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Insulin changes the nature of prostate cancer cells

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Insulin is a hormone that regulates sugar levels in the blood. Scientists suspect that insulin can promote the growth of prostate tumours under certain conditions. Australian researchers have now shown that insulin can change the nature of prostate cancer cells when testosterone levels are low. This research helps us to identify targets for new prostate cancer drugs.

Hormone therapy for prostate cancer

Men with advanced prostate cancer usually start their treatment with hormone therapy. This is known as androgen deprivation therapy (ADT). ADT is a very useful treatment that suppresses the growth of prostate tumours and increases survival times. Unfortunately, most men with advanced prostate cancer find that their tumours become resistant to ADT. This is called castration-resistant prostate cancer.

One of the reasons that prostate cancer develops resistance to ADT is that the tumour starts producing its own testosterone. The tumour no longer needs testosterone produced in the testicles. This castration-resistant prostate cancer can be treated by second line anti-hormone drugs. Enzalutamide (Xtandi) is one of these. This drug stops testosterone from interacting with its receptor inside tumour cells. Abiraterone (Zytiga) is another anti-hormone drug that works by a different mechanism. Abiraterone stops testosterone being made by the tumour cells.

Unfortunately, prostate cancer often becomes resistant to these second-line anti-hormone drugs.

The disadvantages of hormone therapy

Whilst hormone therapy helps men with advanced prostate cancer live longer, there are considerable disadvantages. Side effects from these drugs include loss of sex drive, erection problems, hot flushes, fatigue (tiredness), weight gain, breast swelling, loss of muscle and bone strength. Most men suffer one or more of these side effects whilst taking ADT. Men on ADT are also at risk of developing features of metabolic syndrome. This includes insulin resistance and increased levels of insulin in the blood.

ADT can change the nature of prostate cancer. For some men, ADT can make their cancer more aggressive. ADT still works for these men; it stops their cancer growing for a period of time, prolonging survival. But once the tumours become resistant to the ADT, they adopt a more aggressive nature. They grow and spread more quickly. This effect has been discussed in a research blog from last year.

We desperately need new types of drugs to treat this deadly form of prostate cancer. Targeting different cell processes, other than hormones, is being investigated to generate these new drugs.

Australian prostate cancer research into new drug targets

Prof Colleen Nelson is one of Australia’s most successful prostate cancer researchers. She is the director of the Australian Prostate Cancer Research Centre in Queensland. This large team of researchers are dedicated to improving the treatment of prostate cancer. By increasing our understanding of how prostate cancer develops and grows, they are looking for new ways to stop its growth. Prof Nelson’s team have been awarded many different grants from PCFA, Movember Foundation and the Australian Government for this research.

Prof Nelson’s team are investigating how and why prostate cancers become resistant to ADT. They are interested in the changes that occur when men are treated with hormone therapies for long periods of time. Their latest scientific publication has investigated the effects of insulin on prostate cancer cells.

Insulin: a hormone that controls blood sugar levels

Insulin is a hormone; it’s a small biological molecule that circulates in the body. Insulin is produced in the pancreas and circulates in the bloodstream. The main function of insulin is to clear sugars from the bloodstream. After eating sugars, these foods are absorbed from the gut into the blood. Insulin moves them into muscles or the liver or fat cells. These sugars are either used as an energy source, converted into energy storage in the liver or converted into fats for storage. Insulin is also an important medicine for people with diabetes to reduce sugar levels in the blood.

Insulin resistance is a common feature of metabolic syndrome. Insulin resistance means that the body does not respond to the effects of insulin like it should. There are persistently high levels of sugars in the blood, despite the presence of insulin. It’s common to also develop high levels of insulin in the blood, as the body tries harder to move sugars out.

Insulin resistance and high blood insulin levels are side effects that sometimes arises from ADT. Some men with prostate cancer develop high blood insulin soon after starting ADT.

Increased insulin levels in the blood are more common in men who are likely to die from prostate cancer. But this does not necessarily mean that this insulin is a direct cause of this greater risk of morality. More research is needed to understand the role of insulin in prostate cancer.

The effects of insulin on prostate cancer cells

Prof Nelson’s research group has asked how insulin is influencing prostate cancer. Their recent results have now been published in an international journal.

To perform these experiments the Queensland researchers used prostate cancer cells grown in the laboratory. These cells came from human prostate tumours. With modifications, tumours cells can be grown in the laboratory almost indefinitely. These cell lines are not exactly the same as tumour cells growing in the body. But they give scientists a useful method to study prostate cancer in ways that are otherwise difficult. Prof Nelson’s group used three different prostate cancer cell lines to study the effects of insulin. They grew these cells in the presence of ADT drugs, as well as insulin, at concentrations similar to what would be seen in the body.

Results from these experiments showed that:

  • Insulin increases the prostate cancer cells’ ability to move. It increases the migration and invasion of cells into new areas in three dimensions. This is called cell invasiveness.
  • Insulin caused an increase in cell plasticity. This is the ability of cells to take on the characteristics of other cell types.
  • Insulin increased production of proteins associated with the aggressive neuroendocrine type of prostate cancer.
  • Proteins involved in transmitting signals inside the cell were identified. These were necessary for the cell plasticity.
  • A protein called FOXC2 was necessary for insulin’s ability to increase cell movement.

The researchers also used publicly-available data from clinical trials to examine the relevance of the FOXC2 protein. They found that tumour samples with higher levels of insulin receptors had higher levels of FOXC2 protein. FOXC2 was also higher in metastatic tumours.

Summary of these results

These results infer that insulin has a considerable effect on the nature of prostate cancer cells when testosterone is removed by ADT. Insulin can increase prostate cancer cell invasion into new areas and adoption of characteristics of different types of cells (cell plasticity).

This study also showed that insulin regulates FOX2C protein. The researchers suspect that insulin works through FOX2C to promote invasion and cell plasticity.

Since much of this work was done using cells grown in the laboratory, more research is required to understand what happens in humans.

How does this research help men with prostate cancer?

Most of our current drugs for prostate cancer work by inhibiting the actions of hormones such as testosterone. An unfortunate consequence of these treatments is the risk of conversion to a more aggressive type of cancer once these drugs no longer work. We desperately need different types of treatments for advanced prostate cancer.

This research improves our understanding of the non-hormone drivers of prostate cancer. It is part of the search for new drug targets. Insulin itself is a poor drug target – we need insulin. However, understanding the downstream pathways by which insulin drives prostate cancer growth should point to new drug targets. The researchers state that “The insulin receptor is not suitable to target clinically, however our data shows that actions of insulin in prostate cancer cells may be suppressed by inhibiting downstream signalling molecules, PI3K and ERK1/2”.

PCFA are proud to have provided funding for this research through the Movember Foundation.

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