![1.Non lethal genetic damage is the heart of carcinogenesis . Mutations
acquired from environment- exogenous and endogenous.
2.Clonality
Tumors arise as clones from a single cell that has incurred genetic damage.
[ Tumors are monoclonal]
The development of the malignant clone is due to mutations in DNA due
to:
Random replication errors
Exposure to carcinogens
Faulty DNA repair process
Characteristics of Neoplasia](https://image.slidesharecdn.com/molbasiscancer-241116133912-766ceea2/85/mol-basis-cancer-pptx-carcinoma-molecular-basis-16-320.jpg)
mol basis cancer.pptx, carcinoma molecular basis
- 1. Molecular basis of cancer
- 2. In the process of Development of unicellular fertilized egg into complex multi cellular organism- cellular replication, growth and differentiation. Cellular replication occurs mitosis n it produces two identical daughter cells. Some daughter cells-specialise and bcom teminally d/f cells of mature tissues. Other daughter cells- retain property of stem cells. Cell Cycle
- 3. Cell cycle is the interval period between beginning of one mitosis to the beginning of other division. 2 phases(in the order) Interphase G1 phase S phase G2 phase M phase Mitosis cytokinesis
- 4. Post mitotic phase. Accumulate the energy and prepares themselves for the synthesis of DNA. Active synthesis of RNA and protein. Duplication of DNA and centriole Formation of macro molecules for spindle formation.
- 6. Cell Cycle Checkpoints G1/ S checkpoint: • Checks for DNA damage before replication. • Regulated by proteins called cyclins and associated enzymes (CDK )& inhibitors (CDK inhibitors.) • Cyclins D,E,A and B appear sequentially during the cell cycle and bind to CDK.
- 7. G2/M checkpoint: • Monitors the completion of DNA replication and checks whether the cell can safely enter mitosis. • They delay cell cycle progression, thus providing time for DNA repair. If damage is not repairable then apoptotic pathways are activated. • Hence defects in these checkpoints will cause loss of normal cell cycle control ultimately leading to malignant transformation.
- 8. The orderly progression of cells through the various phases of cell cycle is regulated by Cyclins, cyclin dependant kinases (CDKs) & their inhibitors. CDKs - expressed constitutively during cell cycle , in inactive form. Cyclins- synthesized during specific phases of cell cycle ; activates CDKs Cyclin D – First cyclin to increase in cell cycle - appears in mid G1 - binds to & activates CDK 4 Cyclin D- CDK4 complex phosphorylates retinoblastoma susceptibility protein (RB) Phosphorylation of RB is a molecular on-off switch for cell cycle.
- 10. G0 G1 S G2 M The key enzymes that control the transitions between the different states of the cell cycle, and the entry of nondividing cells into the cell cycle, are the cyclin-dependent protein kinases, or CDKs Cyclin D CDK 4,6 Cyclin E CDK 2 Cyclin A CDK 2 Cyclin B CDK 1 Active Rb+E2F Inactive Rb and E2F • Hypophosphorylated Rb is active form; binds E2F and wont let cell cycle to progress. • E2F when released from Rb will form cyclin E A B and DNA polymerase and helps Mitogenic stimulus
- 12. Neoplasia
- 13. “Cancer is a result of accumulated genetic mutations and it acquire selective growth advantages over their non transformed counterparts, acquires adaptability even to everchanging environment and they proliferates.” Mutations in genes result in altered proteins Most cancers result from mutations in somatic cells Some cancers are caused by mutations in germline cells Molecular basis of cancer
- 16. 1.Non lethal genetic damage is the heart of carcinogenesis . Mutations acquired from environment- exogenous and endogenous. 2.Clonality Tumors arise as clones from a single cell that has incurred genetic damage. [ Tumors are monoclonal] The development of the malignant clone is due to mutations in DNA due to: Random replication errors Exposure to carcinogens Faulty DNA repair process Characteristics of Neoplasia
- 17. 3. 4 principle targets of genetic damage: a)Growth promoting protooncogenes. b)Growth inhibiting tumor suppresor genes. (Both) c)Genes that regulate apoptosis. d) Genes involved in DNA repair. 4. Carcinogenesis is a multistep process resulting from accumulation of multiple mutations; that leads to tumor progression. Tumor progression: Mutations accumulate in different cells, generating subclones with variable ability to grow, invade, metastasize.
- 18. Definition of terms: Oncogenes- promote autonomous cell growth in cancer cells in the absence of growth signals also. Protooncogenes -Unmutated cellular counter part of oncogenes Oncoproteins- are the products of oncogenes 1.Self sufficiency
- 19. Under physiological conditions cell proliferation resolved into 1 2 3 4 5
- 20. Five types of proteins encoded by proto-oncogenes participate in control of cell growth: Class I: Growth Factors Class II: Receptors for Growth Factors and Hormones Class III: Intracellular Signal Transducers Class IV: Nuclear Transcription Factors Class V: Cell-Cycle Control Proteins
- 21. Category Protooncogenes MOA Associated human tumors 1Growth factors PDGF B SIS Overexpression Astrocytoma osteosarcoma FGF HST1 INT2 Overexpression Amplification Stomach carcinoma Bladder, Breast TGF-A TGFA Overexpression Astrocytoma, HCC Selected protoncogenes & MOA Growth factor driven proliferation contributes to malignant phenotype by increased risk of spontaneous or induced muatation in proliferating cell population.
- 22. Category Protooncogenes MOA Associated human tumors Growth factor receptors EGF receptor family ERB1,2 Overexpression SCC FMS like tyrosine kinase 3 FLT3 Amplification Breast ovary Receptor for neurotrophic factor RET Point muat MEN 2A 2B, MTC PDGFR PDGFR B Overexpression Leukemia Receptor for stem cell factor KIT Point muatation GIST, Seminomas, leukemias. Oncogenic variant of normal receptors associated with constitutive dimerization of receptors and activation even with out the growth factor; giving out mitogenic stimulus. overrides the GF
- 23. Category Protooncogenes MOA Associated human tumors Proteins involved in signal transduction GTP binding K RAS H RAS N RAS Point mutation Colon pancreas Bladder kidney Hematological Non receptor tyrosine kinase ABL Translocation CML RAS Signal transduction BRAF Point mutation Melanomas WNT signal pathway B catenin Point mutation HCC -plays imp role in signalling cascade downstreasm. -Point mutation of RAS family genes is the single most common abnormality of dominant oncogenes in human tumors. - Approx. 15-20% of all human tumors contain mutated version of RAS proteins.
- 26. Category Protooncogenes MOA Associated human tumors Nuclear regulatory proteins Transcriptional activators C MYC N MYC L MYC Translocation } Amplification Burkitts Neuroblastoma, small cell carcinoma lung Cell cycle regulators Cyclins Cyclin D Translocation, amplification Mantle cell lymphoma, breast & oesophagus Cyclin E Overexpression Breast ca CDK CDK4 Amplification glioblastoma
- 27. Insensitivity to growth inhibitory signals TUMOR SUPPRESSOR GENES Normal function - inhibit cell proliferation LOSS OF FUNCTION Both gene copies must be defective Absence/inactivation of growth inhibitory signals--> cancer
- 28. Rb Protein Rb protein , product of Rb gene chromosome 13q14. Mechanism :Binds E2F regulatory transcription factors controlling progression of cell cycle. Controls the cell cycle progression b/n G1 and S phases. Exists in active hypophosphorylated state and binds E2F(quiscent) And gets inactived by phosphorylation. • Phosphorylated Rb cannot bind E2F --> S phase Cancer progression- – Disruption/deletion of Rb gene – Inactivation of Rb protein --> uncontrolled cell proliferation
- 29. 1.In sporadic form: both mutation of RB locus acquired after birth 2.Familial: Born with one allele mutation one hit; the second hit acquired after birth leading to LOH
- 30. Gene is c/a TP53 – 17p13 and its protein P53 Molecular policeman. Prevents propogation of genetically damaged cells It is a Transcription factor that is at the centre of large network of signals ,sensing stress like DNA damage, shortened telomeres and hypoxia. >50% tumors in humans show mutation in this gene. Acuired Inactivating mutation both the alleles are known to be acquired in somatic cells Inherited- one mutant allele, other “second hit” i.e. LOH needed to produce Li Fraumeni syndrome. P53
- 31. Mechanism of action: Phosphyorylated p53 activates transcription of p21 gene p21 CDK inhibitor (binds CDK-cyclin complex --> inhibits kinase activity) Cell cycle arrested buys time to let DNA to be repaired If damage cannot be repaire --> cell death (apoptosis) Cancer progression: --> uncorrected DNA damage --> uncontrolled cell proliferation --> cancer
- 33. APC - 5q21 Main fxn – down regulate growth promoting signals. B- Catenin protein fxn - 1. Regulates cell to cell adhesion 2. Gene transcription.(growth pmoting signal) APC/ B catenin
- 34. Imp fxn of APC- downregulate B catenin In case of cancer, mutations in B catenin prevents its destruction by A P C “Loss of contact inhibition” mutation of E cadherin or B catenin. GSK3B
- 35. Germline mutations- individual are born with one mutant allele develop thousands of adenomatous polyp by the age of 20 yrs and later carcinoma of colon. Both the alleles to be lost for a tumor to arise. Other genes functioning as Tumour suppressor genes: INK4a/ARF Locus The TGF-β pathway NF-1 & 2 gene VHL(Von Hippel Lindau) PTEN (phosphatase and tensin) WT-1(Wilms tumour) Cadherins KLF6 Patched(PTCH)
- 36. EVASION OF APOPTOSIS: Normally apoptosis will cause damaged cell to undergo apoptosis, Mutations in genes that regulate apoptosis leads to accumulation of cells - neoplastic cells. Overexpression of BCL-2 (anti apoptotic gene) Prototype of this category Downregulation of BAX pro apoptotic gene Eg. In B cell lymphoma of follicular type, translocation t(14,18) (q32;q21) , BCL2 gene from 18q21 is translocated to 14q32 (Ig heavy chain locus), leading to overexpression of BCL2 & accumulation of B lymphocyte. Additionally Mutations in p53 gene results in decreased transcription of BAX gene thus reducing apoptotic activity .
- 37. 1)Reduced CD95 levels. 2) Inactivation of DISC. 3)Reduced egress of Cytc C, bcos of BCL2. 4)Reduced levels of Proapoptotic BAX frm loss of P53. 5) Loss of APAF 1. 6) Upregulation of inhibitors of IAP
- 38. Limitless replicative potential Telomeres and telomerase. The ends of each chromosome contains , highly variable number o frepeats of sequence (TTAGGG) called as telomeres. Molecular count downclock- regulate the number of times a cell c a n divide. With each division the length of telomere decreases. Shortened telomeres recognized by DNA repair machinery as d sDNA breaks- cell cycle arrest by P53 and RB.– Ageing. This telomere shortening is prevented by the enzyme telomerase i ngerm cells but most of the somatic cells lack this enzyme. Cancer cells prevent telomere shortening by reactivation of telomerase enzyme thus causing unlimited proliferation
- 39. Development of sustained angiogenesis : Tumor cells cannot enlarge beyond 2 mm of size unless they are vascularized. Required for normal metabolism- oxygen and nutrients. Dual effects: Perfusion supplies required nutrients & oxygen. Newly formed endothelial cells secrtes GF and contributes for growth of new tumor cells. Angiogenic switch involves production of angiogenic factors& loss of anti angiogenic factors.
- 40. Tumor associated angiogenic factors ( VEGF & b FGF )are produced by tumor cells & inflammatory cells (macrophages) which infiltrate tumors. Additionally Mutational inactivation of both p53 alleles, causes ↓ in antiangiogenic factors like thrombospondin – 1 & ↑ in VEGF & Hypoxia inducible factor – 1 ( HIF – 1)
- 41. INVASION AND METASTASIS : Biologic hallmarks of malignant tumors. Invasiveness is a reliable feature that differentiates malignant from benign tumors. Metastasis – tumor implants discontinuous with the primary tumor. Dissemination occurs with one of the three pathways- a. Hematogenous spread b. Lymphatic spread c. Direct seeding of body cavities or surfaces. Metastatic cascade can be divided in 2 phases : i. Invasion of extracellular matrix ii. Vascular dissemination and homing of tumor cells
- 42. Invasion of ECM Active process involving the following steps. 1. Loosening up of the tumour cells from each other. Downregulation of E Cadherin. 2. Degradation of ECM proteolytic enzymes MMP, Cathepsin D, UPA. Another mxn- Ameboid migration :cell squeezes thru the spaces in the matrix .
- 43. 3. Attachment of tumor cells to novel ECM proteins Loss of adhesion in normal cell induces apoptosis.(Anoikis) Tumor cells resistant to apoptosis & additionally matrix modified. MMP2, MMP 9 produces novel sites that bind to tumor cells and stimulates migration. 4. Migration: Final step of invasion, tumor propells thru the BM. Complex multistep process . Cells attach at the leading edge, detach from the matrix at trailing edge and contract the actin to move forward.
- 44. In the circulation- tumor cellsforms clumps by homotypic and hetrotypic adhesions. Forms tumor emboli At distant site tumor attach to endothelium, egress thru BM Favoured by adhesion molecules integrins, laminin receptors Vascular dissemination and homing of tumour cells:
- 45. Humans literally swim in the sea of environmental carcinogens causing DNA damges Ionising radiation Sunlight Dietary carcinogens ROS geneerated by cell metabolism Such damage is regularly repaired by DNA repair systems. If the repair system not working optimally leads to accumulated mutations and leads to neoplastic transformation. In some inherited disorders genes encoding DNA repair are defective leading to increased risk of carcinogenesis.- ”Genomic instability syndromes” Defects in DNA repair
- 46. Microsatellite- Are short repeats of Base sequences in genome. Microsatellite instability- During cell division ,DNA polymerase creates another copy of DNA from original strand. DNA polymerase inserts wrong base pairs; which usually gets rectified by a set of system – Mismatch repair system. If mismatch repair system mutated or not fxng properly will lead to a state what is called as Microsatellite instability. Seen in Colorectal carcinoma(15-20%). 2 principal mismatch repair genes mutated ar MLH1 & MSH2. Microsatellite instability
- 47. Defects in 3 types of DNA repair systems Defect in mismatch repair gene- Hereditary Nonpolyposis Cancer Syndrome. Bloom Defect in Nucleotide excision repair system- Xeroderma Pigmentosa Defect in recombination repair system- Ataxia telangiectasia, syndrome and Fanconi anemia. BRCA-1 and BRCA-2 are the two genes that participate in the process o fhomologous recombination of DNA repair. Mutations in these genes will cause increased risk of breast, ovary , colon and several other cancers.
- 48. 1. Robbins Pathologic basis of disease, 8th edition. 2. Recent advances in histopathology 20. 3. Wheaters Functional Histology, 6th edition. 4. Harpers illustrated biochemistry; 29th edition. 5. Internet sources. References