Download CSIRO_The Hungry Microbiome Project_Colon

CSIRO_The Hungry Microbiome Project_Colon Cancer Carcinogenesis-SD
[Image shows a person’s hand writing on a whiteboard and text appears: The Hungry Microbiome. A diagram is drawn
beneath the title]
Narrator: This is Ormando(?). This video was created as part of the Hungry Microbiome Project, which I made at
CSIRO.
[Image changes to show a person’s hand writing on a whiteboard and text appears: Carcinogenesis]
In this video we’ll talk about carcinogenesis of colon cancer, and we’ll look at it at a molecular level and see what kind
of mutations occur along the DNA that will result in cancer of the colon.
[Image changes to show a person’s hand drawing a diagram on a whiteboard and text appears: Normal colon cells]
So we begin by looking at normal colon cells that have their blood supply. Here where the crypts are, stem cells will
migrate up, giving rise to new colon cells.
[Image changes to show a person’s hand drawing on the diagram and text appears: Stem cells; Migrating]
If we look into the genetic material of one of these stem cells, their genetic material is DNA, which is found in
chromosomes.
[Image changes to show a person’s hand drawing on the diagram]
The DNA is all tangled up around histones. If we remove the histones, here we can see the DNA.
[Image changes to show a person’s hand drawing on the diagram and text appears: Histone; DNA]
In a normal colon cell there is a balance between what’s called histone acetylation and histone methylation.
[Image changes to show a person’s hand drawing on the diagram and text appears: There is a balance between
histone acetylation → increase access]
Histone acetylation means that there is a better access for transcription factors to the DNA. Histone methylation
means that there’s decreased access for transcription factors to the DNA, so there is repression.
[Image changes to show a person’s hand drawing on the diagram and text appears: Methylation → decrease access
(repression)]
Therefore if there is a lot of methylation certain genes may not be activated. So looking at the histones here we have
a balance between histone methylation, Me, and histone acetylation, AC.
[Image changes to show a person’s hand drawing on the diagram and text appears: Me; AC]
Now an important enzyme to know is HDAC, which is histone deacetylase.
[Image changes to show a person’s hand drawing on the diagram and text appears: HDAC]
This enzyme essentially removes an acetyl group from the histone.
[Image changes to show a person’s hand drawing on the diagram and text appears: Histone deacetylase removes
acetyl groups on histones]
So here the enzyme is removing the acetyl group from this histone.
Transcribed by: www.transcriberonline.com
1
[8m:46s]
[Image changes to show a person’s hand drawing a connecting line on the diagram and text appears: AC]
And HDAC is an important enzyme in decreasing access for transcription factors essentially. Now along the DNA there
are regions called promoter regions and non-promoter regions.
[Image changes to show a person’s hand drawing on the diagram and text appears: Promoter Region; Non-Promoter
Region]
Promoter regions are regions in the DNA that initiate transcription of particular genes, meaning the synthesis of RNA,
therefore non-promoter regions are regions that contain no functional genes. In a normal cell, colon cell, there is
approximately 70 to 80% methylation in non-promoter regions.
[Image changes to show a person’s hand drawing on the diagram and text appears: ↑ DNA Methylation]
But around the promoter regions genes are usually unmethylated, and this is so there is better access for transcription
factors to activate genes. And we will see the changes that occur in methylation as cancer develops.
[Image changes to show a person’s hand drawing on the diagram and text appears: 80% APC mutation (Tumour
suppressor gene)]
Now in 80% of cases of colon carcinogenesis there is an adenomatous polyposis coli gene mutation, or APC gene
mutation.
[Image changes to show a person’s hand drawing on the diagram and text appears: 80% APC mutation (Tumour
suppressor gene)]
The APC gene is essentially a tumour suppressor gene, because normally it encodes for proteins involved in cell
adhesion and transcription. This APC mutation can result in one of the stem cells to become potentially cancerous.
[Image changes to show a person’s hand drawing on the diagram and text appears: Stem Cells]
And so as the abnormal cell, the potential cancerous cell moves up it will begin dividing and dividing, creating a polyp,
which is usually a small benign growth.
[Image changes to show a person’s hand drawing on the diagram and text appears: Cancerous cells; Polyp, small
benign growth]
However with more mutations, such as in 50 to 60% of colon cancer cases there is activation of the K-RAS oncogene,
as well as more mutations of other tumour suppressor genes.
[Image changes to show a person’s hand drawing on the diagram and text appears: 50-60% activation of K-RAS
oncogene. Loss of more tumour suppressor genes]
Now the K-RAS gene normally controls cellular division, however a mutation of the K-RAS gene results in a K-RAS
oncogene, and thus cell proliferation.
[Image changes to show a person’s hand drawing on the diagram and text appears: Angiogenesis]
The cells will begin to proliferate. This will create an adenoma, which is a larger benign growth.
[Image changes to show a person’s hand drawing on the diagram and text appears: Adenoma, large benign growth]
During this time, as the cells keep dividing, there needs to be more blood supply in order to feed the growing tissue,
so angiogenesis, which is formation and maturation of blood vessels, occur. It should be noted that from when the
potential cancerous cell, the abnormal cells develop, there can be mismatch repair gene inactivation as well as
hypermethylation occurring on the DNA.
Transcribed by: www.transcriberonline.com
2
[8m:46s]
[Image changes to show a person’s hand drawing on the diagram and text appears: Mismatch repair gene inactivation
and hypermethylation]
The mismatch repair gene normally repairs mutations that occur on the genes, in the genes. Hypermethylation
silences genes. Both mismatch repair gene inactivation and hypermethylation can result in mutation rates that are a
hundred time fold greater than mutation rates that occur in normal cells, which is a lot of mutations. A mutation in
the Tp53 gene tends to occur later in colon carcinogenesis.
[Image changes to show a person’s hand drawing on the diagram and text appears: Mutation p53 cells become
resistant to apoptosis]
This mutation will cause resistance of cancer cells to apoptosis, so more cells will divide and less will die.
[Image changes to show a person’s hand drawing on the diagram]
This will cause a massive growth which will cave in and keep growing, resulting in carcinoma, which is a malignant
growth.
[Image changes to show a person’s hand drawing on the diagram and text appears: Carcinoma, malignant growth]
Now that we’re at this stage, let us look at the genetic material of this cancer cell. So here we have the chromosome
again, the histone fibres and the histone, and then the DNA.
[Image changes to show a person’s hand drawing on the diagram]
The DNA which has, remember, the promoter and non-promoter regions.
[Image changes to show a person’s hand drawing on the diagram and text appears: DNA; Promoter Region; NonPromoter Region]
In cancer cells there is a disbalance between histone acetylation and histone methylation, so we see more methylated
histones.
[Image changes to show a person’s hand drawing on the diagram and text appears: Me; There is disbalance between
histone acetylation and methylation]
Remember methylation decreases access to transcription factors. One reason why we see more methylation is
because of HDAC, the enzyme, which appear to be more active in colon cancer cells.
[Image changes to show a person’s hand drawing on the diagram and text appears: HDAC is more active in colon
cancer cells]
So here HDAC is removing all the acetyl groups on histones, resulting in more methylated histones.
[Image changes to show a person’s hand drawing on the diagram and text appears: HDAC; AC]
In colon cancer cells we also see changes in DNA methylation. In promoter regions for example there is usually
hypermethylation, particularly in tumour suppressor genes and DNA repair genes.
[Image changes to show a person’s hand drawing on the diagram and text appears: ↑ DNA methylation; ↓ DNA
methylation]
This results in some of the mutations we talked about earlier. And in non-promoter region there tends to be fewer
methylation. So again there is hypermethylation on promoter regions which contributes to gene silencing and
genomic instability and it will affect apoptosis, DNA repair and cell cycle control.
Transcribed by: www.transcriberonline.com
3
[8m:46s]
[Image changes to show a person’s hand drawing on the diagram and text appears: Hypermethylation contributes to
gene silencing and genomic instability, and effects apoptosis, DNA repair and cell cycle control]
And there tends to be a decrease in methylation on non-promoter regions, which essentially don’t do anything.
[Image changes to show all the diagrams drawn]
I hope you enjoyed this video on colon cancer carcinogenesis. Thank you for watching.
[Music plays and CSIRO logo appears with text: Big ideas start here www.csiro.au]
Transcribed by: www.transcriberonline.com
4
[8m:46s]