Neoplasia Biology & Lab Dx.ppt,presentation on neoplasia
- 1. Neoplasia: Biology & Lab Dx Neoplasia: Biology & Lab Dx
- 2. Normal cell Normal cell vs vs Cancer cell Cancer cell
- 3. Duplication of DNA and centriole Post mitotic phase. Accumulate the energy and prepares themselves for the synthesis of DNA. Active synthesis of RNA and protein.
- 5. Tumor growth Tumor growth Proliferation vs cell death Proportion of cells in the cell cycle A cell approx 10µ in diameter must undergo at least 30 population doublings to produce 109 cells which is the smallest clinically detectable mass
- 6. Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 60:277–300, 2010
- 8. Conditions predisposing to Conditions predisposing to cancer cancer • Regeneration (liver), hyperplasia Regeneration (liver), hyperplasia (endometrium), metaplasia (respiratory tract) (endometrium), metaplasia (respiratory tract) • Chronic inflammation (liver, colon) Chronic inflammation (liver, colon) • Precancerous conditions Precancerous conditions – Atrophic gastritis Atrophic gastritis – Solar keratosis of skin Solar keratosis of skin – Chronic ulcerative colitis Chronic ulcerative colitis – Leucoplakia of oral cavity Leucoplakia of oral cavity
- 9. Molecular basis of cancer Molecular basis of cancer • Non lethal genetic damage reqd for Non lethal genetic damage reqd for carcinogenesis carcinogenesis • Cancer is a genetic disease Cancer is a genetic disease • Tumours are monoclonal Tumours are monoclonal
- 10. Malignant transformation Malignant transformation • Self sufficiency in growth signals e.g., oncogene activation Self sufficiency in growth signals e.g., oncogene activation • Insensitivity to inhibitory signals e.g., Ts genes Insensitivity to inhibitory signals e.g., Ts genes • Evasion of apoptosis e.g., genes regulating apoptosis Evasion of apoptosis e.g., genes regulating apoptosis • Defects in DNA repair e.g., genes reg DNA repair Defects in DNA repair e.g., genes reg DNA repair Also Also • Limitless replication e.g., telomerase Limitless replication e.g., telomerase • Sustained angiogenesis Sustained angiogenesis • Ability to invade and metastasis Ability to invade and metastasis • Avoid immune destruction Avoid immune destruction
- 11. Hallmarks of Cancer Hallmarks of Cancer
- 12. Normal cell DNA Damage Mutations in genome Alterations of genes governing apoptosis Expression of altered gene products and loss of regulatory gene products Inactivation of tumor suppressor genes Activation of proto- oncogenes DNA damaging agents Chemicals Radiation viruses Inherited mutations in genes affecting cell growth or apoptosis Failure of DNA repair Successful DNA repair CANCER Clonal expansion, additional mutations and heterogeneity Genetic basis of cancer
- 14. Malignant transformation Malignant transformation • Self sufficiency in growth signals Self sufficiency in growth signals • Insensitivity to inhibitory signals Insensitivity to inhibitory signals • Evasion of apoptosis Evasion of apoptosis • Defects in DNA repair Defects in DNA repair • Limitless replication Limitless replication • Sustained angiogenesis Sustained angiogenesis • Ability to invade and metastasise Ability to invade and metastasise
- 16. Category Protooncogenes MOA Associated human tumors Growth factors PDGF B SIS Overexpression Astrocytoma osteosarcoma FGF HST 1 INT2 Overexpression Amplification Stomach carcinoma Bladder, Breast TGF-A TGFA Overexpression Astrocytoma, HCC
- 17. 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.
- 19. 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
- 21. BCR/ABL1 probe- two fusion, one red, one green BCR/ABL1 probe- two fusion, one red, one green signal signal pattern : Positive for t(9;22) pattern : Positive for t(9;22)
- 22. 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
- 25. Primary tumor Transformed cell Metastatic clone (clonal expansion,growth diversification angiogenesis) Adhesion to BM and invasion Passage through extracellular matrix Host lymphocytes (Host immunity) Intravasation Tumor embolus Adhesion to BM and extravasation, metastatic deposit and angiogenesis THE METASTATIC CASCADE ECM
- 26. Tumor-host interaction Tumor-host interaction Tumor antigens Tumor antigens • Products of mutated oncogenes and Ts genes Products of mutated oncogenes and Ts genes – Oncogene: ras, EGFR Oncogene: ras, EGFR – Suppressor genes: p53,Rb Suppressor genes: p53,Rb • Over expressed or aberrantly expressed cellular proteins Over expressed or aberrantly expressed cellular proteins – Melanoma associated genes: MART Melanoma associated genes: MART • Tumor antigens produced by oncogenic viruses Tumor antigens produced by oncogenic viruses – Eg. EBV and HPV associated proteins Eg. EBV and HPV associated proteins • Oncofetal antigens Oncofetal antigens – CEA, AFP CEA, AFP
- 27. • Altered cell surface glycolipids and glycoproteins Altered cell surface glycolipids and glycoproteins – CA-125 (Ovary), CA 19-9 (Pancreas) CA-125 (Ovary), CA 19-9 (Pancreas) • Cell-type specific differentiation antigens Cell-type specific differentiation antigens – CD-10, CD-20 in leukemias and lymphomas CD-10, CD-20 in leukemias and lymphomas – IMPORTANT for targeted immunotherapy IMPORTANT for targeted immunotherapy Tumor-host interaction Tumor-host interaction Tumor antigens Tumor antigens
- 28. • Cytotoxic T lymphocytes: esp. against viral antigens Cytotoxic T lymphocytes: esp. against viral antigens • Natural killer cells: may provide first-line defence Natural killer cells: may provide first-line defence • Macrophages: stimulated by IFN Macrophages: stimulated by IFN ע ע from CTL’s and NK from CTL’s and NK cells cells • Antibodies: ? potential Antibodies: ? potential Tumor-host interaction Tumor-host interaction Anti Anti- -Tumor effector mechanisms Tumor effector mechanisms
- 29. TGF ß Apoptosis of CTL’s Antigen masking Antigen –ve variants Immunosuppression Loss of MHC molecules Lack of costimulation ( Activation of CTLA-4, PD-L1 &2) Escape from immune surveillance
- 30. CANCER DIAGNOSIS CANCER DIAGNOSIS Clinical symptoms and signs Radiology X-Ray, ultrasound, CTscan, MRI Cytology Biopsy Tumor markers Haematology & Biochemistry Special Techniques Immunohistochemistry, Electron microscopy, Genetics, Flow cytometry
- 31. MPNST Chest IVC leiomyosarcoma
- 32. LAB DIAGNOSIS OF CANCER LAB DIAGNOSIS OF CANCER • For screening for early diagnosis For screening for early diagnosis • For therapy For therapy – To establish the type To establish the type – To determine extent of spread To determine extent of spread – At a metastatic site to indicate primary site At a metastatic site to indicate primary site – To determine recurrence To determine recurrence
- 33. What do we rely on? What do we rely on? Tissue diagnosis Tissue diagnosis • Cytology Cytology • Biopsy Biopsy • Routine techniques Routine techniques • Immunohistochemistry Immunohistochemistry • Electron Microscopy Electron Microscopy • Cytogenetics Cytogenetics • Flow cytometry Flow cytometry • Tumour markers Tumour markers
- 34. Screening Screening • Useful for tumors that have a long latent period of Useful for tumors that have a long latent period of growth growth • Tries to detect cancer in the preneoplastic stage Tries to detect cancer in the preneoplastic stage – Cancer cervix: Papanicolaou test (cells scraped Cancer cervix: Papanicolaou test (cells scraped from cervix using an Ayre’s spatula) from cervix using an Ayre’s spatula) – Trucut biopsy of mammographically detected Trucut biopsy of mammographically detected breast cancer breast cancer – Endoscopic biopsies in early gastric cancer Endoscopic biopsies in early gastric cancer – Serum Prostate specific antigen in prostate cancer Serum Prostate specific antigen in prostate cancer
- 35. ‘ ‘Tissue’ diagnosis of cancer Tissue’ diagnosis of cancer • Cytology Cytology – Exfoliative cytology Exfoliative cytology • Fluids from body cavities Fluids from body cavities • Scrapes and brushings (bronchial, endoscopic) Scrapes and brushings (bronchial, endoscopic) – Fine needle aspiration cytology (FNAC) Fine needle aspiration cytology (FNAC) • 22 gauge needle 22 gauge needle • 10 ml syringe 10 ml syringe • Aspirate from suspected lesion Aspirate from suspected lesion – ‘ ‘Blind’ Blind’ – ‘ ‘Guided’ (ultrasound or CT scan) Guided’ (ultrasound or CT scan)
- 36. • Biopsy Biopsy – Incisional Incisional • Trucut Trucut • Wedge Wedge – Excisional Excisional • Wide local excision Wide local excision • Total Total • Radical Radical ‘ ‘Tissue’ diagnosis of cancer Tissue’ diagnosis of cancer
- 37. • Special techniques applied to Special techniques applied to tissues/cells tissues/cells – Electron microscopy Electron microscopy – Immunohistochemistry Immunohistochemistry – Flow cytometry Flow cytometry – Cytogenetics Cytogenetics ‘ ‘Tissue’ diagnosis of cancer Tissue’ diagnosis of cancer
- 38. 8 months/F Soft tissue tumor Rt arm
Editor's Notes
- #25: Invasion of extracellular matrix: (a) Loosening of cells from each other (loss of adhesion molecules like cadherins) (b) Attachment to matrix components (fibronectin and laminin); © Degradation of extracellular matrix by enzymes (metalloproteinases). (ii) Entry into the circulation Migration of tumor cells to enter the circulation (locomotion). (iii) Dissemination and homing of tumor cells governed by adhesion to endothelial cells by adhesion molecule CD 44 and chemoattractants that recruit tumor cells to metastatic sites. Genetic control of metastases: Metastases suppressor genes – nm 23, KAI-I, KiSS-I
- #33: Products/secretions of tumor cells circulating in blood