Category Archives: Cancer

All types of cancer (includes leukaemia)

Can the growth rate of brain tumours help predict survival?

Asta HåbergAnne Line StensjøenBloggers: Anne Line Stensjøen, PhD Candidate, Department of Neuromedicine and Movement Science (INB), and Asta Håberg, Professor and Centre Director, Centre of Innovative Ultrasound Solutions (CIUS)

Glioblastomas are tumours that originate from brain tissue. It is both the most common and most aggressive type of brain tumour. The median survival at group level is only 10 months for glioblastoma patients in Norway, but it is difficult to predict how long an individual long patient will survive.

How fast brain tumours grow is important to know to make the best decisions with regard to treatment. Tumour growth can also tell us something about how aggressive the tumour is, and perhaps be used as a marker of prognosis. It has been difficult to assess tumour growth because it requires at least two magnetic resonance images (MRIs) of the brain before treatment is started. Continue reading

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If van Gogh was a pathologist…

Eugene KimBlogger: Eugene Kim, Post Doctor
MR Cancer Group, Department of circulation and medical imaging

 

 

 

This image won the prize for Best Scientific Image at the 8th International PhD Conference in Medical Imaging 2016:

Inspired by Vincent van Gogh’s signature bold, sweeping brush strokes, this contemporary piece evokes a meteor shower back-dropped by the majestic Milky Way stretching across the midnight sky.

It is a false-color image of a human breast cancer tissue section in which blood vessel walls and proliferating (growing/replicating) cells were labeled using immunohistochemistry. A digital image of the tissue section was acquired with a microscope. Then, a computer algorithm was used to segment the image into different classes or types of cellular and tissue components. Each color represents a different class (e.g., orange = blood vessel and yellow = proliferating cell).

A false-colour image of a human breast cancer tissue. Image: Eugene Kim

Technical details

The digital image of the human breast cancer tissue section was acquired at 40x with an Olympus VS120 slide scanner. K-means clustering was performed in MATLAB to segment the image into the different classes. This was part of a larger algorithm to automate the tedious task of counting proliferating blood vessels.

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Fusion makes a difference – also in the prostate!

ansattebilde.may-britt.tessemailin falkmo hansenBloggers:  Ailin Falkmo Hansen (PhD candidate) and May-Britt Tessem (Research Scientist), MR Cancer group

 

Movember is around with a “trøndersk” spirit on Facebook, Instagram, and the city is filled with mustaches in different shapes and varieties. The goal is increased awareness of men’s health and prostate cancer – a disease we in the MR cancer group want to understand better.

vevsbit og MR

Prostate tissue samples are stored in liquid nitrogen prior to MR spectroscopy analyses (photo: Geir Mogen/NTNU)

How can cancer metabolism provide important information about prostate cancer?

Scientists around the world have shown that changes in metabolism are important characteristics of cancer. We have studied how metabolism is altered due to cancer and how metabolism is changed owing to cancer aggressiveness. Previously, we have found that the two molecules citrate and spermine may be markers for prostate cancer and also can reveal information about aggressiveness.

Prostate cancer is a heterogeneous type of cancer, and this is of importance for treatment and prognosis of patients. However, today there are no reliable methods for assessment of type of prostate cancer. Researchers world-wide are therefore searching for new methods that may provide diagnostic and/or prognostic information. Presence of the fusion gene TMPRSS2-ERG have been suggested to be a candidate method for risk stratification, and in a recently published study we investigated the link between prostate cancer metabolism and TMPRSS2-ERG.

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How to outsmart a prostate cancer cell

Siver MoestueBlogger: Siver Moestue, Associate Professor
MR Cancer Group, Department of circulation and medical imaging, NTNU

 

 

Cancer cells are notoriously difficult to deal with – partly because they have the ability to dodge the bullets we aim at them. They are inherently resistant to a lot of hostile conditions and therapies, but they can also activate compensatory mechanisms that rescue them when they are exposed to anticancer drugs. We have therefore tried to find a way to responsibly kill cancer cells (killing cancer cells without harming the normal cells in the body, that is) by identifying the crucial compensation mechanisms, and then applying a second drug that strikes the cancer cells where it hurts the most.

Essentially all the work that is performed inside our cells is carried out by proteins. Not all proteins work at the same time – most of them are responsive to cues from their surroundings that tell them when to work and when to take a break. One such cue is OGlcNacylation. Sounds difficult, but basically the cells put tiny “flags” consisting of amino sugars on proteins, thereby giving them new work orders (Figure 1).

Illustration of O-GlcNac Transferase (OGT)

Figure 1 Proteins can be activated, deactivated or otherwise change function when they are labelled with the amino sugar N-acetylglucosamine on specific amino acid residues. This process is called O-GlcNacylation, and may play an important role in cancer.

In cancer, it has been seen that an enzyme responsible for putting these amino sugar flags on proteins (OGT) is frequently over-activated. In a collaboration with Prof. Ian Mills (Norwegian Centre for Molecular Medicine) and Suzanne Walker (Harvard Medical School), we wanted to find out if a novel drug targeting OGT could be used to kill prostate cancer cells. To cut a long story short, they could – but only to a certain extent. The cells found a way to survive and continue to divide, just a little slower than before. To understand how the cancer cells escaped death, we took a deep dive into their metabolism using magnetic resonance spectroscopy.

Interestingly, we found that OGT inhibition made the cells reprogram metabolism. They stopped consuming glucose, instead turning to the common amino acid alanine as a new source of energy. Since OGlcNacylation is a process that normally allows cells to respond to starvation or altered supply of nutrients, this sort of makes sense. It also raised the question “What if we block the metabolism of the cells so they cannot use alanine anymore?”. Luckily, the well-known drug cycloserine (used to treat tuberculosis), does just that – by blocking the alanine-converting enzyme GPT2.

When we treated the prostate cancer cells with both the OGT inhibitor and cycloserine, the prostate cancer cells activated a self-destruct mechanism and died. Luckily, normal prostate cells tolerated the treatment very well.

MR spectrum of cells treated with an OGT inhibitor.

Figure 2 Left: MR spectrum showing how cells treated with an OGT inhibitor (black line) have low levels of glutamate and are virtually depleted of alanine. Right: Diagram demonstrating how LNCaP prostate cancer cells treated with a combination of an OGT inhibitor + cycloserine (blue bar) are far less viable than untreated control cells or cells treated with each of the drugs alone (grey bars).

What did we learn from all this? First, we demonstrated an important principle: Cancer cells may display metabolic ”soft spots” leaving them in a vulnerable position once they are under attack from anticancer drugs. Finding these – and attacking them with a second drug – could be a way of improving cancer therapy in the future. Second, we proved that it is possible to learn an old dog new tricks: cycloserine was developed to make it hard for tuberculosis bacteria to make their cell wall. However, as a side effect it also blocks the ability of mammalian cells to use alanine as an energy source. This does not seem to be a problem for normal cells, because they don´t depend on this mechanism at all. But under given conditions (such as when they are under attack from drugs blocking OGT), prostate cancer cells are addicted to it – and we can take advantage of that when we try to kill them.

The project was carried out with financial support from the Norwegian Cancer Society and the Research Council of Norway.

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Can a psoriasis drug be used to treat breast cancer? Targeting the link between inflammation and cancer

Hanna Maja TunsetEugene KimBloggers: Hanna Maja Tunset, PhD candidate, Eugene Kim, PostDoc,
MR Cancer group, Department of circulation and medical imaging

 

 

October is nearly over. The good news is that Christmas season is just around the corner. The bad news? This is the final post from the MR Cancer group in our blog series for breast cancer awareness month! If you missed the first two blogs, you can check them out here: A new cure for breast cancer? and Could breast cancer metabolism reveal new therapeutic targets?

Breast cancer is not just one disease, and different breast cancers need different treatment. Targeted treatment according to the type of tumor has increased breast cancer survival for a lot of patients.  However, around 15 % of breast cancer patient have what we call triple negative breast cancer (TNBC), which does not respond to currently available targeted therapies. This subtype also tends to be highly aggressive, develop at a younger age, and have poorer prognosis compared to other types. Going against the overall trend in breast cancer, survival rates for TNBC have not increased in the past few decades. So, new targeted therapies for TNBC are in high demand.

One way of finding a good therapeutic target is to look for something that is unique to that particular disease. We have previously identified that the inflammatory enzyme cytosolic phospholipase A2, or cPLA2, is overly active in TNBC as compared to other breast cancers. We wanted to see if inhibiting cPLA2 could be an effective treatment.  So we teamed up with Berit Johansen, a professor at the NTNU Department of Biology and CSO of Avexxin AS, a Trondheim-based start-up company developing a line of cPLA2 inhibitors intended to treat inflammatory diseases like psoriasis and rheumatoid arthritis.

We tested one of their drugs, AVX235, in a mouse model of TNBC, and the results look promising. Tumors in mice treated with the drug only reached 1/3rd of the size of untreated control tumors after 19 days of treatment.

But how does AVX235, an anti-inflammatory drug, inhibit tumor growth?

Targeting the link between inflammation, blood vessels, and cancer

Cytosolic phospholipase A2 is highly involved in both acute and chronic inflammation in the body. In 1863, Rudolf Virchow, the father of cellular pathology, theorized that cancer was caused by chronic inflammation. Over the years, research has revealed close links between inflammation and cancer. American pathologist Harold Dvorak  went as far as to describe tumors as “wounds that do not heal”. A major component of inflammation and wound healing is angiogenesis –  the growth of new blood vessels. Angiogenesis is a hallmark of cancer and is observed in most solid tumors. As a tumor grows, it produces blood vessels that deliver the oxygen and nutrients necessary to sustain it.

Our study suggests that cPLA2 plays an important role in angiogenesis in TNBC. We found that AVX235 reduced the amount and size of blood vessels in the tumors. High-resolution CT images showed that large portions of tumors treated with AVX235 did not have a blood supply.

 

CT images of breast cancer tumours

CT-based images of representative tumors from control (Ctrl) and treated (Tx) groups, color-coded for vessel caliber (VC), i.e. vessel diameter – the more yellow or red, the larger the vessel. Note the lack of vessels in large areas of the treated tumor (arrows).

We also examined tumor tissue under the microscope, after staining for certain factors that could reveal if blood vessel cells were dividing. Treated tumors had fewer actively growing blood vessels. This indicates that blocking cPLA2 activity hindered the cancer’s ability to produce new blood vessels, resulting in tumors that were under-fed and unable to grow as they normally would.

Next steps towards improving treatment of TNBC

We are still in the early phases, but our initial results show that inhibition of cPLA2 may be a strategy for targeted therapy of TNBC. Continuing our collaboration with Avexxin, we are currently trying to find out more about how this may work. By using breast cancer cells grown in a flask as a model system, we can detect responses on a cellular level, like alterations of metabolism, how fast the cells grow, and their ability to invade new tissues.

Over the past decade, there has been an increasing interest in cPLA2 as an important player in the progression of various cancers, including breast cancer. We hope our research in this field will contribute towards providing a much-needed targeted therapy for triple negative breast cancer patients.

The results from this study was published in BMC Cancer.

This work was funded by the liaison committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology (NTNU), the Norwegian Cancer Society, the Research Council of Norway, and Avexxin AS.

Group photo. Poto: Kari Williamson

From the back (left to righ): Astrid Jullumstrø Feuerherm, Siver Moestue, Jana Kim, Eugene Kim, Berit Johansen and Hanna Maja Tunset

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Menno Oudhoff receives research funding from the Norwegian Cancer Society

Menno Oudhoff, researcher at CEMIR, received 6,5 million kroner from the Norwegian Cancer Society today. He was one of 34 recipients in the country, which in total received  180 million.

Anne Lise Ryel, Secretary-General in the Society, highlighted the research on big patient groups like gastrointestinal cancers. – This can really make a difference, colorectal cancer are among the cancer types that affects the most people. The chosen projects is top class, also in international standards, and they will contribute to prevention and treatment.  As a result even more people can live longer and better with cancer. Continue reading

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A different ballgame outside the cell

Blogger: Jimita Toraskar, Ph.D candidate at the Department of Cancer Research and
Molecular Medicine
 and a participant in Researchers Grand Prix 2016 and Tonje Strømmen Steigedal, researcher at the Department of Cancer Research and Molecular Medicine.TonjeSSJimita Toraskar1

 

 

If you know the enemy and know yourself, you need not fear the result of hundred battles.
Sun Tzu

Breast cancer is that enemy, and we still don’t know everything about it. Every type of cancer is different and each breast cancer patient is unique. We all are haunted by one big question, ‘Have we solved the cancer problem’? But first, shall we take a moment to know our enemy better? Continue reading

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A new cure for breast cancer?

Portrettbilde SiverTrygve AndreassenBloggers: Trygve AndreassenSenior engineer, and Siver Moestue, Associate professor,
The MR Cancer Group, Department of circulation and medical imaging

 

 

Scientists all over the world are strenuously pursuing new ways of killing cancer cells. They look for so called “drug targets” – proteins the cancer cells need for rapid and uncontrolled proliferation. In collaboration with Karolinska Institutet in Sweden, we have discovered such a protein called CHPT1. Based on this discovery we think it may be possible to develop new drugs for treating breast cancer.

A needle in a haystack

Before we can develop a new cancer drug, we must have some idea about what the drug should do. We have to identify a “drug target” – a protein the drug must recognize, bind to and alter the function of. It is not as simple as it might sound – we have about 20,000 different protein coding genes in our DNA, and it has been estimated that they can produce up to 100,000 different proteins (Savage, Nature 2015). These proteins communicate with each other in various ways, which means that we are trying to find a needle in a pretty big haystack.

Cancer drugs are often designed to block processes that are important for cell division, or the copying of DNA that happens prior to every cell division. In our research group, we are interested in the metabolism of cancer cells (in order to grow and divide fast, the cancer cells will reprogram their metabolism), and therefore we have searched for possible target proteins in the biochemical pathways.

In collaboration with Karolinska Institutet in Sweden, we started out with some known characteristics of breast cancer cells: They often grow faster in the presence of oestrogen; and they have an abnormally high turnover of the molecule choline. In order to study the choline turnover we apply a technique called MR-spectroscopy.

Main suspect: CHPT1

First we identified about 18,000 oestrogen binding domains in DNA, and found that these domains control the expression of about 2500 genes. Next we found how many of these genes that could be involved in choline turnover – hereby reducing the number of candidate genes to 19. By interpreting MR-spectra of cancer cells grown with and without oestrogen, we found which metabolic changes that could be derived from oestrogen stimulation. This allowed us to further reduce the number of proteins – and eventually we suspected the protein CHPT1 of being heavily involved in transferring the stimulating effect of oestrogen to the metabolic machinery of cancer cells.

To make sure that our findings are not only valid for cancer cells grown in the lab, we investigated tumour tissue from 70 breast cancer patients. Here we found higher expression of CHPT1 in tumour tissue compared to normal breast tissue. Even more interesting, we could see that tumours classified as oestrogen sensitive had significantly higher CHPT1 expression than the other tumours. This implies that oestrogen actually activates CHPT1 in breast cancer patients.

The next step in proving that CHPT1 is a relevant drug target was to show what happens if we switch off this gene. In the laboratory we have molecular tools which allow us to stop the production of the CHPT1-protein in cancer cells, and we found that cancer cells grew much slower when CHPT1 was switched off (Figure 1).

Figur 1: Brystkreftceller i mikroskop.

Figure 1: The two pictures to the left show to different types of breast cancer, seen in a microscope when growing freely in a dish. In the pictures to the right (marked siCHPT1) we see the same cells, but here we have “switched off” CHPT1. There are clearly fewer cells, which indicates that the cells need CHPT1 to grow and divide.

Killing cells in a dish at the lab is fairly easy, so the next step was to see if we could influence tumour growth in a living organism. Our choice of organism was zebrafish (they are quite transparent which enables us to observe the cancer cells directly). By switching off CHPT1 we could see that both tumour growth, as well as the cancer cells’ ability to spread to other tissue and organs, was reduced (Figure 2).

Sebrafisklarve med svulster.

Figure 2: Above we see a zebrafish larva with implanted oestrogen sensitive MCF-7 cancer cells. They have developed a tumour at the injections site (red colour), and daughter tumours (metastases) have formed along the spine (marked with arrows (6). Below we see a zebrafish larva injected with the same type of cancer cells, but with CHPT1 switched off (siCHPT1). Here, there is no big tumour at the injection site, and there are clearly fewer daughter tumours along the spine (marked with arrows (3)).

All in all, we have presented several indicators suggesting that CHPT1 may be an important drug target for the treatment of oestrogen sensitive breast cancer. But there are still many things we haven’t found out yet: Is it possible to design drugs that block CHPT1? What are the side effects? Are they superior to existing drugs?

We have published our findings and hope that someone will take up the gauntlet and continue working on our ideas. And hopefully be able to develop a new drug based on our basic research.

The project has been partly funded by the Norwegian Cancer Society and the Research Council of Norway.

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Could breast cancer metabolism reveal new therapeutic targets?

Tonje Husby HaukaasBlogger: Tonje Husby Haukaas, Senior engineer
MR Cancer Group at the Department of circulation and medical imaging

 

 

 

Could there be a better day to write my first blog? Especially when it’s a “pink” one! The 1st of October marks the beginning of Breast cancer awareness month. This is a month that has the aim to improve knowledge among the population, show compassion for breast cancer patients, and raise funds for breast cancer research.

Rosa sløyfe. Foto: Deborah Hill/NTNU

In the coming days and weeks, the streets will be filled with pink ribbons, balloons, and accessories, and a variety of pink activities will be organized throughout the country. With this blog I hope to teach you something you didn’t know about breast cancer. I also want to show you what research funding can contribute to.

Breast cancer affects many lives, not only the people who are diagnosed. It is the most common cancer among women in Norway, and just today eight women will be diagnosed with breast cancer. Luckily, due to early detection and improved treatment, 90 % of women with breast cancer are still alive 5 year after the diagnosis. But no two tumors are exactly alike, which makes it hard to predict who will be in the 10 % that respond poorly to the current treatments and have short survival times. Also, even with a good response to treatment the patient can experience post treatment adverse effects and a poorer quality of life.

We wish to improve this.

To provide targeted and optimal treatment that has been tailored to each patient, we first have to learn as much as possible about the cancers’ properties and potential weaknesses. Some important targets are already well established in the clinic, like drugs that attack cancer cells that depend on the hormones estrogen or progesterone to grow. But there are still some cancers that don’t have established targets and researchers are working hard to uncover new ways to treat them.

Important differences can be hidden in cancer metabolism

One of the aims of the MR Cancer group has been to reveal potential treatment targets by exploring cancer metabolism.

Cancer cells grow and divide uncontrollably, which increases the need for energy and building blocks compared to normal cells. This can be observed when MR spectroscopy is used to study which small molecules, called metabolites, are present in tissue samples. The result of such an experiment is called a ‘spectrum’, where the peaks originate from different metabolites (see figure). Some of the metabolites are more common than others, such as glucose and lactate. Others are perhaps less known, such as glycerophosphocholine and glutathione, but are still important to study. The metabolites can tell us something about which processes are ongoing at the time the sample is taken.

Previous studies have shown that the cancer tissue’s metabolic fingerprint, meaning the metabolites present, is related to the tumor grade (how aggressive the cancer is), potential for metastasis, and 5 year survival.

By studying the metabolic fingerprint, it is possible to increase the knowledge about which types of breast cancer exist, how aggressive they are, and at the same time look for more biological markers that can identify new targets for treatment.

The figure shows some of the metabolites we can observe by performing MR spectroscopy on breast cancer tissue.

The figure shows some of the metabolites we can observe by performing MR spectroscopy on breast cancer tissue.

The Oslo2-study: A large-scale breast cancer study from multiple biological levels

In the Oslo2-study, a large-scale breast cancer study at the Oslo University Hospital, sample material from 228 patients has been sent to Trondheim and analyzed by MR spectroscopy. Based on the samples’ metabolic fingerprints we have identified three new subgroups of breast cancer. These three groups displayed differences in metabolism; understanding what makes them different helps us to identify more precise drug targets specific for each of the three groups.

Metabolske_grupper

Three new subgroups of breast cancer, called Mc1, Mc2 and Mc3, was found by comparing their metabolic fingerprint.

 

The unique feature of this study is that the sample materials from the same group of patients have been analyzed with multiple methods. Both the expression of genes and level of breast cancer related proteins have been analyzed. This gives us the possibility to look for new relationships between genes, proteins, and metabolites in breast cancer. By combining the levels of data, we saw that one group in particular expressed big differences in genes and proteins compared to the two other groups.

Lab_PhotoGeirMogenNTNU

Tissue samples are stored in liquid nitrogen prior to MR spectroscopy. The samples are kept frozen while they are cut to fit the sample tubes. Photo: Geir Mogen/NTNU.

Based on this, we suspect that this group has a more aggressive cancer type, and would therefore benefit from a different type of treatment than the two other groups.

We will soon acquire follow-up data from the patients in this study, which will provide us with new information on survival and relapse. Based on our metabolic findings, the hypothesis is that the patient survival is different depending on which metabolic subgroup they belong to. If this hypothesis is correct, it means that the metabolic classification can indicate which patients need extra follow-up, and possibly more intensive treatment to get well.

Finally: Why not wear something pink today to show your appreciation for Breast cancer awareness month?

The research is financed by the K.G. Jebsen Center for Breast Cancer Research.

Reference:

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How water motion can tell us about cancer treatment effectiveness

Jana CebullaBlogger: Jana CebullaPostDoc
MR Cancer Group, Department of Circulation and Medical Imaging

 

 

 

Just as every human being is a unique individual, every cancer has its own characteristics, and this is increasingly being recognised in cancer treatment. Targeted therapies are being developed that attack cancers on the molecular level and treatment strategies are tailor-made for each patient.

But how do we know that a treatment actually works?

Typically, treatment response is measured as a change in tumour size using anatomical MRI or CT images, or tumour markers found in body fluids. However, these changes usually occur quite late in the course of the treatment. This is especially true of new, targeted therapies that do not directly kill cancer cells, but cause more subtle structural changes in the tumour tissue. These new therapies aim for a better treatment effect with less side-effects, but because the changes are so subtle, it also means it could be more difficult to see if a treatment is effective or not. Continue reading

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