Patho 3PA2: Cancer (part 2)

systems in place that help cells avoid runaway division (other than POgenes and TSGs) (3)

- DNA repair system

- Apoptosis

- NK cells/immune system

DNA repair system function

instructs damaged cells to fix their DNA

DNA repair system operates in these body cells:

almost every single one, finds and corrects errors

purpose of the DNA repair system

across the lifespan, genes are under constant attack by carcinogens from the environment and from cell products (chemicals) --> this system helps fix mutations

mutations can occur in several ways:

- a change in a single base along the base sequence of a gene

- sometimes 1 or more bases may be added/removed

- sometimes large segments of a DNA molecule are accidentally repeated, deleted, or moved

Errors can also occur here

DNA replication

most of the time, this happens when errors in DNA replication occur

- the DNA repair system of the cell kicks in and fixes the error

- proteins find the mistakes and correct them

repair proteins recruit this enzyme:

EX01

EX01

an exonuclease that chops off the mutant strand, then allows a DNA polymerase to come by and synthesize the correct strand, thereby fixing the DNA and making it normal

mutations in the DNA repair system can lead to this:

a failure of repair, which in turn allows subsequent mutations to become permanent features of the cell and its descendants

Xeroderma Pigmentosum

- disease from an inherited defect in the DNA repair system

- can't repair DNA after sun exposure --> ++ rates of skin CA

purpose of apoptosis process in the body

balance the generation of new cells via division and loss of cells through cell death

old cells, damaged over time, are eliminated by this process

apoptosis

TSGs and apoptosis

specific TSGs --> p53 protein can stim cells with DNA damage to commit cell suicide

why is it a good thing that cells do apoptosis

prevents damaged cells from growing out of control

mutation in p53 protein of TSG leads to

defective cell suicide system --> damaged cell goes on in the cell cycle and divides

there is an abnormal p53 gene present in this proportion of cancers

about 50% --> TSG and its p53 protein are among the most frequently mutated genes in human cancers

immune system in cancer

the first and last defence against cancer

NK cells

part of the innate immune system, very important because they can target tumors and cancer cells and kill them

our immune system is constantly doing this (over 10k times a day!!)

goes about destroying cells that could become cancer

a number of chemo drugs require this for them to be effective

an intact immune system

are NK cells non-specific or specific?

non-specific. they will kill anything (and we love them for that)

what is metastasis?

- the spread of cancer from one location to other parts of the body

- critical event in cancer

about 90% of cancer deaths are from:

metastatic disease

2 ways in which metastasis can occur

1. malignant cells directly invade or extend into adjacent organs or sites

2. cancer cells can move away from the primary tumor and enter the blood or lymph circulation

example of direct invasion in metastasis

colon cancer with liver mets bc the cancer breaks through the colon wall into the liver space

journey of cancer cells once they've entered the circulation

- travel around and get stuck in the capillary bed of a distant site (or organ)

what happens to cancer cells that have landed somewhere else from the circulation

they grow until they burst through the capillary wall

most common sites for metastasis of disease

- lungs

- bones

- liver

researchers have found that this is a critical event required for cancer to spread

angiogenesis

angiogenesis

the formation of a new network of blood vessels

when does angiogenesis begin in cancer?

when a tumor is big enough to where it needs to increase supply of nutrients and oxygen (and blood)

how is angiogenesis triggered in cancer?

hypoxic conditions trigger the tumour and its surrounding envt. to release signals that result in the growth of BVs towards and into the tumour

new blood vessels provide tumour with:

- o2

- nutrients

- more opportunity to grow

can angiogenesis be a normal body process?

yes! it occurs at diff. times in the lifespan

when is angiogenesis normal?

- fetus: has to grow own circulatory system

- females: endometrium buildup in every menstrual cycle

- everyone: wound healing = generation of new BVs and repairing of damaged tissues

tumour angiogenesis:

- proliferation of a network of BVs that penetrates into cancerous growths, supplying nutrients and O2 and removing waste products

how is tumour angiogenesis stimmed:

- tumor cells release molecules that send signals to surrounding normal host tissues

- activates certain genes in host tissues that in turn make proteins that encourage the growth of new BVs

treatment implications of understanding that tumours require angiogenesis to grow:

- BV generation is a target in some cancer treatments because we know this!

angiogenesis inhibitors in clinical use:

- we're testing about 2 dozen angiogenesis inhibitors clinically right now to see if we can slow or stop the growth/spread of cancer cells

endostatin

- a naturally occurring protein known to inhibit tumour growth in animals

- included in a class of angiogen. inhib. that directly inhibit the growth of endothelial cells

Thalidomide

- a sedative, used in the 1950s for nausea (TAKEN OFF MARKET BC OF BIRTH DEFECTS) ((never give it to pregnant ppl))

- its ability to stop endothelial cells from making new BVs might make it useful for cancer tx

Bevacizumab (Avastin):

- monoclonal antibody drug

- first approved by FDA of its kind

Avastin class of medication

molecules that interfere with steps in the angiogenesis signalling cascade

Avastin proven effect:

delay tumour growth and more importantly, extends lives of patietns

Interferon Alpha

a naturally occurring protein that inhibits the production of growth factors from starting the angiogenesis signalling cascade

Angiogenesis Inhibitor Protein drugs

- angiostatin

- endostatin

- interferons

- platelet factor 4

- prolactin 16Kd fragment

- thrombospondin

- TIMP-1

- TIMP-2

- TIMP-3

Characteristics of Cancer cells (6)

- immortality

- produce 'go' signals

- override 'stop' signals

- resist apoptosis --> immortal

- angiogenesis

- metastasis

Immortality

cancer cells manipulate the cell to keep dividing indefinitely by producing proteins that enable them to do so

Produce 'go' signals

most cells wait for a 'go' signal before dividing --> cancer cells don't bother waiting, they make their own

Override 'stop' signals

even if neighboring cells produce a stop signal, cancer cells override these signals and keep dividing

Resist apoptosis

normal cells sometimes react to age or mutations by killing themselves. Cancer cells sneak past these signals and keep dividing

Angiogenesis in cancer cells

cancer cells make sure they can continue growing by stimming new BV generation to keep their nutrient supply open

Metastasis and cancer cells

the final stage of tumor progression is the migration and spread of cancers to different places from where they originated