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Important clues to chemo resistance found

“Fish oils block chemotherapy drug,” BBC news has reported.

The broadcaster said that tumours could become immune to treatment due to processes involving two fatty acids that are also produced by stem cells in the blood.

This news story is based on research carried out in the Netherlands that examined the role of a specific type of cell, called mesenchymal stem cells (MSCs), in the development of resistance to chemotherapy. Although these non-cancerous cells occur naturally in the body, some research has indicated that they can play a role in tumours growing and spreading. This latest research involved a series of experiments in mice to determine whether these cells were also involved in tumours developing drug resistance. It looked at whether they produced resistance against a variety of chemotherapy drugs. The researchers found that MSCs brought about chemotherapy resistance by producing two specific fatty acids.

This was not a study that looked primarily at dietary consumption of fish oils, and the link between dietary intake of selected fatty acids in humans and mice with resistance to drugs will need further study. However, the study was well-designed and offers detailed insight into the development of chemotherapy resistance. Further research is needed to confirm that the mechanism and results from mice holds true in people. Healthy people who already take fish oil supplements or consume oily fish are safe to continue, and people receiving chemotherapy should always inform their doctor of any drugs or supplements they use.

Where did the story come from?

The study was carried out by researchers from the University Medical Centre Utrecht, the Netherlands Cancer Institute and Japan’s National Research Institute of Fisheries Science. The research was funded by the Dutch Cancer Society and the Netherlands Metabolomics Centre.

The study was published in the peer-reviewed journal Cancer Cell.

The research was covered accurately by the media, although the conclusions on fish oil supplements from this study were exaggerated. Both the BBC and The Daily Telegraph accurately reported that the experiments were carried out in mice, not humans. The BBC also appropriately reported that the fatty acids measured in this study were produced by cells in the blood, and not simply present due to the consumption of oily fish or supplements.

What kind of research was this?

This was a series of animal studies that aimed to explore how tumours become resistant to chemotherapy. The researchers studied a specific type of non-cancerous cell, mesenchymal stem cells (MSCs), examining how the cells behaved when exposed to platinum-based chemotherapy drugs.

The researchers say that as tumours grow, they signal for the non-cancerous MSCs to move from the bone marrow into the bloodstream. MSCs then stimulate further tumour growth and spread. The researchers hypothesised that, in addition to promoting tumour growth, MSCs may play a role in the development of resistance to chemotherapy.

The researchers examined the potential role of MSCs in chemotherapy resistance through a series of controlled animal experiments. They sought to identify which drugs were likely to become ineffective, and to determine what specific substances and processes were responsible for this resistance.

What did the research involve?

The researchers conducted multiple experiments to test different aspects of their theory. First they sought to confirm that MSCs behaved as expected in cancerous mice. To do this, they injected mice that had cancer with MSCs, and examined whether or not the MSCs moved to the tumour. They found that after four days a small number of MSCs had been taken up into the tumour cells, but not into organs such as the lungs, kidneys and liver.

The researchers then examined the effect of cisplatin, a platinum-based chemotherapy drug, on three groups of cancerous mice:

  • group one received MSCs through an intravenous injection and then received chemotherapy
  • group two only received the chemotherapy
  • group three, the control group, received neither MSCs nor chemotherapy

The researchers then compared tumour growth among these three groups.

Since only a small number of MSCs were taken up into the tumour cells, the researchers thought that any resistance to chemotherapy must occur outside of the tumour cells, in the bloodstream. To test this, they injected MSCs under the skin of cancerous mice far away from the tumour, and once again compared tumour growth among the groups of mice. They also added another group of mice, which were injected with MSCs that had been mixed with cisplatin before being injected under the skin. This injection was given at the same time as a regular dose of chemotherapy. The researchers did this to test whether or not exposure to the drug activated the MSCs in some way, priming them to cause resistance.

The researchers then examined resistance to other types of chemotherapy drugs. They repeated the experiments with other platinum-based drugs (oxaliplatin and carboplatin), as well as other chemotherapy drugs (fluorouracil and irinotecan).

MSCs produce multiple substances once activated, including proteins and fatty acids. The researchers injected each of these substances independently into cancerous mice to determine which ones were involved in chemotherapy resistance.

The researchers also analysed various foods and supplements to determine whether or not they contained the substances involved in chemotherapy resistance. To test whether or not eating such products effected chemotherapy resistance, they fed the mice the products and then treated them with cisplatin.

What were the basic results?

In the experiments where mice were given intravenous MSC injections, the researchers found that:

  • Chemotherapy was less effective in mice that received an injection of MSCs. This occurred in a ‘dose response manner’, meaning that the greater the number of MSC cells injected, the less effective the chemotherapy.
  • Tumours in mice that received 50,000 MSCs and chemotherapy were the same size as those in the control mice that received no chemotherapy.

In the under-the-skin injection experiments, the researchers found that:

  • MSCs injected under the skin kept the chemotherapy from working at lower doses than indicated in previous research. Even a very small number of MSCs (1,000) caused partial resistance to the chemotherapy.
  • The mice that were injected with the ‘primed MSCs’ (those that had been premixed with cisplatin before injection) at the same time as chemotherapy displayed complete resistance to the chemotherapy.
  • When testing the range of chemotherapy drugs, the researchers found that MSCs were activated by platinum-based drugs (cisplatin, oxaliplatin and carboplatin), but not non-platinum based drugs (fluorouracil, irinotecan, paclitaxel and doxorubicin). They did, however, find that when injecting mice with MSCs premixed with a platinum-based drug, those receiving fluorouracil or irinotecan exhibited resistance to the chemotherapy.
  • When testing the different substances produced by the activated MSCs, the researchers found that two fatty acids, called KHT and 16:4(n-3) were involved in the development of chemotherapy resistance. They found that the more platinum-based drugs the MSCs were exposed to, the more of these fatty acids the cells produced.
  • The researchers found that cancerous mice that were fed the fish oil products and then treated with cisplatin exhibited significantly larger tumours after 14 days, compared with mice only treated with cisplatin.
  • Finally, when measuring the MSC levels in the blood of cancer patients, the researchers found that high levels of these cells existed in the blood of patients with advanced disease. They say that having these MSCs present in the blood during chemotherapy could lead to chemotherapy resistance. They found higher concentrations of the fatty acid 16:4(n-3) in the blood of patients treated with platinum-based chemotherapy compared with those who had received other types of chemotherapy drugs.

How did the researchers interpret the results?

The researchers say that their results show that cells outside of the tumour play a role in chemotherapy resistance, and that these cells (MSCs) are activated by platinum-based chemotherapy drugs very quickly.

The researchers say that only platinum-based drugs activate the MSCs and cause them to produce substances that lead to chemotherapy resistance. However, they say that, once present, these substances confer resistance to multiple types of chemotherapy drugs.

They say that the presence of the fatty acid 16:4(n-3) in the blood of people treated with platinum-based chemotherapy indicates that this substance is produced in response to chemotherapy in people as well as in mice. Finally, they suggest that, in order to prevent possible resistance to platinum-based chemotherapy, people receiving such treatment should avoid foods and products containing these two fatty acids.

Conclusion

This was a well-controlled and extensive animal study that identified a possible mechanism involved in chemotherapy resistance.

It is important to remember that these studies were largely carried out in mice, and that the mechanism may not work the same way in humans. While finding higher concentrations of both MSCs and the 16:4(n-3) fatty acid in cancer patients does support the hypothesis that the mechanisms are similar in mice and humans, this cannot be confirmed until further controlled studies are conducted in people.

Among the results and findings given most prominence in the press were those suggesting that consuming oily fish and fish oil supplements should be limited or avoided by chemotherapy patients, based on the researchers’ findings that the fatty acids KHT and 16:4(n-3) are present in various foods and supplements. While the study authors say that such products are often used by cancer patients due to perceived benefits, the platinum-induced fatty acid 16:4(n-3) was primarily produced by the stem cells, and not obtained through diet. While part of the experiment examined the fatty acid content of fish oil supplements, it is important to note that the fatty acids involved in resistance development were produced by the mice regardless of fish oil consumption.

Also, different free fatty acids are present in different supplements. For example, eicosapentaenoic acid (EPA), the main component of most fish oil products, was used as a control in both tumour models and had no effect on tumour growth. Given the different range of components in fish oil and the fact that the mice produced their own fatty acids in their blood it is not clear how this part of their experiments relates to taking fish oil supplements or eating oily fish.

However, it should be noted that this was a thorough set of experiments that studied multiple drugs, cells and fatty acids to assess a precise way resistance to chemotherapy drugs may develop. It provides a lot of information that should be applied when designing future human studies to determine the effectiveness of chemotherapy in various circumstances. The researchers say, however, that very little is known about the two fatty acids they identified as involved in resistance development, and that this is not the only mechanism that leads to chemotherapy resistance. They say that further research is needed to determine the best method of interfering with this resistance-inducing pathway.

The researchers’ claim that their results indicate that the use of such products may actually be harmful in terms of certain cancer treatments needs much more testing. People who are receiving chemotherapy treatment should speak to their physician before making changes to their diet or treatment regimen. Healthy people who take such supplements and eat fish could safely carry on.

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