Why does cell proceed towards carcinogenesis when there are

mechanisms to remove cells unfit for survival?

Why does cell proceed towards carcinogenesis when there are

mechanisms to remove cells unfit for survival?

MonikaRoll no: M-5626

Division of veterinary medicine

MonikaRoll no: M-5626

Division of veterinary medicine

Robinns basic pathology

• Process of actual formation of cancer which is characterised by progression of changes at the

- Genetic

- Epigenetic level

- Ultimately lead to uncontrolled cell division

• Multistep process Robinns basic pathology

Carcinogenesis?Carcinogenesis?

Hanahan et al.,2011

Robinns pathology

MECHANISMS TO REMOVE CELL UNFIT FOR SURVIVAL

MECHANISMS TO REMOVE CELL UNFIT FOR SURVIVAL

Apoptosis Apoptosis

• Apoptosis is a active energy dependent process that involves cleavage of DNA by endonucleases and proteins by proteases called CASPASES.

Lowe et al., 2000

Robinns pathology

Necrosis

• Local death of tissue within living tissue after degradative action of enzymes on the irreversible injured cell

• Potentially reversible process in which a cell that is stressed EATS itself.

Elmore., 2007

• Characterized by the formation of cytoplasmic AUTOPHAGIC VESICLES

• Targeted disruption of genes such as ATG5 that are involved in autophagy can inhibit cell death.

• Autophagy has dual roles in cancer:- a tumor suppressor by preventing the accumulation of damaged

proteins and organelles- as a mechanism of cell survival that can promote the growth of

tumors Tait et al., 2014

Factors leading to defective autophagy:

a)Beclin 1 mutation b) PI3K-Akt-mTOR pathway dysregulation

Panda et al., 2015

What makes the cell to evade cell death and makes it cancerous?

What makes the cell to evade cell death and makes it cancerous?

Hanahan et al., 2011

Robinns pathology

Over expression of telomeraseOver expression of telomerase

Checkpoints in cell cyclethe cell cycle is controlled by two classes of cell cycle

proteins,cyclins and cyclin dependent kinases (CDKs),which physically associate to form a protein

kinase that drives the cell cycle forward

the cell cycle is controlled by two classes of cell cycle proteins,

cyclins and cyclin dependent kinases (CDKs),which physically associate to form a protein

kinase that drives the cell cycle forward

most tumor cells lack the DNA damage-induced p53-dependent G1 checkpoint, increasing the likelihood that mutations will be propagated in these cells.

most tumor cells lack the DNA damage-induced p53-dependent G1 checkpoint, increasing the likelihood that mutations will be propagated in these cells.

Molecular Biology of Cancer

• Situated at the short arm of 17 chromosome

• Mutated in most of the cancer cases

• Repair of damaged DNA before S-phase in the cycle by arresting cell cycle in G1 phase untill the damage is repaired

• Apoptic cell death if there is extensive DNA damage

• p53 can lost its function:a) Non sense mutation or mis sense mutationb) Binding of normal p53 to viral oncoproteins

p53p53

Molecular Biology of Cancer

Mutated p53Mutated p53

Fas/FADD downregulationFas/FADD downregulation

High levels of FLICE

FADD like IL-1 converting enzyme FADD like IL-1 converting enzyme

Binds with DISC(death inducing signalling complex)Binds with DISC(death inducing signalling complex)

Prevents activation of caspases 8Prevents activation of caspases 8

No apoptosis

No apoptosis

Elmore.,2007

Over expression of Bcl-2Over expression of Bcl-2

• Caretaker genes- Maintain the integrity of the genome by repairing DNA

damage

• Gatekeeper genes- Inhibit the proliferation or promote the death of cells with

damaged DNA

Categories of tumor suppressor genesCategories of tumor suppressor genes

28

Rb geneRb gene

RAS gene

• APC regulates the rates of proliferation and apoptosis

• APC is important for cytoskeletal integrity, cellular adhesion, and Wnt signaling.

• APC plays a role in the G1/S transition of the cell cycle by modulating expression levels of c-myc and cyclin D1

• full length APC is also important in maintaining intestinal cell migration up the crypt and inducing apoptosis

APC(Adenomatous polyposis coli)APC(Adenomatous polyposis coli)

Martinez et al.,2003

tumor suppressor gene ,role in induction of cell cycle arrest and apoptosis

tumor suppressor gene ,role in induction of cell cycle arrest and apoptosis

acts as a negative regulator of Akt activation acts as a negative regulator of Akt activation

can induce apoptosis of mutated Or stressed cells to prevent tumor formation

can induce apoptosis of mutated Or stressed cells to prevent tumor formation

PTEN suppresses the PI-3K-mediated induction of blood vessel growth factors

PTEN suppresses the PI-3K-mediated induction of blood vessel growth factors

PTENPTEN

Martinez et al.,2003

Other factors..

family of Inhibition of Apoptosis Proteins- xIAP,BIRC2,BIRC3

Heat Shock Proteins- HSP27,HSP70 Casarett & Doull’s Toxicology 7th

edition

• deregulation in anoikis execution is emerging as a hallmark of cancer cells and contributes to the formation of metastasis in distant organs

Paoli et al., 2013

Conclusion

Oncogenic mutation distrupt apoptosis ,leading to tumor initiation,progression and metastasis

Agents that induce apoptosis,autophagy can be used as anticancer drugs

p53 mutation causes Li- Fraumenic syndrome

Bcl-2 alteration causes hodgkin disease,breast cancer

Bax deletion causes brain tumors