Cancer cells: reduced death rate

… rates are high in tumours because the cell environment is…

Apoptosis is high due to inhospitable and cell signalling is dysregulated. Apoptotic cells stimulate wound healing and responses that promote tumour groth and regrowth after therapy

High cancer cell mitosis rates are balanced by…

Programmed cell death

although lytic necrotic cell death can also occurs, large sale normally “tidy“ apoptosis can trigger inflammation and wound healing

Apoptosis can occur at any point in the tumour development to promote the initial tumor growth or regrowth after cytotoxic therapy

Apoptosis promotes wound healing

Effector caspase-3 cleaves phosphoplipase A (iPLA) from cell membrane lipids, which produces aranchodionic acid which is metabolised by COX2 into PGE2 which promote the increase in vasodilation for cancer cell proliferation

Apoptotic bodies are coated with phosphatidylserine (PS) which isan eat me signal for macrophage to come and ingest which then release

VEGF → angiogenesis

MMPs, PDGR, TGFb → extracellular matrix remodelling/ fibrosis

Suppression of apoptosis

Individual malignant cells can suppress apoptosis, which is important for the proliferation of cancer cells from initiation → progression → treatment resistance

Suppression of apoptosis at the premalignant stage

Extend lifetime of cells so allow accumulation of potential “driver” mutation

Alters normal tissue homeostasis resulting in over production of cells (hyperplasia)

Supression of apoptosis pre malgnant to malignancy

Allow suppression of anoikis - cells can survive without attachment to the basement membrane

Cells can therefore move to invade tissue -metastasis

From metastatic to resistant: advantage from suppression of apoptosis

Allow cells to survive in the inhospitable environment (full of pro-apoptotic signals from immune cells eg FasL)

Allow cells to be resistant to therapies such as hormonal treatments that are used to kill cancer cells

Stages of cancer cell

Normal - Premglinant - Maglinant - Metastatic - Resistant

What are the two apoptosis pathways

Mitochondrial (intrinsic pathway) or death receptor (extrinsic pathway)

Apoptosis by extrinsic pathway is driven by

External signals detected by cell surface receptors eg Fas receptor

Fas receptor binds to FasL (Fas ligand)

Fas ligand binds an intracellular adaptor molecule FADD via a ‘death domain’then activates an initiator caspase

The initiator caspase then activates effector caspase which cleaves target proteins triggering the cell apoptosis process

Switching off death receptor pathways in cancer

Fas receptor and FADD can be switched off by mutations in the death domain (inactivated protein) or through promoter methylation (less transcription)

Initiator caspase expression can also be switched off in cancers methylation

This leads to resistance to pro-apoptotic signal

Death of tumour infiltrating lymphocyte cells by secretion of FasL from resistance cancer cells (counter-attack)

Intrinsic apoptosis - BCL2, Bax

intrinsic apoptosis is balanced by pro and anti apoptotic proteins which sit on the outside membrane of mitochondria

BCL-2 is a key sensor of cell stress, it is an ANTI APOPTOTIC protein that is OVEREXPRESSED by chroosome translocacation to the PGH locus in B cell follicular lymphoma, this turns it into an ocogene which extends the life of B cells but does not affect the cell cycle (proliferation rate)

BCL-2 and Bax regulate the movement of pro-apoptotic proteins like Cytochrom C from mitochondria so they do not interact with and activate the APAF-1 apoptosome

BCL-2 closes mitochon membrane pores (no release of CytC, anti-apoptotic_

Bax opens membrane pore (release of CytC, pro-apoptotic)

Oncogenic, anti apoptotic BCL-2 is over expressed in 50% of all cancers

Activating mutant EGFR protein (delEx2-7) can also induce anti-apoptotic BCL-XL expression (as well as activating the cell cycle) leading to treatment resistance

Pro-apoptotic Bax, a tumor supressor gene, is inactivated in colon and stomach cancers

The master regulator - p53 protein (which is encoded by TP53 gene)

Is the most inactivated protein in cancer (it is a tumor suppressor gene)

It is mutated in families which inhereited Li Fraumeni cancer syndrome

It normally regulated apoptosis (pro-apoptotic) and IS A CELL CYCLE CHECK POINT PROTEIN) upon detection of DNA damage (an adaptive stress response to genotoxic damage)

p53 is normally kept in check by

MDM2, which binds and target it for destruction

p53 regulates itself by triggering the expression of MDM2 in a feed-back loop, keeping its activity under control once the emergency stress is resolved

Activated p53 normally induces transcription of proteins that

ARRESTS the cell cycle at G1 by inducing expression of p21cip1, an inihibitor which represses Cyclin E-CDK2 hence allow DNA repair

Failure of repair or excessive DNA damage promotes apoptosis via pro-apoptoxic Fas and Bax (→ cytochrom C release from mitochon)

p53 in cancer (5 effects)

Deleted/ inactivated p53

Gene amplified MDM2

=?

Deleted/ inactivated p53: p53 dependent genes are no longer transcriptionally activated

Gene amplified MDM2: too much MDM2 protein targets p53 for destruction

= no cell cycle arrest = no DNA repair = No apoptosis

If cells survive:

• Acccumulation of mutation (DNA damage not repaired)

• Proliferation of cells (loss of cell cycle checkpoint)

• Malignant transformation

• Expansion of the tumour mass

• Chemotherapy can select for cells with p53 mutations that are resistant to apoptosis

Which cancer type has the highest proportion of p53 mutation?

• Esophageal Squamous Cell carcinoma

inactivating mutation - gene product having no function

Why is tumour growth supported by increased rates of apoptosis and decreased sensitivity to apoptosis? Describe mechanisms by which apoptosis is perturbed in cancer cells.