Targeting TGF-beta 1 signalling in Pancreatic Cancer

Pancreatic tumours are a particularly horrible type of cancer with 5-year survival rates less than 5% and it is one of the leading causes of death from cancer. Pancreatic cancer received international awareness in 2011, when Steve Jobs the co-founder and CEO of Apple died after his tumour returned. 

One of the key biological pathways that is altered in pancreatic cancer is the TGF-beta signalling pathway. 

Normally this pathway regulates and keeps the cell growth and proliferation in check. This pathway also suppresses the immune system so that a balance can be achieved where the white blood cells can fight infection and detect cancerous cells but without harming and attacking your own healthy normal cells. TGF-beta can also cause a cell to commit apoptosis, which is a form of cell death. Finally, TGF-beta causes angiogenesis, which means that it promotes a blood supply to the cells, allowing nutrients to reach the cells. 

So  basically the TGF-beta pathway, suppresses the immune system and promotes angiogenesis (blood supply), however it also leads to cell death (if the cell is out of control) and stop the cell from growing and proliferating.

Below is a detailed schematic of the pathway. Don't worry about the details here, but the key thing to get from this image is that this pathway has different components that ensure the functions of the cell that I described earlier take place.

Source: http://www.genome.jp/kegg/pathway/hsa/hsa04350.html

In pancreatic cancer, parts of the TGF-beta pathway that cause apoptosis (cell death) and inhibit cell growth are mutated whereas TGF-beta itself and the other parts of the pathway are elevated. In this way, pancreatic tumours exploit the TGF-beta to its benefit, so their environment now has a rich supply of blood, the white blood cells are not suppressed.

So in summary, the pancreatic cancer (and other forms of cancer btw), cunningly benefit from the good parts of the TGF-beta pathway whilst avoiding the 


In the latest issue of the journal Cancer Research, a German research team led by Professor Max Schnurr published their findings where they knocked out the expression of the TGF-beta gene using shRNA technology (we might talk about that in another post) and at the same time activated the immune system in mice models of pancreatic cancer.

Source: Ellermeier J et al. Cancer Res 2013;73:1709-1720

A group of 20 mice had no treatment. A group of 16 mice had the TGF-beta knockdown treatment only. And a third group of 15 mice had both the TGF-beta knockdown AND the activation of the immune system.

Here is the key finding:

Source: Ellermeier J et al. Cancer Res 2013;73:1709-1720 

The above graph is called a survival curve and the different coloured lines represent different groups of mice. The important lines are the black line which represents mice that did not get any treatment (no knockdown of TGF-beta). The green line represents mice that had TGF-beta knockdown. The red line represents mice that had both the TGF-beta knockdown AND the activation of the immune system treatment. 

As you can see the untreated mice (black line) do not do so well. By 40 days, they had to be killed because the tumour was so bad. 

The mice who recieved TGF-beta knockdown treatment alone did much better and survived on average 39% longer.

The mice who recieved the combined treatment of TGF-beta gene knockout and immune system activation did even better and survived on average 58% longer than mice who recieved no treatment. Importantly, the pancreatic tumour completely regressed in 33% of mice.

Of course treating mice is a long way off from doing the same in humans, however the findings in this paper opens up potentially novel targets