cigarette smoke and lung cancer, alcohol) (global changes) Natural compounds (eg. aflatoxins and liver cancer, diet Cells affected exhibit genomic instability and obesity) Aberrant DNA methylation in cancer cells → responsible for silencing some tumor suppressor genes ONCOGENIC VIRUSES Carry genes that dictate the production of neoplasia MODIFICATION OF HISTONES → Human papillomavirus (HPV) implicated in most Histone: protein that packages DNA into chromatin that squamous cell carcinoma of cervix and anogenital may either dampen or enhance gene expression squamous papillomas Catalyzed by enzyme associated with chromatin regulatory → Epstein Barr virus (EBV) implicated in African Burkitt’s complexes lymphoma Tumor specific changes in histone modification → far → Hepatitis B and C virus (HBV and HCV) implicated in ranging effects on gene expression in cancer cells the development of hepatocellular carcinomas B. CELLULAR AND MOLECULAR HALLMARKS OF RADIATION CANCER Ultraviolet light and skin cancers Eight fundamental changes in cell physiology: Hallmarks → Ultraviolet light induces pyrimidine dimers in DNA of Cancer Gamma radiation in leukemia, thyroid, lung, colon, and breast cancer → ionizing radiation induces mutations in the DNA HEREDITARY Chromosomes which have absent or defective anti-oncogenes that control growth (e.g. retinoblastoma that results from defective chromosome 13) OBSCURE DEFECTS: RACIAL PREDILECTIONS Higher incidence of breast cancer in American than Japanese women Far higher incidence of stomach cancer in Japanese than American men ALTERED DNA Mutation or damage to cell DNA Tumor suppressor genes → P53 - suppresses abnormal growth Figure 2. Hallmarks of Cancer[Lecture PPT] ▪ Fails to exert a controlling influence upon growth activation leading to neoplasia 1. Self sufficiency in growth signals ▪ Majority of malignancies are caused by p53 2. Insensitivity to growth-inhibitory signals mutations 3. Altered cellular metabolism (metabolic switch to aerobic Proto-oncogenes glycolysis: Warburg effect) → Genes that control cell growth Enables synthesis of macromolecules and organelles → Undergo mutation → become oncogenes → give rise to needed for rapid growth neoplasia 4. Immortality Limitless replicative potential → stem-like → avoid AGE cellular senescence and mitotic catastrophe Older persons have greater propensity to develop 5. Evasion of apoptosis neoplasms from lack of effective control mechanism 6. Sustained angiogenesis 7. Ability to metastasize 8. Ability to evade host immune response PATHOLOGY Neoplasia II PAGE 2 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP SILENT MUTATION Base substitutions resulting in no change in the amino acid or amino acid functionality when the altered messenger RNA is translated → E.g. codon AAA is altered to become AAG, the same amino acid (Lysine) will be incorporated into the peptide chain → Typically this occurs at the “Wobble Position” (the third base/base pair in a codon) ▪ Wobble positions are protection from point mutations through codon degeneracy/redundancy, leaving the produced amino acid unaltered. ▪ There are 64 codons (61 for amino acids, 3 are stop codons), but only 20 amino acids Figure 3. Number of new cases and rates, by age, sex, of all MISSENSE MUTATION malignant neoplasms (exc NMSC), UK 2003[Lecture PPT] Nonsynonymous mutation Single nucleotide change → different amino acid produced III. GENOMIC CHANGES IN TUMORS → Can manifest as a malignancy or a disease Turned on upon exposure to carcinogens → In sickle mutation: CTC (glutamic acid) → CAC Molecular mechanisms which proto-oncogenes are (valine) activated and cause damage: Two variations: conservative and nonconservative → Point Mutation: due to change in a particular nucleotide → Conservative: New amino acid has similar chemical base in the DNA properties to the original. Resulting functionality isn’t → Translocation: due to exchange in genetic information changed significantly. or formation of new genes ▪ i.e., Lys -> Arg. While steric interactions may be → Gene Amplification: reduplication of thousands of altered, both are still basic AAs. amino acids → Nonconservative: New amino acids are significantly First step to cancer formation is the transformation of cell different in terms of chemical properties. Functionality is → A transformed cell is a neoplastic cell which cannot altered drastically. revert back to normal ▪ i.e., Lys -> Val. Lys is basic, Val is a polar, branched AA. NONSENSE MUTATION Results in a premature stop codon (UAA, UGA, UAG) or nonsense codon in the transcribed mRNA → There is a change in sequencing, but encoding is abruptly stopped No new amino acids formed = no new manifestations Becomes truncated, incomplete, and usually nonfunctional Figure 4. A normal cell bombarded with carcinogens such as chemicals, radiations, infectious agents leading to DNA damage. The damage causes mutation and eventual formation of a transformed cell[Lecture PPT] 5 A. POINT MUTATIONS A.K.A. single base modification Causes a single nucleotide base change, insertion, or deletion of the genetic material, DNA or RNA → Frameshift mutation indicates the addition or deletion of Figure 5. Examples of how the various point mutations affect a base pair the transcribed mRNA codon and the resulting translated Recall the complementary base pairs: protein[Lecture PPT] → DNA: AT (adenine, thymine), GC (guanine, cytosine) B. CHROMOSOMAL STRUCTURAL MUTATIONS → RNA: AU (adenine, uracil), GC (guanine, cytosine) → Stop codons: These involve alterations to the genome on the level of the ▪ UAG (U Are Gone) chromosome ▪ UAA (U Are Away) TRANSLOCATION ▪ UGA (U Go Away) Occurs when two chromosomes switch/exchange → Effects of point mutation: segments with each other, altering their resulting ▪ Silent mutations functionality. Most common forms are: ▪ Missense mutations ▪ Nonsense mutations PATHOLOGY Neoplasia II PAGE 3 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP → Reciprocal translocation: Two chromosomes simply GENE AMPLIFICATION switch segments with each other, these do not have to Gene duplication → massively increased gene product be the same size Gene amplification is a cytogenetic hallmark of cancer. → Robertsonian translocation: Two chromosomes split Amplification typically takes two forms: off a small segment each. These small segments join → Homologous Staining Regions (HSR): The gene is together as a “new” hetero-chromatic chromosome, duplicated and remains in the chromosome. while the larger remainders of the originals join as a ▪ When viewed on a karyotype with Giemsa Banding, “new metacentric” chromosome HSRs are bands that are much larger than they should be. → Double Minutes: The duplicated gene exists as fragments of extrachromosomal DNA. Figure 6. Reciprocal translocation. Segments of the original blue and pink chromosomes have been swapped, producing the recombinant chromosomes[Lecture PPT] Figure 10. Amplification of the N-MYC gene is found in human neuroblastomas. The gene is on Chromosome 2p, but Figure 7. The original pink and green chromosomes have both its HSR are integrated into other autosomes (4, 9, 13 [Lecturer] shed small segments, recombining into a hetero-chromatic chromosome. The remainders of the original have fused into a IV. DNA ALTERATIONS AND ONCOGENESIS “new metacentric” chromosome[Lecture PPT] Proto-Oncogenes → May play a role in promoting growth and regulation in normal cells and even embryogenesis → Typically “turned off” in adults → May be “turned on” by the following transformations: ▪ Point mutations ▪ Chromosomal Translocations − These in particular are associated with Leukemias and Lymphomas, i.e., Philadelphia Chromosome (Ph1) of Chronic Myelogenous Leukemia, and the t(8:14) translocation in Burkitt’s Lymphoma. ▪ Gene Amplification (duplication) Neoplasms have a greater tendency to karyotypic Figure 8. Chronic Myelogenous Leukemia (CML) is caused by a reciprocal translocation between Chromosomes 9 & 22. abnormalities including: Chromosome 22’s BCR (breakpoint cluster region) produces a → Translocations chimeric gene with Chromosome 9’s ABL region. The resulting ▪ These in particular are associated with Leukemias mutant protein enhances tyrosine kinase activity, an oncogenic and Lymphomas, i.e. Philadelphia Chromosome change[Lecture PPT] (Ph1) of Chronic Myelogenous Leukemia, and the t(8:14) translocation in Burkitt’s Lymphoma. → Deletions (both point and chromosomal scale) → Gene amplification ▪ Also activators of proto-oncogenes This also explains why neoplasms tend to develop more and more abnormalities over time Figure 9. Burkitt’s Lymphoma is caused by a reciprocal translocation between Chromosome 8’s myc oncogene, and a Space intentionally left blank gene adjacent to Chromosome 14’s Ig gene. The resulting chromosome produces increased myc protein: an oncogenic change[Lecture PPT] PATHOLOGY Neoplasia II PAGE 4 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP A. PROTO-ONCOGENES Speed up the cell division or help cells live longer Unmutated cellular counterpart of oncogenes Receptor tyrosine kinase pathway is the most frequently mutated oncogenic pathway in human neoplasms Tumor suppressor genes slow down division, or cause cells to die at the right time DNA repair genes → Genes engaged in DNA repair → Mutations pile up throughout when the DNA repair gene is altered Apoptotic genes ONCOGENES, ONCOPROTEINS, AND UNREGULATED Figure 11. Neoplasia results from mutations that either CELL PROLIFERATION activate one oncogene from a proto-oncogene, or deactivate Proto-oncogenes: normal cellular genes whose products both allele copies of tumor suppressor genes. [Lecture PPT] promote cell proliferation ADDITIONAL INFORMATION ON DNA ALTERATIONS & Oncogenes: mutated or over expressed versions of ONCOGENESIS proto-oncogenes that function autonomously with lost 1. What genes are mutated to cause cancer? dependence on normal growth promoting signals → Proto Oncogenes speed up cell division or help cells → Promote autonomous cell growth in cancer cells to live longer Oncoproteins: protein encoded by an oncogene that → Tumor Suppressor Genes: Cells that slow down drives increased cell proliferation through one of several division or cause cells to die at the right time mechanisms ▪ p53 regulates both BCL-2 & BAX, two proteins → Resemble normal products of proto-oncogenes but are heavily involved in apoptosis autonomous → DNA Repair Genes engage in DNA repair. When → Freed from normal checkpoints, and controls that limit mutated, other mutations will begin to pile up growth excessive proliferation throughout the DNA → Constitutive expression of growth factors and their → Apoptotic Genes: When mutated, confers cognate factor receptors, setting up an autocrine cell resistance to apoptosis for the neoplastic cell(s). signaling loop Resistance can be gained through: GROWTH FACTOR RECEPTORS ▪ Expression of an anti-apoptotic protein i.e. BCL-2 ▪ Downregulation/mutation of pro-apoptotic Mutation in growth factor receptors, non-receptor tyrosine pathways or proteases i.e. BAX kinases, or downstream signaling molecules that led to 2. How is apoptosis related to cancer? constitute signaling → DNA damage → useless cell / harm to individual Growth Factor Receptors: receptor tyrosine kinases are → Apoptosis/programmed cell death evolved as a rapid transmembrane proteins with extracellular ligand-binding & irreversible process to efficiently and safely domain and a cytoplasmic tyrosine kinase domain eliminate dysfunctional cells Key players in receptor tyrosine kinase signaling: RAS and → A hallmark of cancer is the ability of malignant cells P13K to evade apoptosis → Mutations → constitutive, growth factor-independent 3. Are all cancers genetic? tyrosine kinase activity → Cancers are not just caused by one gene → Mutant receptors deliver continuous mitogenic signals to → Most cancers occur when several genetic changes the cell, even in the absence of growth factor in the occur in a cell, known as sporadic cancer environment → Some people inherit mutated genes which makes Receptor tyrosine kinase is constitutively activated by their chance of developing a particular cancer higher multiple mechanisms, and gene amplifications. than normal Targeted therapy focus on genes enhancing tyrosine → Usually an illness of older people kinase activity 4. Is cancer hereditary? Downstream components of receptor tyrosine kinase → Hereditary cancers tend to strike at younger ages signaling pathway: → Hereditary cancer develops as a result of gene → With RAS mutations, activating tyrosine kinases are mutation passed down from a parent to a child almost always absent implying that the activated RAS → Cancer is not inherited, only the gene that increases can completely substitute for tyrosine kinase activity the risk of developing it 5. What gene is mutated in more than 50% of cancers? → Germline mutations in BRCA1 or BRCA2 genes increase a woman’s risk of developing hereditary breast or ovarian cancers → p53 is the most commonly mutated gene in people Space intentionally left blank who have cancer → More than 50% of all cancers involve a damaged or missing p53 gene PATHOLOGY Neoplasia II PAGE 5 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP GENE MUTATIONS MUTATIONS INVOLVING RAS PROTEIN Table 1. Gene Mutation and Associated Cancer Point mutation of RAS family gene: most common type Associated of abnormality in proto oncogenes in human tumors. Gene Mutation There are 3 RAS genes in humans (HRAS, KRAS, NRAS) Cancer Expressions of mutated RAS protein: EGF Receptor Point Mutation Lung Cancer → 15-20% of all human tumors express mutated RAS Tyrosine Kinase proteins HER2 Receptor Gene Breast Cancer → 90% of pancreatic adenocarcinoma and cholangioma Tyrosine Kinase Amplification → 50% of colon, endometrial and thyroid carcinoma JAK2 Tyrosine Point Mutation Myeloproliferativ → 30% of large adenocarcinoma and myeloid leukemia Kinase e Disorder ABL Chromosome Chronic Non-receptor Translocation Myelogenous Tyrosine Kinase and Leukemia (CML) Creation of and Acute BCR-ABL fusion Lymphoblastic gene Leukemia (ALL) RAS Point Mutation Many Cancers P13K and BRAF Point Mutation Many Cancers Serine/ Threonine Kinase MUTATIONS INVOLVING BRAF The BRAF gene plays a role in regulation of the RAS/MAPK pathway which ultimately controls cell Figure 12. Model for Action of RAS genes[Lecturer’s PPT] differentiation When a normal cell is stimulated through a growth factor BRAF: proto-oncogene of Ras signal transduction receptor, inactive (GDP-bound) RAS is activated to a Serine/ threonine protein kinase that sits on top (upstream) GTP-bound state of other serine/threonine kinases of the MAPK family Activated RAS recruits RAF → stimulates MAP-kinase → Mutation → significant pro-growth signal in most cells pathway to transmit growth-promoting signals to the ▪ Unlike other serine/ threonine protein kinases on the nucleus lower cascade (downstream) which do not produce The mutant RAS protein is permanently activated significant pro-growth signals because of inability to hydrolyze GTP → continuous → Mutation → activate transcription factor → pro-growth stimulation of cells without any external trigger signals The anchoring of RAS to the cell membrane by the Noted in 100% hairy cell leukemia, 60% of melanoma, farnesyl moiety is essential for its action 80% of benign nevi (birthmark or mole on the skin) ONCOGENES IN NEOPLASMS MUTATIONS INVOLVING PI3K FAMILY OF PROTEINS Table 2. General Mechanism of Growth Promotion and PI3K is recruited by receptor tyrosine kinase activation to Summary of Oncogenes Involved in Neoplasm plasma membrane-associated signaling protein complexes PTEN negatively regulates PI3K Action Example → PTEN is a tumor suppressor gene whose function is lost Overexpression of growth factor receptors c-erb-B2 through mutation or epigenetic silencing (particularly in (i.e., epidermal growth factor or EGF) making endometrial carcinoma) cells more sensitive to growth stimuli PI3K and its antagonist PTEN are most frequently mutated Increased growth factor signal transduction by ras 30% of breast carcinoma have gain of function mutation an oncogene that lacks the GTPase activity of its alpha-isoform of the PI3K catalytic subunit that limits GTP induction of cytoplasmic kinases that drive cell growth MUTATIONS INVOLVING NUCLEAR TRANSCRIPTION Overexpression of a gene product by c-sis FACTORS stimulation from an oncogene (such as ras) Increased expression of MYC, a master transcription factor Lack of normal gene regulation through c-abl that regulates genes needed for rapid cell growth by: translocation of a gene where it is controlled → Deregulation through chromosomal translocations by surrounding genes to a place where it is no (Burkitt’s lymphoma, other hematologic malignancies) longer inhibited → Gene amplification (neuroblastoma) Binding of oncogene product to the nucleus c-myc → Increased activity of upstream signaling pathways with DNA transcriptional activation to promote (many cancers) entry into the cell cycle Mutations that increase the activity of cyclin-dependent kinase (49CDK4/D cyclin complexes), which promote progression PATHOLOGY Neoplasia II PAGE 6 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP Table 3. Common Oncogenes with their Associated Neoplasms 🔺Introduction to Cancer Biology (Part 1)- Abnormal Signal Transduction Oncogene Associated neoplasm Normal cells require external signals to regulate growth c-erb-B2 Breast and ovarian carcinomas and stop dividing. These signals are transmitted via ras Many carcinomas and leukemias receptors on the cell surface. c-sis Gliomas Cancer cells can bypass these controls by producing c-abl Chronic myelogenous leukemia, acute their own growth signals, overproducing receptors (gene lymphocytic leukemia amplification), or activating receptors without ligands (ligand-independent activation) leading to uncontrolled c-myc Lymphomas growth and division. BRCA-1 Breast and ovarian carcinomas EGF Receptor Overexpression: The epidermal growth APC Colonic adenocarcinomas factor receptor (EGFR) is often overexpressed in NF-1 Neurofibromas and neurofibrosarcomas cancers , promoting tumor growth. Rb Retinoblastomas, osteosarcomas, small cell Two major pathways involved in cancer growth are the Ras-Raf-MAPK pathway and the PI3K-Akt-mTOR lung carcinomas pathway. Disruptions in these pathways are implicated p53 Many carcinomas in tumor progression. bcl-2 Chronic lymphocytic leukemia, lymphomas Anti-cancer therapies can target different parts of the cancer cell growth process: Legend: → Bevacizumab (Avastin) → VEGF to inhibit blood Yellow: Oncogenes that promote growth and increased supply to tumors. cellular division → Cetuximab (Erbitux) → EGFR to prevent ligand Green: Suppressor genes which are supposed to regulate binding. the cell division but it’s being suppressed → Gefitinib (Iressa) and Erlotinib (Tarceva) → RTK to Blue: Apoptotic genes responsible for automated cell death stop signaling pathways that lead to cancer growth. 15 to 20% of human cancers have been linked to B. TUMOR SUPPRESSOR GENES oncogenic activity Oncogenic viruses may bring oncogenes with them, Tumor Suppressor Genes so-called viral oncogenes → Slow down division, or cause cells to die at the right → Typical of RNA containing “retroviruses” such as human time T-lymphotropic viruses (HTLV) → Puts brakes on cell cycle progression and DNA Assist Oncogene Activity: Receptors replication → Growth factors such as epidermal growth factor receptor → Alters cell metabolism and ensuring genomic stability (EGFR/c ErbB1 or Her1) DNA Repair Genes: gene that is engaged in DNA repair. → Platelet-derived growth factor (PDGF) When a DNA repair gene is altered mutations pile up → Colony-stimulating factor-1 (CSF-1) throughout the DNA Promotes tumor growth: transforming growth factor Apoptotic Genes (TGF-alpha) Chromosome 17 Breast cancers with ERBB2 amplification and → Location of most suppressor genes overexpression of HER2: → p53, BRCA1, CMT1A → Generally respond to treatment with antibodies or drugs that block HER2 activity → Cessation of tumor growth, induce apoptosis and tumor regression Lung adenocarcinoma falls into mutually exclusive molecular subtypes associated with mutations involving RAS or various tyrosine kinase genes 🔺 Cancer cell biology- mutated KRAS & reciprocal signaling Tumors contain various cell types, including cancer cells, immune cells, and stromal fibroblasts Healthy Kras occasionally sends a message that tells the cell to divide Mutated Kras: hyperactive and can't switch off anymore Figure 13. Chromosome 17: Location of most of the Cell Autonomous Signaling Suppressor Genes[Lecturer’s PPT] → Transmits excessive growth signals within the cancer TP53 GENE cell. “Guardian of the Genomes” Non-Cell Autonomous Signaling Most common target for genetic alteration in human tumors → Allows mutated KRAS in cancer cells to alter the Most important ‘brakes’ on tumor formation behavior of neighboring fibroblast cells Plays an essential role in suppressing tumor formation by Reciprocal Signaling two different mechanisms → Activates new signaling pathways in cancer cells that → Responds to a wide array of cellular stresses such as they cannot initiate on their own; these signals DNA damage originate from mutant KRAS, travel through → Activates p21 Cdk inhibitor gene fibroblasts, and return to the cancer cells PATHOLOGY Neoplasia II PAGE 7 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP ▪ If p53 is lost in cells → increased Cdk activity which Table 5. Phases & Checkpoints in the Cell Cycle are normally turned off by p21 → cell proliferation Phase / Suppresses tumorigenesis by inducing apoptosis Function & Involved processes Checkpoint Majority of human cancers demonstrate two alleles loss of functions mutation in TP53 G0 Phase Cells that are recycled goes out of the → Li Fraumeni syndrome: Inheritance of only one cell-cycle process, and the quiescent, stable defective copy of TP53 (patients with high incidence of cells that need to be repaired enter the G1 a wide variety of cancers.) phase Like RB, p53 is inactivated by a variety of oncoproteins G1 Phase Centrosome duplication and growth such as the E6 protein of HPV G1/S First restriction point can be seen after the G1 Checkpoint phase, where the cell can be examined. Table 4. Loss of Tumor Suppressor Gene Function Between the G1 and S checkpoints, this is Suppressor where the cell is checked for DNA damage. Action Gene S Phase Chromosome duplication BRCA-1 Loss of normal growth inhibition G2/M Checks for damaged or unduplicated DNA APC Lack of regulation of cell adhesion with loss Checkpoint of growth control through cell interaction Mitosis If the cell has been repaired or has no NF-1 Loss of down-regulation of growth promoting damage, it can proceed to mitosis and start signal transduction cell division. Rb Loss of regulation of cell cycle activation through sequestration of transcriptional RETINOBLASTOMA factors p53 Loss of regulation of cell cycle activation through lack of inhibition of cell proliferation that allows DNA repair bcl-2 Overexpression of gene, activated by (limitation of translocation, prevents apoptosis apoptosis) Rb GENE “Governor of the cell cycle” Loss of normal cell cycle control is central to malignant transformation and that at least one of four key regulators of the cell cycle (p16/INK4a, cyclin D, CDK4, RB) is dysregulated in the vast majority of human cancer The transforming proteins of several oncogenic animal and Figure 15. Pathogenesis of retinoblastoma[Robbins & Cotran] human DNA viruses also act, in part, by neutralizing the Retinoblastoma growth-inhibitory activities of RB → Rare disease in which malignant cells form in the THE CELL CYCLE tissues of the retina Cells from Labile tissues such as the epidermis and → Leukocoria: patient presents with white reflex in 📖 gastrointestinal tract may cycle continuously. affected eye Stable cells, such as hepatocytes are quiescent but can Knudson’s “two-hit” hypothesis of oncogenesis enter the cell cycle → Developing retinoblastoma can be familial or formed Permanent cells such as neurons and cardiac myocytes sporadically have lost the capacity to proliferate. → Two mutations (hits), involving both alleles of RB (chr → No regeneration for permanent cells 13q14), are required to produce retinoblastoma → Extruded out from the cell cycle and unable to enter → Familial anymore ▪ One of the parents has the defective RB gene ▪ Children inherit one defective copy of RB gene in the germline (first hit) ▪ Retinoblastoma develops when normal RB allele is mutated in retinoblasts as a result of spontaneous somatic mutation (second hit) ▪ Most individuals inheriting a germline defect in one RB allele develop unilateral or bilateral retinoblastoma – disease is inherited as autosomal dominant → Sporadic ▪ Somatic cells, germ cells, and zygotes of both parents are normal ▪ Both normal Rb alleles must undergo somatic mutation in the same retinoblast (two hits) Figure 14. Cell Cycle Landmarks [Lecturer’s PPT] ▪ Low probability of occurring (hence why the Figure 14 shows the cell-cycle phases: G0, G1, S, G2, and M, disease is quite rare) the location of the G1 restriction point, and the G1/S and G2/M − Results in a retinal cell that has completely lost cell-cycle checkpoints RB function and becomes cancerous PATHOLOGY Neoplasia II PAGE 8 of 27  PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP 🔺Table 6. Mutations of the p53 protein involved in cancer ▪ This binding allows the important tumor Mutation Description suppressor gene to be expressed. Many proteins p53 Protects cells from cancer and stops then stick to the transcription factor and form a cells from dividing unnecessarily protein machine to make RNA for the tumor Mutations or changes to its amino acid suppressor gene. This production prevents the cell structure can change its functions – from dividing. can result in cancer This cell divides when it is not supposed to. ARG249SER Arginine (residue 249) → Serine → Inside the nucleus, the transcription factor searches Results in liver and cervical cancer the DNA for its binding site. VAL157PHE Valine (residue 157) → Phenylalanine → Different types of cancer have unique mutations. In Results in liver cancer this specific type of breast cancer, the binding site SER241PHE Serine (residue 241) → Phenylalanine has been mutated. Results in liver and bone cancer → The altered nucleotide pattern is not recognized by ARG273HIS Arginine (residue 273) → Histidine the transcription factor. Results in thyroid cancer → It passes by without sticking. Without the transcription GLY325VAL Glycine (residue 325) → Valine factor binding, the gene stays inactive, and the critical Results in lymphoma and colon tumor suppressor gene is not expressed. cancer → The cancer cells continue to divide without control. Over time, more mutations accumulate, causing the PRO151THR Proline (residue 151) → Threonine or cancer to grow. or SER Serine LEU35PHE Results in breast cancer Leucine (residue 35) → Phenylalanine 🔺 Molecular Action of p53 in Carcinogenesis p53 is a transcription factor which consists of four Results in pancreatic cancer subunits, and a subunit contains: ARG337HIS Arginine (residue 337) → Histidine → C terminal regulatory domain Results in cancer of adrenal cortex → Tetramerization domain ALA189VAL Alanine (residue 189) → Valine → DNA binding Results in colorectal cancer → End terminal transactivation domain ARG181LEU Arginine (residue 181) → Leucine p53 monomers form tetramers via the association of Results in glial cell cancer the tetramerization domains Li-Fraumeni Rare genetic disorder where one of the → The p53 tetramer binds to p53 consensus sequences Syndrome copies of p53 is inactive throughout the in the DNA body → Transcription factors bind to the transactivation → Subsequent mutation in life that domain and mediate the transcription of the gene by inactivates the other copy, cancer RNA polymerase 2 can develop Deletion of both TP53 alleles Results in more frequent occurrence → In tumors such as bone and soft tissue sarcomas, of cancer both TP53 alleles may be deleted 🔺 Tumor Suppressor Genes Mutation of one TP53 allele, conformational change of wild type p53: dominant negative mutation, inhibition Cancer is a disease in which cells divide uncontrollably. of DNA binding → Over the past 30 years, detailed studies have shown → In many tumors, one TP53 allele carries a point that genes such as tumor suppressor genes are often mutation whereas the second allele is wild-type destroyed by DNA mutation, allowing cancer cells to → When mutant p53 monomers associate with wild-type grow. monomers → In recent studies of certain breast cancers, it has ▪ The wild-type monomers are forced into a different been observed that parts of the DNA that control conformation, binding to p53 DNA consensus tumor suppressor genes are frequent targets of sequences is blocked, and the respective genes cancer mutations. Normal cell (not dividing) are not transcribed ▪ Inside the nucleus of the cell, transcription factors Tetramers consisting of mutant p53 monomers only: are constantly scanning the DNA for their binding Inhibition of specific DNA binding, binding to non-B-DNA sites. → In cases where one TP53 allele is mutated, and the ▪ The transcription factor moves along the double second allele is wild-type, some of the resultant helix until it encounters a place where the tetramers consists of mutant p53 monomers only nucleotide pattern is in the exact sequence for it to → Similarly, mutant only tetramers are present when the stick. wild-type allele is deleted ▪ Once the exact sequence is found, the ▪ Mutant only tetramers cannot bind to p53 transcription factor changes shape and binds consensus sequences in the DNA tightly to the DNA. ▪ Instead they may interact with non-B DNA (conformation of which differs from double-stranded DNA) Amplification of the MDM2 gene → Inhibition of transcription ▪ The MDM2 gene is amplified in about 1⁄3 of human soft tissue sarcomas PATHOLOGY Neoplasia II PAGE 9 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP ▪ The gene product binds to amino terminal transactivation domain of p53 ▪ MDM2 associated with the transactivation domain inhibits the binding of transcription factors to the transactivation domain − Transcription of target gene is blocked Amplification of the MDM2 gene: ubiquitination and proteolysis of p53 oligomers → MDM2 is an E3 ubiquitin ligase → After binding to the N-terminal domain of p53, MDM2 is involved in the formation of multi ubiquitin chains from ubiquitin monomers ▪ Ubiquitinated p53 is degraded in the proteasome Infection with HPV: ubiquitination and proteolysis of Figure 17. Energy production comparison between normal p53 oligomers after association with E6 and E6AP cells and cancer cells (warburg effect)[Lecture PPT] proteins Based on Figure 17 → Subtypes of human papilloma viruses are causal → Normal cells only resort to glycolysis when oxygen agents in the formation of cervical carcinomas tension is going down → Viral proteins E6 and E6AP, a ubiquitin ligase, bind to → Cancer cells will always undergo glycolysis, even with p53 adequate oxygen ▪ Both proteins mediate ubiquitination of p53 Warburg effect is not only for cancer cells → Ubiquitinated p53 is degraded in the proteasome → Can apply to all rapidly growing cells such as fetal cells WARBURG EFFECT that rely on aerobic fermentation 📖 Also known as aerobic glycolysis Warburg effect provides more than enough ATP for the metabolic activity of cancer cells → Form of pro-growth metabolism favoring glycolysis over oxidative phosphorylation Carcinogenesis is synonymous with aerobic glycolysis → When there is carcinogenesis, there is aerobic glycolysis C. DNA REPAIR GENES Gene that is engaged in DNA repair → Alteration of this gene can cause mutations to pile up throughout the DNA Figure 16. Warburg effect[Lecture PPT] Based on Figure 16 → In normal tissues, glucose is bio-transformed to pyruvate and carried into the mitochondria for oxidative phosphorylation (A) → Most types of cancer engage themselves in glycolysis, Figure 18. Cell cycle [Robbins & Cotran] irrespective of the presence of oxygen (aerobic Cell cycle: series of events that take place in a cell to glycolysis or Warburg Effect) (B) produce daughter cells → Some cancer cells reprogram cancer associated → Interphase fibroblasts (CAFs) to undergo aerobic glycolysis and ▪ G1 phase (cell growth) to secrete energy-rich nutrients that feed into ▪ S phase (DNA synthesis) mitochondrial oxidative metabolism in cancer cells (C) ▪ G2 phase (cell growth) Could represent evolutionary adaptation to harsh → Mitosis – leads to the formation of two daughter cells microenvironmental conditions ▪ Mitosis → Aerobic glycolysis: less efficient in producing ATP ▪ Cytokinesis ▪ Allows for the production of carbon moieties that → Cell cycle checkpoints could be used to build cellular components (proteins, ▪ G1/S checkpoint – checks for DNA damage lipids, and nucleic acids) ▪ G2/M checkpoint – checks for damaged or → Mitochondrial oxidative phosphorylation: yields unduplicated DNA before mitosis abundant ATP ▪ Does not provide metabolic intermediates that are necessary for cellular growth PATHOLOGY Neoplasia II PAGE 10 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP 🔺 Introduction to Cancer Biology - Loss of Apoptosis Apoptosis = “Programmed cell death” → Used by organisms to limit the growth and replication of cells. If absent → no control of cell growth and tissue homeostasis → One of the key mechanisms behind cancer. The genetic alterations in the cancer cell not only lead to increased cellular proliferation and growth, they also lead to loss of apoptosis. → There is too little cell growth in malignant tissue. Apoptosis occurs in normal cells to allow for removal of damaged cells, maintain a constant number of cells and regenerate tissues. → It’s an important part of embryogenesis. In an avg. human adult: 50-70 billion cells undergo apoptosis daily. Characterized by: → Cell shrinkage → Mitochondrial cytochrome c release → Fragmentation of cell DNA into multiples of 180 base pairs → Ultimate breakage cells into small apoptotic bodies, which are cleared by phagocytosis Phagocytosis: process where cells take in cell Figure 19. Role of p53 in maintaining genome integrity fragments or microorganisms in membrane bound vesicles → fuse with lysosomes containing proteases, The p53 is activated and binds to DNA and the engulfed material is processed for recycling. → Resulting in transcriptional upregulation of target genes: There are 2 pathways that can activate apoptosis: ▪ P21 (CDK inhibitor) – leads to G1 arrest and → Extrinsic pathway / Death receptor pathway successful repair to normal cells ▪ Triggered by activation of tumor necrosis factor ▪ GADD45 (DNA repair) – either successful repair or receptor superfamily apoptosis if the repair fails → Intrinsic pathway / Mitochondrial pathway ▪ BAX (apoptosis) – an apoptotic gene, leads to cell ▪ Triggered by DNA damage, among other triggers death → Both trigger caspases (enzymes), which interact Loss of p53 (as a result of mutation) can lead to with apoptosis inhibitors (IAP protein and BCL-2 p53-dependent genes not being activated where there is family). They may have pro or anti-apoptotic DNA damage properties, but caspases trigger the apoptotic → Formation of Mutant cells – leads to expansion and functions. additional mutations In some malignant cells, anti-apoptotic proteins are D. APOPTOTIC GENES over-expressed: Tumor cells that can acquire resistance to apoptosis by the → Survivin: an IAP family protein in many cancers that expression of: predicts poor outcomes. → Anti-apoptotic proteins (Bcl-2) → BCL2 is over-expressed in B cell lymphomas as a → Downregulation or mutation of pro-apoptotic proteins result of the translocation of its gene. (BAX) Deactivating mutations of pro-apoptotic molecules are Expression of both Bcl-2 and Bax is regulated by the p53 seen in some GI tumors and leukemias (eg. BAX) tumor suppressor gene Anticancer agents have been developed that target → If p53 is damaged, Bcl-2 and Bax are not activated anti-apoptotic molecules. Apoptotic pathways stimulate a set of enzymes called → Eg. Short DNA segments complementary to BCL2 caspases mRNAs have reduced translation of these → Caspases interact with inhibitors of apoptosis proteins anti-apoptotic proteins by binding to them. or IAP and the bcl-2 family of proteins which individually Activation of transcription factors can also lead to have either pro- and anti-apoptotic properties apoptotic resistance. → When members of the nuclear factor kappa B APOPTOTIC PATHWAYS (NF-kB) family of transcription factors are INTRINSIC (MITOCHONDRIAL) PATHWAY over-expressed in certain tumors, which leads to Triggered through severe cell stress, mitochondrial increased transcription of IAP and BCL2 families, stress, or DNA damage, which activates members of TNF also inhibiting apoptosis. receptor superfamily → Ubiquitin proteasome pathway regulates Pro-apoptotic proteins are released to activate caspases, expression of transcription factors and other cell inducing apoptosis commonly blocked in tumor cells cycle proteins. It also inhibits the inhibitor for NF-kB. EXTRINSIC (DEATH RECEPTOR) PATHWAY Certain molecules can suppress or reduce NF-kB and Triggered by DNA damage AP1 activation and inhibit tumor promotion. Activated in response to external signal via the death Bortezomib/Velcade are proteasome inhibitors that receptor pathway (CD95) show promising results in multiple myeloma. PATHOLOGY Neoplasia II PAGE 11 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP V. TELOMERE SHORTENING B. ANGIOGENESIS Telomeres: protective caps composed of repeating DNA A tumor even if endowed with all the genetic aberrations sequences that allow cells to distinguish the ends of cannot enlarge to more than 1 to 2 mm in diameter chromosomes from broken DNA ends unless it has a capacity for angiogenesis Telomerase: enzyme that maintain telomeres and prevent Angiogenesis is controlled by a balance between them from shortening during cell division angiogenesis promoters and inhibitors; in angiogenic → Responsible for: tumors this balance is skewed in favor of promoters ▪ Inhibition of apoptosis Trigger of angiogenesis: Hypoxia ▪ Modulation of cell signaling → RAS, MYC and MAPK stimulates angiogenesis by ▪ Regulation of gene expression upregulating VEGF ▪ Cell cycle regulation VEGF inhibitors are used to treat a number of advanced ▪ Promotion of tumorigenesis cancers to prolong clinical course but its not curative → If these cells suffer damage to oncogenes and tumors, → Only palliative to lengthen the health of the patient suppressor genes during crisis are at risk for malignant transformation C. INVASION AND METASTASIS Telomere shortening Results of complex interactions between cancer cells and → Telomeres shortens after multiple rounds of cell normal stroma, and the major cause of cancer-related replication morbidity and mortality → Hayflick limit: point at which telomeres can no longer Sequence of events in the invasion of epithelial basement protect the chromosomes from damage; it becomes too membranes by tumor cells short. → Tumor cells detach from each other due to reduced adhesiveness ▪ Attract inflammatory cells → Proteases from tumor and inflammatory cells degrade the basement membrane. Hallmark of Malignancy Capacity to invade tissues STEPS IN INVASION Table 7. Steps in invasion No. Steps 1 Dissociation of cancer cells from one another due to alterations in intercellular adhesions → Beta-catenin binds to intracellular portion of cadherins which anchor cells together and the Figure 20. Telomere extension leading to malignancy[Lectuer’s loss of this function results to less adhesiveness PPT] that favors tumor cell infiltration and metastasis Short telomeres arise from constant cell replication. → Inactivation of E-cadherin May lead to two situations: 2 Degradation on the basement membrane → Checkpoint intact (G1/S Checkpoint is not → Protease and proteolytic enzymes secreted by bypassed) tumor cells release growth factors that have ▪ Leads to cell death by proliferative arrest or apoptosis been sequestered in the extracellular matrix. → Checkpoint bypassed: additional telomere shortening → Cleavage of ECM glycoproteins generates ▪ Leads to apoptosis, chromosome fusion, chemotactic and angiogenic fragments non-reciprocal recombination, and genomic instability, resulting in malignancy or cell death 3 Changes in the attachment of tumor cells to the extracellular matrix (ECM) VI. HALLMARKS OF CANCER 4 Locomotion A. LIMITLESS REPLICATIVE POTENTIAL → Propelling of tumor cells through the degraded basement membrane and zone of matrix Cancer cells have a stem cell-like potential and are proteolysis. referred to as cancer stem cells Increased lesions → inactivate senescence signals and VASCULAR DISSEMINATION AND HOMING OF TUMOR reactivate telomerase → limitless reactive potential. CELLS Has been attributed to progressive shortening of telomeres The site at which circulating tumor cells leave the at the ends of chromosomes capillaries to form secondary deposits is related to: → Cell cycle checkpoints are activated by shortened → Anatomic location telomeres generated by cell division leading to → Vascular drainage of the primary tumor senescence and placing a limit on the number of → Tropism of particular tumors for specific tissues divisions a cell may undergo[Robbins] Tumor cells may have ligands preferentially located at In cells that have disabled checkpoints, DNA repair Presence of chemokines on target organs (i.e., breast pathways are inappropriately activated by shortened cancer cells express chemotactic receptors CXCR4 and telomeres, leading to massive chromosomal instability and CCR7) mitotic crisis[Robbins] “Unfavorable soil” – though vascularized, skeletal muscle Tumor cells reactivate telomerase, thus staving off mitotic and spleen are rare sites of metastasis. catastrophe and achieving immortality[Robbins] PATHOLOGY Neoplasia II PAGE 12 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP MOLECULAR GENETICS OF METASTASIS HOMOLOGOUS RECOMBINATION DNA REPAIR DEVELOPMENT (CLONAL EVOLUTION MODEL) SYSTEM Metastasis is caused by rare variant clones that develop in Patients with the following autosomal-recessive disorders the primary tumor are hypersensitive to DNA-damaging agents such as Gene expression pattern of most cells of the primary ionizing radiation, BRCA1 and BRCA2: tumor referred to as metastatic signature → Ataxia-telangiectasia A combination of rare variant clones and metastatic → Bloom syndrome signature where metastatic variants appear in a tumor with → Fanconi anemia gene signature. BRCA1 and BRCA2 are said to take part in homologous Metastasis is greatly influenced by tumor stroma, which recombination DNA pathway may regulate angiogenesis, local invasiveness, and → Mutated in familial breast cancers involved in DNA resistance to immune elimination allowing cells of the repair primary tumor to become metastatic D. EVASION OF HOST DEFENSES DEFECTS IN THE EXPRESSION OF GENE TUMOR ANTIGENS PRODUCTS Tumor cells can be recognized by the immune system Induces genomic instability as non-self and be destroyed. 9RAG1, RAG2, AID: Antitumor activity is mediated primarily by the → Gene products that permit receptor gene and cell-mediated immune response: immunoglobulin assembly. → Presentation: MHC I → Mutation of these genes in lymphoid cells are important → Recognition: CD8+ and CTLs causes of lymphoid neoplasms Different classes of tumor antigens: → Products of mutated proto-oncogenes → Tumor suppressor genes → Overexpressed or aberrant proteins → Tumor antigens produced by oncogenic viruses → Oncofetal antigens → Altered glycoproteins in immunocompromised patients → Tumors, glycolipids, and cell type-specific differentiated antigens Immunodeficient patients: greater risk of developing cancers as tumors may avoid the immune system by several mechanisms. Antibodies that overcome these mechanisms of immune evasion are showing promise in clinical trials. ANTITUMOR EFFECTOR MECHANISM Cell-mediated immunity includes: → Cytotoxic T lymphocytes Figure 21. DNA repair systems, the genes involved, and → Natural killer cells its associated cancer[Lectuer’s PPT] → Macrophages F. CANCER ENABLING EFFECTS OF INFLAMMATORY IMMUNE SURVEILLANCE AND ESCAPE CELLS AND RESIDENT STROMAL CELLS There is a selective outgrowth of antigen-negative variants 1. Release of factors that promote proliferation Loss or reduced expression of MHC molecules 2. Removal of growth suppressors Activation of immunoregulatory pathways 3. Enhanced resistance to cell death Secretion of immunosuppressive factors by cancer cells 4. Induce Angiogenesis Induction of regulatory T cells (Tregs) 5. Activating Invasion and Angiogenesis 6. Evading Immune Destruction E. GENOMIC INSTABILITY AS ENABLER OF 7. Infiltrating Cancer MALIGNANCY Provoke chronic inflammatory reaction: Person with inherited mutations of genes involved in DNA → “Wounds that do not heal” repair systems are at increased risk for cancer → Marked anemia: DEFECTS IN THE REPAIR SYSTEMS ▪ Inflammation-induced sequestration of iron and downregulation of erythropoietin production MISMATCH REPAIR SYSTEM ▪ Fatigue and cachexia (muscle wasting) Patients with Hereditary Nonpolyposis Cancer (HNPC) syndrome → colon carcinoma G. DYSREGULATION OF CANCER ASSOCIATED There is microsatellite instability leading to changes in GENES lengths of short repeats throughout the genome CHROMOSOMAL CHANGES NUCLEOTIDE EXCISION REPAIR SYSTEM Loss of telomeres (Early stage) → Early-stage in cancer progression Patients with Xeroderma pigmentosum: → Initiates the transformation process → Development of cancer of skin due to exposure to UV light → Inability to repair pyrimidine dimers. PATHOLOGY Neoplasia II PAGE 13 of 27 PATHOLOGY | LE 1 Neoplasia II |Joselli C. Rueda-CU, MD, RN LLB, MHA, MPH, FPSP ANEUPLOIDY AND STRUCTURAL CHANGES IN Genesis of these dozens of chromosome breaks is CHROMOSOME (LATE STAGE) unknown Late-stage in cancer progression → Results from a single event in which dozens to hundred Aneuploidy: Changes in chromosome number and of chromosome breaks occur within part or across the structure. entirety of a single chromosome or several chromosomes CHROMOSOMAL TRANSLOCATIONS DNA repair genes stitch the pieces together in a Burkitt’s lymphoma: haphazard way → Overactivity of MYC is essential to the pathogenesis of → Results to chromosomal rearrangement and loss of tumors, and is evident through the presence of MYC some chromosome segments translocations. May simultaneously activate oncogene and inactivate Philadelphia chromosome of CML: tumor suppressors expediting the process of → BCR ABL fusion gene encodes a chimeric BCR-ABL carcinogenesis protein with constitutive tyrosine kinase activity Table 8. Oncogene Translocation IMPORTANCE OF KNOWING THE CHROMOSOMAL Malignancy Translocation Affected Gene CHANGES Chronic (9;22)(q34;q11) ABL 9q34 Genes in the vicinity of chromosomal breakpoint or myelogenous BCR 22q11 deletion are likely to be: leukemia → Oncogenes: MYC, BCL2, ABL Acute myeloid (8;21)(q22;q22) AML 8q22 → Tumor suppressor genes: APC, RB leukemia (15;17)(q22;q21) ETO 21q22 Karyotypic abnormalities may have diagnostic value, PML 15q22 prognostic and therapeutic implications RARA 17q21 → E.g., BCR-ABL fusion genes, mRNA products are Burkitt (8;14)(q24;q32) MYC 8q24 essential for diagnosis of CML lymphoma IGH 14q32 DELETIONS OF SPECIFIC REGIONS OF Mantle cell (11;14)(q13;q32) CCND1 11q13 CHROMOSOME ASSOCIATED WITH THE LOSS OF lymphoma IGH 14q32 PARTICULAR TUMOR SUPPRESSOR GENE At the site of RB gene - deletion of chromosome 13q14 Follicular (14;18)(q32;q21) IGH 14q32 Associated with retinoblastoma lymphoma BCL2 18q21 Deletion of VSL tumor suppressor gene on chromosome Ewing Sarcoma (11;22)(q24;q12) FLI1 11q24 3p: EWSR1 22q12 → Renal cell carcinoma Prostatic (7;21)(p22;q22) TMPRSS2 “Cryptic” deletions may activate oncogenes: adenocarcinom (17;21)(p21;q22) (21q22.3) → T cell acute lymphoblastic leukemia (T cell ALL) a ETV1 (7p21.2) ETV4 (17q21) GENE AMPLIFICATION OF DNA SEQUENCES Patterns expressed: EPIGENETIC CHANGES → Double minutes Epigenome: therapeutic target since the epigenetic state → Homogenous staining region is reversible Amplification of gene expression typically occurs when Drugs are now available to “erase” the histone-related there is reduplication of DNA sequences changes in the affected cell → Often with hundreds of copies greatly increasing the Includes: amount of protein produced which drives cellular → DNA methylation: created by DNA methyltransferases proliferation ▪ Silencing of tumor suppressor genes by local IMPORTANT AMPLIFICATIONS FROM A CLINICAL hypermethylation of DNA. PERSPECTIVE ▪ Global changes in DNA methylation throughout N-MYC in neuroblastoma the genome → Amplified 25 to 30% and associated with poor prognosis ▪ Cells affected exhibit genomic instability ERBB2 in Breast cancer → Histone modifications catalyzed by enzyme → Occurs in 20% of breast cancers