APOPTOSIS, NECROSIS and CANCER

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

CELL DEATH

Cells are born,

live for a given period of time and then die

Bowen, 1998

Cell Injury

A cell maintaining a steady state called Homeostasis

Cell Injury

Altered Homeostasis

To die or not to die?

Integrated balance between positive survival factors and negative death

signals decides fate of cell

CELL DEATHThe 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

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

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

APOPTOSIS IN PHYSIOLOGIC SITUATIONS

• Chronic viral diseases• Neurodegenerative diseases• Reperfusion injury• Insulin-dependent Diabetes• Atherosclerosis• Myocardial Infarction• AIDS• Development and Treatment of Malignancies

onic viral diseases...

APOPTOSIS IN PATHOLOGICALSITUATIONS

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.

APOPTOSIS ; MORPHOLOGIC CHANGES

• Early : Chromosome condensation, cell body shrink • Later : Membranes become irregular-Blebbing ;

Nucleus and cytoplasm fragment- Apoptotic bodies• At last : Phagocytosed

Membrane blebs during apoptosis

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.

Excessive apoptosisUncontrolled cell loss

Diseases featuring excessive apoptosis

NeurodegenerativeParkinson’s diseaseAlzheimer's diseaseAmyotrophic lateral sclerosis (ALS)Huntingdon’s disease

Uncontrolled growth of cellsInsufficient apoptosis

Diseases featuring insufficient apoptosis

Many cancersAutoimmune Lymphoproliferative

Syndrome (ALPS)

CLINICAL 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.

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.

COAGULATIVE 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.

CASEOUS NECROSIS

• Tissues bear soft, granular,

friable appearance• cream-cheesy(caseous) material• Architecture completely destroyed.

Examples;

Tuberculosis,

some systemic fungal infectionA tuberculous lung with a large area of caseous necrosis

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

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

FIBRINOID NECROSIS• It is marked by deposition of

fibrin-like proteinaceous material in arterial walls,

• appears smudgy and eosinophilic on light microscopy.

Examples;• Immune vasculitis• Malignant hypertension

DIFFERENCE B/W APOPTOSIS AND 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

DIFFERENCE B/W APOPTOSIS AND NECROSIS

CANCER; INTRODUCTIONNeoplasm - (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

Diseases featuring excessive apoptosis

NeurodegenerativeParkinson’s diseaseAlzheimer's diseaseAmyotrophic lateral sclerosis (ALS)Huntingdon’s disease

CANCER

Cancer is a disorder of cellular homeostasis disease in which there is uncontrolled cell division caused by:

• by mutation• or by some other abnormal

activation of cellular genes that control cell growth and cell mitosis.

•The abnormal genes are called oncogenes. •Also present in all cells are antioncogenes, which suppress the activation of specific oncogenes. •Therefore, loss of or inactivation of antioncogenes can allow activation of oncogenes that lead to cancer.

•A factor which brings about a mutation is called a mutagen.•Any agent that causes cancer is called a carcinogen and is described as carcinogenic.

CANCER

CARCINOGENS• Ionising radiation – X Rays, UV light

• Chemicals – asbestos,

tar from cigarettes

• Virus infection – papilloma virus can be responsible for cervical cancer.

• Hereditary predisposition – • Some families are more susceptible

to getting certain cancers.

carcinogen sign

HALLMARKS OF CANCER

BENIGN OR MALIGNANT?

• Benign tumours • do not spread from their site of origin• can crowd out (squash) surrounding cells• slow growing• well differentiated

• Malignant tumours• can spread from the original site

and cause secondary tumours. This is called metastasis. • Fast growing• Poorly differentiated• They interfere with neighbouring

cells and can block blood vessel, gut etc.

BENIGN OR MALIGNANT?

GENERAL AND LOCAL EFFECTS OF CANCER

• Cancer can kill the patient by:• Local effects• Systemic effects

• Why Do Cancer Cells Kill? • Cancer tissue competes with normal tissues for nutrients. • Because cancer cells continue to proliferate indefinitely, cancer

cells soon demand essentially all the nutrition available to the body or to an essential part of the body.

• As a result, normal tissues gradually suffer nutritive death.

REFERENCES

• Text book of medical physiology , Guyton and Hall

• Robbins & Cotran Pathologic Basis of Disease

• Rapid Review Pathology, By Edward F. Goljan, MD

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages

SELF ASSESSMENTQ1. Is cell death necessary? why?

Q2. Which type of cell death is called programmed cell death?

Q3. Identify the processes labeled as A & B.

A B

SELF ASSESSMENTQ4. Identify the type of necrosis in fig A& B

A B

Q5. Name some of the common carcinogens.

Q6. Differentiate b/w benign and malignant tumors.

SELF ASSESSMENT