Pathology A - Neoplasia (Part 2) PDF

Far Eastern University – Nicanor Reyes Medical Foundation Malignant neoplasms have several cancer hallmarks such as Pathology A – Neoplasia (Part 2) excessive growth, invasiveness, and the ability to metastasize Linda Tamesis M.D....

Far Eastern University – Nicanor Reyes Medical Foundation Malignant neoplasms have several cancer hallmarks such as Pathology A – Neoplasia (Part 2) excessive growth, invasiveness, and the ability to metastasize Linda Tamesis M.D. all of which stem from genetic alterations. Driver Mutations – mutations that contribute to the Molecular Basis of Cancer development of malignant phenotype. Initiating Mutation – first driver mutation that starts the cell Role of Genetic and Epigenetic Alterations on its path to malignancy.  Non-lethal damage lies at the heart of carcinogenesis, the initial However, no single mutation can fully transform; the damage may be caused by exposures, inheritance, or it can also initiated cell needs to accumulate additional driver be spontaneous. mutations which contribute to cancer development.  Tumors are formed by the clonal expansion of a single precursor  Loss-of-function mutations in the genes that maintain genomic cell that has incurred the DNA damage which is being passed to integrity appear to be a common early step in the road to the daughter cells. Thus, all individual cells in the tumor share malignancy, particularly in solid tumors. the same set of mutations.  Tumors evolve genetically during their outgrowth and  Four principal genes are the principal targets of cancer-causing progression under the Darwinian selection (Survival of the mutations: fittest), there is competition among tumor cells for access to 1. Growth promoting: Proto-oncogenes nutrients. 2. Growth inhibiting: Tumor Suppression Genes This activity to become more aggressive over time is referred 3. Genes that regulate apoptosis to as Tumor Progression. 4. Genes involved in cell repair  Gain-of-function mutations of the proto-oncogene will cause an Epigenetics in Cancer excessive increase in one of more normal functions of the  DNA methylation, which silences gene expression and encoded gene product. modification of histones, may either enhance or dampen gene  Loss-of-function mutations of the tumor suppressor genes (in expression. most cases, both allele should be mutated before cancer  In some cancer cells, it is responsible for the silencing of the occurs), permit growth of cells even when they are damaged. tumor suppressor gene. TSG mutations behave in a recessive manner Haploinsufficiency – a condition wherein a single allele Cellular and Molecular Hallmarks of Cancer mutation in the TSG is enough to permit tumor proliferation.  Apoptosis-regulating genes may acquire mutations that may result in less cell death and permit cell survival. Gain-of-function mutations that inhibit apoptosis. Loss-of-function mutations that promote cell death.  Loss-of-function mutations on the DNA repair genes contribute to carcinogenesis indirectly by impairing the ability of the cell to recognize and repair non-lethal DNA damage. Cell acquires mutations at an accelerated rate, a state referred to as mutator phenotype marked by genomic instability.  Carcinogenesis results from accumulation of complementary mutations in a stepwise fashion over time. 1. Self-sufficiency in growth signals – tumors have the capacity to proliferate without any external stimuli, as a consequence of oncogene activation. 2. Insensitivity to growth signals 3. Altered cellular metabolism – cells switch to aerobic glycolysis called Warburg effect which enables synthesis of macromolecules and organelles. 4. Evasion of apoptosis 5. Limitless replicative potential (Immortality) 6. Sustained angiogenesis – tumor cells need vascular supply to bring oxygen and nutrients, and remove waste products. 7. Ability to invade and metastasize 8. Ability to evade immune response  These may be accelerated by genomic instability and cancer- promoting inflammation. Page 1 of 13 NORMAL CELL PROLIFERATION GROWTH FACTOR RECEPTORS  Receptor tyrosine kinases are the most important in cancer.  The oncogenic versions of these receptors are associated with mutations that lead to constitutive, growth-factor independent tyrosine kinase activity.  Mutant receptors deliver continuous mitogenic signals to the cell even in the absence of GF.  Can be activated by point mutations, gene rearrangements, and gene amplifications.  Example: ERBB1 – encodes for epidermal growth factor receptor (EGFR), involved in point mutation which activates EGFR Tyrosine kinase. Commonly found in lung adenocarcinomas. 1. Growth Factor binds to a specific receptor on the cell membrane. ERBB2 – encodes for HER2. The ERBB2 gene is amplified 2. Activation of the GF Receptor results to the activation of the leading to overexpression of HER2 receptors and activity. signal transducing protein on the inner membrane. Commonly seen in breast carcinomas. 3. Signal is transduced from the cytosol to the nucleus via the use Gene rearrangements – Fusion of EML4 and ALK gene would of secondary messengers. encode for a chimeric EML4-ALK protein having constitutive 4. Activation of DNA Transcription. tyrosine kinase activity. 5. Integration and progression in to the cell cycle.  Most of them respond to treatment with antibodies or drugs that block certain tyrosine kinase activities. These inhibitors also PROTO-ONCOGENES, ONCOGENES, and ONCOPROTEINS induce apoptosis and tumor regression.  Genes that promote autonomous cell growth is called an  However, advanced lung cancer develops resistance to EGFR ONCOGENE, and their unmutated counterpart is called the inhibitors and express another gene called MET, which is another PROTO-ONCOGENE. tyrosine kinase receptor.  The mutated oncogenes encode for proteins called ONCOPROTEINS that have the ability to promote cell growth in SIGNAL TRANSDUCING PROTEINS the absence of an external stimuli.  Oncoproteins can mimic signal transducing proteins. These oncoproteins resemble the normal products of a  RAS Mutations proto-oncogene but they bear mutations. Point mutation of RAS family is the most common type of Oncoproteins have been linked to accelerators that speed th abnormality involving proto-oncogenes in human tumors. replication of cells and their DNA. Three RAS genes in humans: HRAS, KRAS, NRAS.  Pro-growth proto-oncogenes encode for the ff: RAS proteins are members of a family of membrane- Growth factors associated small G-proteins that bind guanosine nucleotides, Growth factor receptors similar to large trimolecular G proteins. Signal transducers They are active when bound to GTP, and inactive when they Transcription Factors are bound to GDP. Cell cycle components (cyclins) Active RAS that has undergone conformational change  The corresponding oncogene may encode oncoproteins that stimulates both MAPK and PI3K/AKT arms of the RTK serve functions similar to their normal counterpart. signaling pathway. Mutated RAS have reduced GTPase activity rendering the GROWTH FACTORS RAS trapped in the activated GTP bound form and the cell  Stimulate cells to proliferate. receives pro-growth signals continuously.  Most soluble growth factors are made by one cell type and act Pancreatic adenocarcinoma, cholangiocarcinoma (90%) on neighboring cell to stimulate proliferation (paracrine). Colon, Endometrial, and Thyroid cancers (50%)  Some cancer cells are able to synthesize the same growth factors Lung adenocarcinomas and myeloid leukemia (30%) to which they are responsive (autocrine).  Alterations in Tyrosine kinase Glioblastomas express both PDGF and the PDGF receptor BRAF mutation tyrosine kinases.  BRAF is a serine/threonine protein kinase that sits at the Sarcomas overexpress TGF-α and its receptor. It also top of a cascade of other families. expresses EGFR (Epidermal growth factor receptor).  Similar to RAS mutations, BRAF stimulate each of the downstream pathways ultimately activating transcription factors. Page 2 of 13   Mutations of other MAPK family which is present on the It can also be Point Mutations that abrogate the function of lower part of the cascade is uncommon. the negative regulatory domain. PI3K Proteins Example of which is a receptor in JAK2, which participates in  A heterodimer composed of regulatory subunit and a the JAK-STAT signaling pathway. catalytic subunit. Examples are Polycethemia vera, essential thrombocytosis,  It activates a cascade including AKT. and primary myelofibrosis are associated with point  mTOR, a substrate of AKT, is a sensor of cellular nutrient mutations. status activated by AKT and stimulates protein and lipid synthesis. TRANSCRIPTION FACTORS  BAD (a pro-apoptotic protein) is also activated by AKT.  The ultimate consequence of deregulated mitogenic signaling  FOXO factors, which turn on genes that promote apoptosis, pathway is inappropriate and continuous stimulation of nuclear are negatively regulated by ATK. TF that drive growth-promoting genes.  PTEN negatively regulates PI3K.  Transcription factors of this call include the products of:  PI3K and PTEN mutations are the most common. MYC, MYB, JUN, FOS, and REL proto-oncogenes  PI3K mutations affect its catalytic sub unit resulting to an increased enzyme activity MYC oncogene  Gain-of function mutations in PIK3 is found in 30% of  MYC proto-oncogene belongs to immediate early response breast carcinomas. genes, which are rapidly induced by RAS/MAPK signaling.  Loss-of-function of PTEN, which is a suppressor gene, is  MYC concentrations are tightly regulated. common in endometrial carcinomas.  SNP (Single Nucleotide polymorphisms) are strongly linked to an  Alterations in Non-receptor Tyrosine Kinase elevated risk of cancer such as prostate and ovarian cancer. Chromosomal translocations or rearrangements produce  These SNPs fall within a large region devoid of recognizable constitutively active tyrosine kinase even if not membrane genes that lies next to MYC on chromosome 8. bound.  Functions of MYC: Most of these activate the same signaling pathways as RTKs. Activates expression of many genes that are involved in cell Example is Chronic Myelogenous Leukemia and Acute growth. Lymphogenous Leukemia: Upregulates expression of telomerase. Reprograms somatic cells into pluripotent stem cells.  ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22 where it fuses with BCR  MYC Translocation is involved in Burkitt’s lymphoma, and a gene. subset of other B and T cell tumors.  This results to a chimeric gene encoding for a constitutively  NMYC amplification is involved in human neuroblastoma, active oncogenic BCR-ABL tyrosine kinase. normally present on chromosome 2p.  Treatment for CML is Imatinib mesylate which has a low toxicity but with high therapeutic efficacy inhibiting the BCR-ABL kinase. Page 3 of 13 CYCLINS AND CYCLIN-DEPENDENT KINASES  Major cancer-associated mutations that affect the G1/S checkpoint can be broadly classified into two: 1.) Gain-of-function mutations in D cyclin genes and CDK4, oncogenes that promote G1/S progression  D1, D2, D3 are functionally interchangeable and often dysregulated in mutations, in cancer including chromosomal translocations (lymphoid tumors), and gene amplification (variety of solid tumors).  CDK4 gene is also amplified in cases of melanoma, sarcoma, and glioblastoma.  Cyclin-dependent kinases (CDKs) control the orderly progression  Mutations in cyclin B, E, and other CDKs but less frequent. of cells through cell cycle, which are activated by binding to cyclins and phosphorylate crucial target proteins that drive cells 2.) Loss-of-function mutations in tumor suppressor genes that forward through the cell cycle. inhibit G1/S progression  CDK Inhibitors silence the CDKs and exert negative control in the  CDKI that inhibit cyclin D/CDK complexes are frequently mutated cell cycle. These are downregulated by mitogenic signaling or sometimes silenced. pathway, promoting cell cycle progression.  P16 (CDKN2A) germline mutations are present in 25% of  Defects in G1/S checkpoint are more important in cancer, in that melanoma-prone kindred; somatic mutations however are seen these lead to dysregulated growth as well as a mutator in pancreatic CA, Gliobastoma, esophageal CA, ALL, and non- phenotype. small cell lung CA, soft tissue sarcoma, and bladder CA.  CDK4 – G1 restriction site  RB and TP53 encode proteins that inhibit G1/S progression.  CIP/WAF – Inhibits all stages  INK4 – Inhibits cyclin D  RB (Tumor suppressor) – G1/S SELF SUFFICIENCY OF GROWTH SIGNALS  P53 (Tumor suppressor) – G1/S and G2/M, major cause of  Overexpression of growth factors genetic instability. PDGF and TGF α  Altered growth factor receptors RET  Mimicry of signal transducing proteins RAS  Oncoproteins as transcription factors MYC Dysregulation of proteins INSENSITIVITY TO GROWTH INHIBITION  Most products of TSG apply brakes to cell proliferation.  Abnormalities of these genes lead to failure of growth inhibition.  Many tumor suppressors (RB, TP53) are part of a regulatory network that recognizes specific genotoxic stress and shuts down proliferation. Retinoblastoma Gene  The first discovered tumor suppression gene.  It was identified by studying a rare familial disease retinoblastoma. Page 4 of 13 KNUDSON’S HYPOTHESIS  Growth factors signaling pathways generally upregulate the  Two mutations (hits), involving both alleles of the RB at activity of CDK/cyclin complex and drive cells through the G1/S chromosome locus 13q14 are required to produce transition. retinoblastoma.  Growth inhibitors stimulate CDK inhibitors that inactivate the  In familial cases, children inherit one defective copy of the RB CDK/cyclin complexes. gene (first hit), and the other copy is normal. Retinoblastoma  RB gene mutation is associated with retinoblastoma and develops when the normal allele gets mutated as a result of osteosarcoma, similar somatic RB mutations in a subset of sporadic mutation (second hit). glioblastomas, small cell lung CA, breast CA, and bladder CA.  Most individuals with one defective RB allele develop unilateral or bilateral retinoblastoma and the disease is inherited as Mutations in the RB genes are not widespread in human tumors. autosomal dominant. Most of the tumors have mutations that control the phosphorylation  In sporadic cases, both normal RB alleles must undergo somatic of RB, mimicking the effect of RB loss. mutation; end result is a total loss-of-function of the RB gene.  Inherited mutant RB alleles in all somatic cells follow an TP53 (Guardian of the genome) autosomal recessive pattern of inheritance. One defective RB gene does not affect cell behavior Heterozygotes do not express cancer. Germline mutation or the genetic trait, which is increased risk for cancer, in RB is inherited in an autosomal dominant pattern. On the other hand, at the level of the individual cell, a loss-of-function mutation in the RB gene behaves in an autosomal recessive pattern. RETINOBLASTOMA GENE (Governor of proliferation)  A key negative regulator of the G1/S cell cycle transition.  It exists as an active hyophosphorylated state in quiescent cells, and inactive hyperphosphorylated state in cells passing the G1/S cell cycle.  Can be compromised in two ways: Loss-of-function mutation involving the two RB alleles Shift from active to inactive state by gain-of-function mutations that upregulate CDK/cyclin D activity, or loss-of- function mutations that abrogate the activity of CDK inhibitor  A tumor suppressor gene that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis.  Most common target for genetic alteration.  Located on chromosome 17p13.1  Inheritance of a mutated copy of the TP53 predisposes an individual to malignant tumor, only one additional hit is needed for the normal gene to have loss-of-function mutation of TP53.  Individuals with one mutant p53 have 25% increased risk of having Li-Fraumeni Syndrome.  Released with DNA damage and hypoxia  Ataxia-telangiectasia mutated (ATM) and Ataxia- telangiectasia and Rad3 related (ATR) proteins stimulate the phosphorylation of p53. Oncogenic stress  Activation of oncoproteins result to increased proliferation create cellular stress and lead to increased proliferation of p14/ARF (encoded by CDKN2A) which is a tumor suppressor gene, displaces p53 allowing its level to rise. Page 5 of 13 APC (Gatekeeper of Colonic Neoplasia) CDKN2A  Encodes 2 proteins: P16/INK4a cyclin-dependent kinase inhibitor: blocks the CDK4/cyclin D mediated phosphorylation of RB. P14/ARF: activates p53 pathway by inhibiting MDM2 and preventing p53 destruction.  Germline mutations can cause melanoma.  Sporadic mutations have been detected in bladder cancer, head & neck tumors, ALL, and cholangiocarcinomas.  In cervical cancer, p16 is silenced by hypermethylation. TGF-β PATHWAY  Normally, it is an inhibitor of proliferation.  Signals from the receptor activate intracellular signals (SMAD family) turn on anti-proliferative genes and turn off genes that drive cell growth.  Loss-of-function mutations in TYPE II TGF-β are common in cancers of the colon, stomach, and endometrium.  A member of class of TSG that function by downregulating  Mutational inactivation of the SMAD family is common in growth promoting signaling pathways. pancreatic cancer.  Germline loss-of-function mutations involving the APC locus (5q21). PTEN (Phosphatase and Tensin homologue)  Associated with familial adenomatous polyposis, an autosomal  Encoded by a gene on chromosome 10q23. dominant disorder in which individuals with one mutant develop  Acts as tumor suppressor by serving a brake on PI3K/AKT arm. thousands of polyps.  Mutated in Cowden syndrome, an autosomal dominant disorder  APC is a component of the WNT signaling pathway which as has marked by frequent benign growths such as skin appendage a major role in controlling cell fate, adhesion, and cell polarity tumors. during embryonic development.  Loss of APC causes continuous WNT signaling and β-catenin NF1 enters the nucleus and promotes proliferation  Inheritance of 1 mutant allele develops numerous benign  In resting cells, APC forms a destruction complex to degrade β- neurofibromas and optic nerve gangliomas as a result of catenin and inhibit proliferation. nd inactivation of the 2 normal copy.  WNT binds to FRZ (Frizzled) receptors and blocks the formation  A condition called neurofibromatosis Type 1. of the destruction complex, permitting β-catenin to activate the  Neurofibromin, a protein product of NF1, has a GTPase domain DNA-binding factor TCF, permitting cell proliferation. that acts as brake on RAS signaling.  Tumor cells with mutated APC permit the entry of β-catenin into  Loss-of-function mutation makes RAS trapped in an active, the nucleus even without the binding of WNT, permitting signal-emitting state. continuous cell proliferation. NF2 OTHER TUMOR SUPPERSSOR GENES  Germline mutation leads to predisposition to neurofibromatosis type 2. E-Cadherin  Individuals with mutations develop benign bilateral  Loss-of-contact inhibition by mutation of the E-cadherin and β- schwannomas of the acoustic nerve. catenin is a key characteristic of carcinomas.  Somatic mutations have been foiund in sporadic meningiomas  Loss of E-cadherin can contribute to malignant phenotypes and ependymomas. allowing easy disaggregation of cells, which can then invade or  Neurofibromin 2 or Merlin, a protein product of NF2, is locally metastasize. structurally similar to the red cell membrane. Cells lacking merlin  Reduced E-cadherin expression has been noted in many do not establish stable cell-to-cell junction and insensitive to carcinomas including esophagus, colon, breast, ovary, and normal growth inhibitors. prostate.  Germline loss-of-mutation of E-cadherin gene causes familial gastric carcinoma. Page 6 of 13 WIT EVASION OF PROGRAMMED CELL DEATH  Loss-of-function mutation located on chromosome 11p13 is associated with the development of Wilms tumor, a pediatric kidney cancer. PATCHED (PTACH)  PTCH1 is a tumor suppressor gene that encodes a cell membrane protein called PATCHED1 which are negative regulators of the Hedgehog signaling pathway.  The absence of PATCHED makes the hedgehog signaling that increases the expression of pro-growth genes.  Germline loss-of-function mutations cause Gorlin’s Syndrome, also known as nevoid basal cell carcinoma syndrome.  They are also at risk of medulloblastoma, an aggressive cerebellar tumor. VHL (Von Hippel-Lindau)  Germline loss-of-function gene on 3p is associated with renal cell cancer, pheochromocytoma, hemangioblastoma of the CNS, retinal angioma, and renal cysts. STK11 (LKB1)  Encodes a serine/threonine kinase that is an important regulator 1. Reduced levels of Fas/CD95. of cellular metabolism. 2. Inactivation of caspase 8.  Loss-of-function mutation gives rise to Peutz-Jeghers Syndrome, 3. Protection of the tumor by increasing the levels of anti- an autosomal dominant disorder associated with benign polyps apoptotic factors such as BCL-2, BCL-XL, MCL-1. of the GIT. 4. Loss of P53. 5. Loss of APAF or Apoptotic peptidase activating factor 1. 6. Upregulation of inhibitors of apoptosis (IAPs) WARBUG EFFECT  Most commonly inhibited in cancers is the intrinsic pathway. LIMITLESS REPLICATIVE POTENTIAL  All cancers contain cells that are immortal.  Three interrelated factors that appear critical to the immortality of cancer cells: Evasion of senescence Evasion of mitotic crisis Capacity for self-renewal  Replicative senescence lies on telomere shortening.  As the cell divides, the telomeres get shorter and shorter until it activates p53 and initiate apoptosis.  Tumors shift to aerobic glycolysis, high levels of glucose uptake,  Cancer cells have telomerase activity (like that of the stem cells) and increased conversion of glucose to lactate. that prevents shortening of the telomeres.  Clinically “glucose hunger” of tumors is used to visualize tumors via positron emission tomography (PET) scan. SUSTAINED ANGIOGENESIS  A patient is injected with F-Fluorodeoxyglucose which is taken  Tumors greater than 2mm needs blood supply. up by tumor cells.  The current paradigm is that angiogenesis is controlled by a  Warburg metabolism is not cancer specific, but instead it is a balance between angiogenesis promoters and inhibitors; in general property of growing cells that becomes fixed in cancer. angiogenic tumors this balance favors promoters.  Possible explanations:  Angiogenic switch – change in phenotype that induces Increased need for energy of the dividing cells. angiogenesis mostly controlled by hypoxia. Abnormal vasculature Loss of inhibitors (angiostatin, endostatin, vasculostatin) Reduction in autophagy Increase in Growth factors (VEGF, FGF) Decrease p53, increase angiogenesis Page 7 of 13  Relative lack of oxygen due to hypoxia stabilizes HIF1α, an INVASION oxygen sensitive transcription factor that activates the 1.) Detachment of tumor cells from one another transcription of the pro-angiogenic cytokines VEGF and FGF. These factors create an angiogenic gradient that stimulates proliferation of endothelial cells towards the tumor. VEGF increases the exression of ligands that activate the Notch signaling pathway that regulates the branching and density of new vessels.  Neovascularization or Vasculogenesis  The vasculature generated by the tumor is usually abnormal. METASTATIC CASCADE  Down regulation of E-cadherins 2.) Degradation of the basement membrane and interstitial connective tissue  Secretion of proteolytic enzymes (MMPs or matrix metalloproteinases) themselves or by inducing stromal cells ECM-sequestered growth factors.  MMP9 is a gelatinase that cleaves type IV collagen of epithelial and vascular basement membranes. 3.) Attachment to matrix components  Integrins in the epithelial cells attach to fibronectin and laminin present in the basement membrane.  Normally, loss of adhesion leads to apoptosis, tumor cells are resistant to this form of cell death.  Involves two phases: Invasion of the ECM Vascular Dissemination, homing of tumor, and colonization. Page 8 of 13 4.) Locomotion TUMOR ANTIGENS  Tumor antigens elicit an immune response and can be classified according to their molecular structure and source. Tumor-specific antigen: present only on tumors Tumor-associated antigen: present on both normal and tumor cells. 1.) Products of mutated genes  Final step of invasion.  Propelling tumor cells through the degraded basement  These mutated genes encode variant proteins that have never membranes and zones of matrix proteolysis. been seen by the immune system and thus recognized.  Cells must attach to the matrix at the leading edge, detach from  These “passenger mutations” are neutral in terms of cancer cell the matrix at the trailing edge, and contract the actin to ratchet fitness and thus unrelated to the transformed phenotype. forward.  The products of the altered genes are translated in the cytoplasm and may enter MHC processing recognized by CD8 VASCULAR DISSEMINATION CTLs.  Tumor cells from clumps with lymphoid cells and form an  Some dead tumors may undergo class II antigen processing and emboli. activate CD4 T cells.  The site at which circulating tumor cells leave the capillaries to  Examples: form secondary deposits is related to the anatomic location and Oncogene products : RAS, BCR/ABL fusion proteins vascular drainage of the primary tumor. TSG products: p53 mutated proteins  Organ Tropism Adhesion molecules on endothelial cells of the target organ 2.) Overexpressed or aberrantly expressed cellular proteins (CD44). Chemokine receptors (CXCR4) Unfavorable tissues: Skeletal Muscles and Spleen MOLECULAR BASIS OF METASTASIS  All of these are theories.  Among candidates for metastasis oncogenes are SNAIL and  It may also be normal cellular proteins that are abnormally TWIST. expressed in tumor cells.  Examples: Tumor Immunity Mutant proteins in carcinogens or radiation. Mutated proteins in melanomas 3.) Produced by Oncogenic Viruses  Immune surveillance is a term that implies that a normal function of the immune system is to constantly scan the body for emerging malignant cells and destroy them.  These viruses produce proteins that are recognized as foreign.  The fact that cancers occur in immunocompetent individuals  Most pottent of these are proteins produced by latent DNA indicate that immune surveillance is imperfect. viruses.  Cancer Immunoediting has been used to describe the ability of  CTLs recognize antigens of these viruses. immune system to shape and mold the immunogenic properties  Examples: of tumor cells which ultimately leads to the Darwinian selection Human Papilloma Virus (HPV) that are best able to avoid immune elimination. Epstein Barr Virus (EPV) Page 9 of 13 4.) Oncofetal proteins GENOMIC INSTABILITY  Proteins expressed at high levels in cancer cells and in normal  Inherited defects in DNA repair genes allow mutations of the developing fetal tissues. other genes  Two most thoroughly characterized are: Carcinoembryonic antigen (CEA) 1.) Mismatch repair and microsatellite instabilities α-fetoproteins (AFP)  HNPCC Syndrome (Hereditary Nonpolyposis Colon Cancer) 5.) Altered cell surface glycolypids and glycoproteins 2.) Nucleotide Excision Repair  Higher than normal levels or abnormal forms of surface proteins.  Xeroderma Pigmentosum  May be diagnostic markers for therapy.  Particularly following exposure to UV lights  These include ganglioside, blood group antigens, and mucins.  These UV radiation causes cross-linking of pyrimidine dimers. 6.) Cell type-specific differentiate antigens 3.) Recombination Repair  Do not induce immune system response.  Rare autosomal diseases  These molecules are normally present on the cell origin.  Bloom Syndrome and Ataxia Telangiectasia – hypersensitivity to ionizing radiation. ANTITUMOR EFFECTOR MECHANISMS  Fanconi anemia – sensitivity to chemotherapeutic agents.  Cytotoxic T lymphocytes  Breast Cancers  NK Cells  Macrophages 4.) Gene Products that induce instability  Antibodies  Lymphoid Neoplasia IMMUNE EVASION BY TUMORS CANCER ENABLING INFLAMMATION  Release of factors that promote proliferation. Secrete wide variety of GF such as EGF Proteases that liberate GF from ECM  Removal of Growth Supperssors Proteases released by inflammatory cells can degrade adhesion molecules removing a barrier to growth.  Enhanced resistance to cell death Anoikis is a type of cell death from the detachment of epithelial cells from the basement membrane. Tumor associated macrophages resist anoikis by expressing adhesion molecules such as integrins.  Inducing angiogenesis (VEGF)  Activation invasion and metastasis  Evading immune destruction TGFβ released by macrophages and stromal cells are immunosuppressive. A number of soluble factors are also secreted that favor recruitment of immunosuppressive T cells or suppress CD8.  COX-2 inhibitors have shown decrease the incidence of colonic adenomas, and now been approved as treatment for patients with familial adenomatous polyposis.  Selective outgrowth of antigen-negative variants CHROMOSOMAL ABNORMALITIES Strongly immunogenic subclones may be eliminated. 1.) Translocation Example of immunoediting  For these translocations to occur: double stranded DNA breaks  Loss or reduced expression of MHC molecules must occur simultaneously in at least two places of the genome May fail to express normal levels of HLA class 1 and free DNA ends must be joined to create two new derivative Thereby escapes attack by cytotoxic T cells. chromosomes.  Activation of immunoregulatory pathways  Overexpression of proto oncogenes  Secretion of immunosuppressive factors MYC of Burkitt’s Lypmhoma involving chromosome 8q24  Induction of regulatory T cells Page 10 of 13 2.) Chimaric Genes (Hybrid, translocation and fusion) Overexpressed in human B cell lymphomas.  The Philadelphia chromosome, characteristic of CML and B-cell Upregulates genes that promote proliferation (e.g MYC) acute lymphoblastic leukemia.  Tumor Suppresive miRs  In this instance, two chromosomes breaks lie within the ABL gene on chromosome 9 and within the BCR gene on MULTISTEP CARCINOGENESIS chromosome 22.  Non-homologous end-joining then leads to a reciprocal translocation that creates an oncogenic BCR-ABL fusion. 3.) Deletions  Deletions involving chromosome 13q14 at the site of RB gene associated with retinoblastoma.  Deletion of the VHL tumor suppressor gene on chromosome 3p is very common in renal cell carcinoma. 4.) Gene Amplification  Reduplication and amplification of the DNA sequences.  Two mutually exclusive patterns can be identified: Multiple small extra chromosomal structures called double minutes (dms). Homogenous staining regions (HSR)  HSRs are derived drom insertion of amplified genes into new chromosomal locations which may be distant from the normal  Cancer must result from accumulation of multiple mutations. location.  The chromosome lacks normal light and dark-staining pattern. Carcinogenesis  Examples: NYMC – neuroblastoma ERBB2 – Breast Cancer 5.) Chromotrypsis  Chromosome shattering results to haphazard repair  Ex: Osteosarcoma EPIGENETIC CHANGES  Post translational modifications: Hypermethylation Hypomethylation Changes in histones  Local hypermethylation of DNA results to silencing of tumor suppressor genes.  Tumors commonly exhibit abnormal DNA methylation such as  Initiation acute myeloid leukemia. Results from exposure of cells to a sufficient dose of  Sometimes there are mutations in the genes encoding for DNA carcinogenic agent. methyltransferases. The initiated cell is altered making it potentially capable of giving rise to a tumor. NON-CODING RNAs  Initiation causes permanent DNA damage and has a memory.  MicroRNAs (miRs) are small noncoding, single-stranded RNA, approximately 22 nucleotides length, mediate sequence-specific Thus, tumors are produced ven if application of the inhibition of mRNA translation via the RNA-induced silencing promoting agent is removed for years. complex (RISC).  Promoters  Mediate post-transcriptional gene silencing Can induce tumors to arise from initiated cells, but they are  OncomiRs non-tumorigenic by themselves. Promote epithelial mesenchymal transitions. Retroviral insertions in avian lymphomas. Page 11 of 13 DIRECT-ACTING INITIATORS MICROBIAL CARCINOGENESIS  Require no metabolic conversion to become carcinogenic.  Bacteria  Most are weak carcinogens because they are cancer Helicobacter Pylori chemotherapeutic drugs (e.g. alkylating agents).  Associated with gastric adenocarcinoma and MALTomas  Highly reactive electrophils.  CagA cytotoxin gene and cytokines induce chronic inflammation. INDIRECT-ACTING INITIATORS  RNA Viruses  Require metabolic activation by cytochrome p450 dependent HTLV-1 causes adult T-cell leukemia/lymphoma. mono-oxygenase. Tax genome causes proliferation and instability  The carcinogenic product is called an ultimate carcinogen.  DNA Viruses  Reaction varies among individuals. Human Papilloma Virus  An important cause of benign warts, cervical cancer, and CARCINOGENIC CHEMICALS oropharyngeal cancer  Oncogenic types encode two viral oncoproteins: E6, E7 which binds to RB and P53 and neutralize their function.  Can be prevented with vaccines. Epstein Barr Virus  Ubiquitous herpesvirus associated with Burkitt lymphomas, B-cell lymphoma in HIV, Hodgkin’s lymphoma, and nasopharyngeal cancer.  LMP-1 is oncogene Hepatitis B and C virus  Causes 70-85% of hepatocellular carcinoma  Multifactorial oncogenic effects.  Dominant effect seems to be immunologically mediated chronic inflammation, hepatocellular injury, and reparative  Aflatoxin B hepatocyte proliferation. Toxin produced by Aspergillus fungi. Herpes Virus 8  Asbestos  Associated with Kaposi’s Sarcoma Fire-proof material used in construction materials. CLINICAL FEATURES OF TUMORS PROMOTERS  Effects of Tumors on the host  These are chemical agents that are not mutagenic, but which Location and impingement on adjacent structures. instead stimulate cellular proliferation. Functional activity such as hormone synthesis.  Examples: Bleeding and secondary infection – ulceration to the surface Hormones Initiation of acute symptoms – rupture or infarction. Chronic Inflammation Local and Hormonal Effects RADIATION CARCINOGENESIS  A small (1cm) pituitary adenoma can compress and destroy the  Radiant energy in the form of UV rays of sunlight or as ionizing surrounding normal gland thus lead to serious pituitary electromagnetic and particulate radiation is carcinogenic. hypopituitarism.  UV rays  Neoplasia in the gut may cause obstruction as they enlarge. UV B is linked to all forms of skin cancer  Obstructing intussusception can occur. Formation of pyrimidine dimers  Beta cell adenoma can cause fatal hypoglycemia.  Ionizing Electromagentic Forcers  Hematuria in Renal neoplasia. X-rays and Gamma rays  Melena and Hematemesis in GIT neoplasia.  Particulate α and β particles Page 12 of 13 CANCER CACHEXIA GRADING AND STAGING  Cancer patients commonly suffer progressive loss of body fat  Grading and lean body mass accompanied by profound weakness, Degree of differentiation of the tumor cells. anorexia, and anemia referred to as cachexia. The number of mitosis within the tumor.  Cachexia is associated with: Range from two to four categories. Equal loss of both fat and lean muscle Done by the pathologist Elevated BMR  Staging Evidence of systemic inflammation Based on the size of the primary lesion.  TNFα (cachecdin) is a leading suspect among several mediators Its extent of spread to the regional lymph nodes. released by immune cells may contribute to cachexia. The presence or absence of blood-borne metastases.  Humoral factors released by tumors cells such as proteolysis- 2 staging systems: UICC (TNM) and AJCC inducing factors may play a role in loss of muscle mass.  T for the primary tumor  N for the regional lymph node involvement PARANEOPLASTIC SYNDROME  M for metastases  Some cancer patients develop signs and symptoms that cannot Staging is usually done by the clinician. readily be explained by the anatomic distribution of tumors or by Staging is more important than grading. the elaboration of hormones indigenous to the tissue. May be the earliest manifestation of an occult neoplasia LABORATORY DIAGNOSIS May present significant clinical problems and be even lethal.  Histologic and Cytologic Methods They may mimic metastatic disease and therefore confound Biopsy treatment. Fine needle Aspiration  Endocrinopathies Cytologic Smears Frequently encountered paraneoplastic syndrome.  Immunohistochemistry Re cancer are not of endocrine origin and the secretory Categorization of undifferentiated malignancies activity of such tumor is referred to as ectopic hormone Determination of site of origin production. Detection of molecules that have prognostic or therapeutic Cushing Syndrome values.  Hypercalcemia  Flow Cytometry Most common. Membrane antigens Two general processes are involved: DNA content in liquid tumors Osteolysis induced by cancer whether as primary or  Molecular Diagnosis (PCR, FISH) metastatic. Diagnosis of signature genes. Calcemic Humoral Substance (PTHRP) – Parathyroid Prognosis hormone related protein. Detection of residual genes  Neuromyopathic Syndrome Hereditary Predisposition Antibodies induced against tumor cell antigens that cross- Guiding therapy – personalized therapy react with neuronal cell antigens.  Molecular Diagnosis is still the best for diagnosing cancer but it is  Acanthosis Nigricans expensive. Characterized by gray-black patches of thickened, hyperkeratotic skin with a velvety appearance. TUMOR MARKERS It occurs rarely.  Hypertrophic Osteoarthropathy Formation of new bones. Arthritis of the adjacent joints Clubbing of the digits  Vascular and Hematologic Migratory Thrombophlebitis Thrombotic Endocarditis DIC  The different tumor markers are NON-DIAGNOSTIC but they can be used to monitor and check the prognosis of the patient. “Ñuhor līr gūrēnna.” (I will take what’s mine) Page 13 of 13