APOPTOSIS, NECROSIS AND CANCER. Dr. S. P. Pattanayak

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1 APOPTOSIS, NECROSIS AND CANCER Dr. S. P. Pattanayak

2 LEARNING OBJECTIVES At the end of the lecture, students should be able to: Know the importance of cell death. Define various modes of cell death. Identify features of necrosis, apoptosis. Differentiate between necrosis and apoptosis. Define cancer Describe the mechanism of cancer development

3 CELL DEATH Cells are born, live for a given period of time and then die Bowen, 1998

4 CELL INJURY A cell maintaining a steady state called Homeostasis

5 CELL INJURY Altered Homeostasis

6 TO DIE OR NOT TO DIE? Integrated balance between positive survival factors and negative death signals decides fate of cell

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8 CELL DEATH The 100 trillion cells of the body are members of a highly organized community The total number of cells is regulated by; controlling the rate of cell division and controlling the rate of cell death. Cells die by one of two mechanisms Necrosis or Apoptosis Two physiologically different processes Apoptosis and necrosis have different characteristics

9 APOPTOSIS Apoptosis is an energy dependent programmed cell death for removal of unwanted individual cells

10 APOPTOSIS IN PHYSIOLOGIC SITUATIONS Programmed cell death during embryogenesis Formation of free and independent digits Development of the brain Development of reproductive organs Programmed cell death during adult stage Cell loss in proliferating cell populations Death of cells that have served their useful purpose Elimination of harmful self- reacttive lymphocytes

11 POPTOSIS IN PATHOLOGICAL ITUATIONS Chronic viral diseases Neurodegenerative diseases Reperfusion injury Insulin-dependent Diabetes Atherosclerosis Myocardial Infarction AIDS Development and Treatment of Malignancies onic viral diseases...

12 THE MECHANISMS OF APOPTOSIS This process involves a specific proteolytic cascade There are 3 different mechanisms by which a cell commits suicide by apoptosis by signals arising within the cell; by death activators binding to receptors at the cell surface: TNF-α Lymphotoxin Fas ligand (FasL) third that may be triggered by dangerous reactive oxygen species.

13 APOPTOSIS ; MORPHOLOGIC CHANGES Early : Chromosome condensation, cell body shrink Later : Membranes become irregular-blebbing ; Nucleus and cytoplasm fragment- Apoptotic bodies At last : Phagocytosed

14 Membrane blebs during apoptosis

15 THE ENZYMATIC REGULATION OF APOPTOSIS Apoptosis is initiated by activation of a family of proteases called caspases. These are enzymes that are synthesized and stored in the cell as inactive procaspases. once activated, the enzymes cleave and activate other procaspases, triggering a cascade that rapidly breaks down proteins within the cell The cell thus dismantles itself, and its remains are rapidly digested by neighboring phagocytic cells.

16 Excessive apoptosis Uncontrolled cell loss

17 DISEASES FEATURING EXCESSIVE APOPTOSIS Neurodegenerative Parkinson s disease Alzheimer's disease Amyotrophic lateral sclerosis (ALS) Huntingdon s disease

18 Uncontrolled growth of cells Insufficient apoptosis

19 DISEASES FEATURING INSUFFICIENT APOPTOSIS Many cancers Autoimmune Lymphoproliferative Syndrome (ALPS)

20 LINICAL IMPORTANCE OF APOPTOSIS Recent studies suggest that abnormalities of apoptosis may play a key role in neurodegenerative diseases such as Alzheimer s disease, as well as in cancer and autoimmune disorders. Some drugs that have been used successfully for chemotherapy appear to induce apoptosis in cancer cells. Cancer Loss of the ability to undergo apoptosis leads to cancer.

21 NECROSIS DEATH BY INJURY cell death as the result of injury, disease, or pathological state usually involves large numbers of cells. Necrotic cells may spill their contents, causing inflammation and injury to neighboring cells.

22 OAGULATIVE NECROSIS Cell outlines remain intact after cell death and can be observed by light microscopy is typically seen in hypoxic(low-oxygen) environments Examples; infarcts of solid organs, heart, spleen, kidney.

23 CASEOUS NECROSIS Tissues bear soft, granular, friable appearance cream-cheesy(caseous) material Architecture completely destroyed. Examples; Tuberculosis, some systemic fungal infection A tuberculous lung with a large area of caseous necrosis

24 LIQUEFACTIVE NECROSIS (OR COLLIQUATIVE NECROSIS) Necrotic degradation of tissue that softens and liquify tissues grossly. Examples Infarction of central nervous system Abscess in bacterial infection

25 FAT NECROSIS results from the action of lipases on fatty tissues Chalky yellow white deposits formed Basophilic calcified areas Examples: acute pancreatitis traumatic breast tissue necrosis

26 FIBRINOID NECROSIS It is marked by deposition of fibrinlike proteinaceous material in arterial walls, appears smudgy and eosinophilic on light microscopy. Examples; Immune vasculitis Malignant hypertension

27 IFFERENCE B/W APOPTOSIS ND NECROSIS APOPTOSIS Chromatin condensation Cell shrinkage Preservation of organelles and cell membranes Rapid engulfment by neighboring cells preventing inflammation Biochemical hallmark - DNA fragmentation NECROSIS Nuclear swelling Cell swelling Disruption of organelles Rupture of cell and Release of cellular contents Inflammatory response

28 IFFERENCE B/W APOPTOSIS ND NECROSIS

29 ANCER; INTRODUCTION Neoplasm - (new growth) abnormal mass of tissue, the growth of which exceeds and is uncoordinated with the normal tissues Tumor - a non-specific term meaning lump or swelling. Often syn. for neoplasm Cancer - malignant neoplasm or tumor Metastasis - discontinuous spread of a malignant neoplasm to distant sites

30 DISEASES FEATURING EXCESSIVE APOPTOSIS Neurodegenerative Parkinson s disease Alzheimer's disease Amyotrophic lateral sclerosis (ALS) Huntingdon s disease

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