Cholesterol byproduct hijacks immune cells to spread breast cancer

High cholesterol levels have been associated with breast cancer spreading to other sites in the body, but doctors and researchers don’t know the cause for the link. A new study by University of Illinois researchers found that the culprit is a byproduct of cholesterol metabolism that acts on specific immune cells so that they facilitate the spread of the cancer instead of stopping it.

The study, published in the journal Nature Communications, identifies new potential drug targets that could inhibit the creation or actions of the dangerous cholesterol byproduct, a molecule called 27HC.

Breast cancer impacts roughly 1 in 8 women. We’ve developed fairly good strategies for the initial treatment of the disease, but many women will experience metastatic breast cancer, when the breast cancer has spread to other organs, and at that point we really don’t have effective therapies. We want to find what drives that process and whether we can target that with drugs,” said Erik Nelson, a professor of molecular and integrative physiology who led the study.

Nelson’s group fed mice with breast cancer tumors a diet high in cholesterol. The researchers confirmed that high levels of cholesterol increased tumor growth and metastasis, and that mice treated with cholesterol-lowering drugs called statins had less metastasis. Then they went further, specifically inhibiting the enzyme that makes 27HC during cholesterol metabolism.

By inhibiting the enzyme that makes 27HC, we found a suppressor effect on breast cancer metastasis. This suggests that a drug treatment targeting this enzyme could be an effective therapeutic,” said Amy Baek, a postdoctoral researcher at Illinois and the first author of the paper.

The researchers also saw unusual activity among specific immune cells – certain types of neutrophils and T-cells – at metastatic sites high in 27HC.

Normally, your body’s immune system has the capacity to attack cancer,” Nelson said, “but we found that 27HC works on immune cells to fool them into thinking the cancer is fine. It’s hijacking the immune system to help the cancer spread.”

See a video of Nelson describing the study on YouTube.

Because 27HC acts through the immune system, and not on the breast cancer itself, the researchers believe their findings have broad applicability for solid tumors. They performed experiments looking at colon cancer, lung cancer, melanoma and pancreatic cancer, and found that 27HC increased metastasis for all the tumor types, suggesting that a treatment targeting 27HC could be effective across multiple cancer types.

The researchers are working to further understand the pathway by which 27HC affects the immune cells. With clinical partners at Carle Foundation Hospital in Urbana, the team is working to establish whether 27HC has the same pathway in human patients as in mice.

We hope to develop small-molecule drugs to inhibit 27HC,” Nelson said. “In the meantime, there are good cholesterol-lowering drugs available on the market: statins. Cancer patients at risk for high cholesterol might want to talk to their doctors about it.

Baek et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nature Communications 8, Article number: 864 (2017) doi:10.1038/s41467-017-00910-z [Article]

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Decreased blood vessel leakage can improve cancer therapy and reduce tumor spread

Cancer therapy is often hampered by the accumulation of fluids in and around the tumour, which is caused by leakage from the blood vessels in the tumour. Researchers at Uppsala University now show how leakage from blood vessels is regulated. They have identified a novel mechanism whereby leakage can be suppressed to improve the result of chemotherapy and reduce the spread of tumours in mice. The results have been published in the scientific journal Nature Communications.

When a tumour grows, new blood vessels are formed that supply the tumour with nutrients and oxygen. However, these vessels are often malfunctioning and fluids and other molecules leak out of the vessels. This results in edema in the tissues, which in turn makes it more difficult for drugs to reach into the tumour during cancer therapy. The malfunctioning vessels can also contribute to the spread of metastases from the tumour.

The leakage from the blood vessels is controlled by specific protein complexes that connect the cells in the blood vessel walls. By regulating these protein complexes, the cells are joined more or less tightly, which affects the leakage from the vessels.

Recent findings from Uppsala University show how a specific alteration of the protein complex in the vessel walls can reduce leakage, without affecting any other vessel functions.

We have studied mice that have a mutation in a certain part of one of the proteins in the protein complex. The regular blood vessels in these mice function normally, but vessels in tumours showed less leakage, and there was a decrease in edema formation. In addition, the mutant mice responded better to treatment with chemotherapy‘, says Lena Claesson-Welsh, professor at the Department of Immunology, Genetics and Pathology,at Uppsala University and Science for Life Laboratory, who led the study.

The growth factor VEGFA functions as a signalling molecule, regulating the protein complexes in the blood vessel walls. One way of treating cancer is by inhibiting VEGFA, which decreases leakage and edema and improves the effects of chemo- and radiation therapy. However, VEGFA affects blood vessels in several ways and sustained anti-VEGFA therapy deteriorates vessel function and can cause increased metastasis.

The specific mutation that we have studied allowed us to examine one of the signalling pathways in which VEGFA is involved. An important finding was that mice with the mutated protein complex also showed a reduced spread of metastases. We, therefore, believe that a targeted inhibition of this specific signalling pathway, which controls how the cells in the vessel walls are connected, might work better as a cancer therapy than the more general VEGFA inhibition that is used today,’ says Lena Claesson-Welsh.

Li et al. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications. 2016;7:11017 doi:10.1038/ncomms11017 [Article]

Pancreas cancer spreads from multiple types of wayward cells

Penn animal study has implications for better drug design, ‘unprecedented window’ into tumor evolution.
Tumor cells associated with pancreatic cancer often behave like communities by working with each other to increase tumor spread and growth to different organs. Groups of these cancer cells are better than single cancer cells in driving tumor spread, according to new research from the Perelman School of Medicine at the University of Pennsylvania published in Cancer Discovery online in advance of the print issue.

This is a multi-colored metastasis in the peritoneal lining of the abdomen comprised of red and yellow fluorescent cells demonstrating that pancreatic cancer spreads through interactions between different groups of cells. CREDIT Ravi Maddipati , MD, Perelman School of Medicine, University of Pennsylvania

Ben Stanger, MD, PhD, a professor in the division of Gastroenterology, and first author Ravi Maddipati , MD, an instructor in the division of Gastroenterology, say that these results may prove useful in designing better targeted therapies to stop tumor progression and provide an improved non-invasive method for detecting early disease states in this highly lethal cancer. Stanger is also a professor in the department of Cell and Developmental Biology and the Abramson Family Cancer Research Institute.
From other earlier studies, the Penn team also knew that cells from a primary tumor do better replicating and surviving in a group rather than if they are grown on their own. From this, the researchers asked if the spread of cancer is primarily derived from one cell or a cell cluster derived from the interactions between different cancer cell types. Stanger and Maddipati tested the hunch that clusters of cells of different genetic makeup were better at establishing secondary tumors and found that a significant fraction of metastases involve seeding by more than one type of tumor cell during the natural course of pancreatic tumor progression.

To understand this spread, the Penn researchers developed a mouse model that uses multiple fluorescent proteins to tag and track different pancreatic cancer cells as they enter the bloodstream and spread to distant organs. In this mouse model, mutations in Kras and p53 genes resulted in the formation of individual tumor cell populations that were labeled with different colors. Similar to humans, the mice developed tumors at secondary sites including the liver, lung, peritoneum, and diaphragm. They observed that these metastases were often made of cells from at least two different colors of tumor cell populations. To understand how these multi-colored lesions originated they examined blood from these mice and found that tumor cells in circulation frequently occurred as clusters comprised of different colored cancer cells.

What’s more, they also found that once these multi-colored clusters arrived at the secondary sites, the exact characteristics of subsequent growth was heavily dependent on the organ in which they now resided. During cell expansion in the peritoneum and diaphragm the lesions remained multi-colored, whereas in the lung and liver only a single color population was able to grow out. This suggested that specific factors in each organ may also influence the evolution of metastases.

These results provide an unprecedented window into the cellular dynamics of tumor evolution and suggest that interactions between subpopulations of tumor cell types contribute to metastatic progression from initial tumors,” Stanger said. “The finding that metastases are frequently polyclonal and that subsequent cellular behavior is site-dependent also gives us insight into the origins and evolution of clonal diversity in metastatic disease.

If cells do cooperate during metastasis, what is the molecular basis for their communication, and can we hit that?,” Stanger asked. The work also reinforces the importance of finding tumor cell clusters in the blood as a mechanism of detecting cancer metastasis earlier.

Maddipati R and Stanger BZ. Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discovery. 2015; doi: 10.1158/2159-8290.CD-15-0120 [Abstract]

Cancer survivors have evolving information needs

Cancer patient’s information needs appear to differ depending on the type of cancer they have and where they are in their survivorship. Clinicians caring for cancer survivors may need to understand these needs in order to better address survivor’s concerns about cancer recurrence, late effects, and family member’s risks.

A three-year study of over 2,000 cancer survivors by the University of Pennsylvania’s Annenberg School for Communication discovered that, across survivors, the most frequently sought information was about cancer recurrence. However, interest in other topics varied by cancer type: breast cancer survivors were more likely to seek information about topics related to late effects and family members’ risks than prostate and colon cancer survivors. The patterns of seeking for these topics also changed over time. For instance, breast cancer survivors were less likely to seek information about their risks of cancer recurrence in later years than during the first year after their diagnosis. These findings are reported in the journal Cancer Epidemiology, Biomarkers & Prevention (online first, 2015).

The findings from the study are important because understanding how people seek cancer information during their cancer survivorship is an important component as clinicians help to address the physical and emotional issues their patients may be experiencing. Clinicians may need to intervene at distinct points during the cancer survivorship period with timely information to address their patients’ concerns about cancer recurrence, late effects, and family members’ risks.

Researchers Andy Tan (Dana-Farber Cancer Institute), Rebekah H. Nagler (University of Minnesota), Robert C. Hornik (Annenberg School, University of Pennsylvania), and Angela DeMichele (Abramson Cancer Center, University of Pennsylvania) surveyed over 2,000 cancer survivors three times over a three-year period (2006 to 2008). The participants were survivors of colon cancer (males and females), breast cancer, and prostate cancer. They were, on average, in their early 60s, and the survey population was split evenly between men and women.

In this series of three surveys administered over three years, the researchers asked what type of information participants sought, including:

  • How to reduce the chance of their cancer coming back
  • How to reduce their chance of getting another cancer
  • How to reduce the risk of their children or family members getting breast/prostate/colon cancer or a different type of cancer
  • Whether they are at risk of having other health problems as a result of their cancer or treatment

Across all participants, reducing the chance of cancer coming back was the number one researched subject in all three surveys. Over 28 percent of cancer survivors expressed looking for information about their risk of cancer recurrence, compared with only 12 percent who said they had looked for information about the risks of their family members getting a different cancer from their diagnosis.

Cancer type was related to survivor’s information seeking patterns over time. Although breast cancer survivors were more likely to seek information about survivorship topics earlier in their trajectory, their seeking declined over time. In comparison, female colon cancer survivors were more likely to seek information about certain topics than female breast cancer survivors in later years. The researchers surmised this may be due to the ample amount of breast cancer information readily available and the existence of robust survivorship organizations to support breast cancer survivors.

Not surprisingly, information about reducing risks of recurrence was the most frequently sought after topic among cancer survivors and over all three years of the study,” says Dr. Tan, lead author of the study. He noted that the study points to several “teachable moments” for clinicians, as well as avenues for additional study.

Additionally, Dr. Tan said, “clinicians should consider the early survivorship timeframe as an opportunity to counsel patients on other positive health behaviors, from diet to smoking cessation, to help manage risks of cancer recurrence, since this window of opportunity may be when a patient is most open to receiving such information.

Tan et al. Evolving information needs among colon, breast, and prostate cancer survivors: Results from a longitudinal mixed-effects analysis. Cancer Epidemiol Biomarkers Prev. 2015; doi: 10.1158/1055-9965.EPI-15-0041 [Abstract]

Key factor discovered in the formation of metastases in melanoma

Patients who visit the doctor because of malignant skin cancer often go too late – the aggressive cancer has already formed numerous metastases in their bodies.

This rapid, malignant metastatic formation of melanoma, was previously put down to the high mutation rate that is characteristic of melanoma, i.e. genetic changes that stimulate the growth of cancer cells. Various cancer drugs therefore target the signaling pathways activated in the process, some of which have recorded astonishingly positive results in the clinic and are able to prolong the lives of seriously sick patients.

Unfortunately, however, in most cases a kind of resistance develops: Eventually, the cancer cells no longer respond to the drug and the tumor spreads again. Evidently, the cancer cells have found new ways to grow. A team of researchers headed by Professor Lukas Sommer from the University of Zurich’s Institute of Anatomy has now found a possible explanation for this dynamic behavior in cancer cells: The scientists believe that, depending on the prevalent conditions, cancer cells are able to “read” different genes and use them to their own end.

A highly active epigenetic factor in cancer cells

The readability of genes is controlled by epigenetic factors, namely factors which do not influence the gene sequence directly, but rather cause certain genes and chromosomal segments to be packed in different densities – and thus make them accessible for reading. Consequently, the Zurich-based researchers studied whether epigenetic factors are especially active in melanoma cells – and stumbled across EZH2, an epigenetic control protein found very frequently in malignant melanoma cells compared to normal cells.

Joining forces with dermatologists and oncologists from the University Hospital in Zurich and backed by the University Research Priority Program “Translational Cancer Research”, Sommer’s team was able to demonstrate that, in melanoma cells, the epigenetic factor EZH2 controls genes that govern tumor growth as well as genes that are important for the formation of metastases. In their study, the researcher exploited this central position of EZH2 to combat the cancer: They used a pharmacological inhibitor to suppress the activity of EZH2. As a result, the researchers were able to prevent the growth and malignant spread of the cancer in the animal model and human melanoma cells.

To our astonishment, we were able to use the approach to influence the progression of the disease, even if tumors had already developed,” explains Sommer. Epigenetic factors like EZH2 therefore appear to be highly promising targets for future cancer treatments, especially combined with other drugs that are already available.

Zingg et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nature Communications, 2015. Doi: 10.1038/ncomms7051 [Abstract]

Osteoporosis treatment may also benefit breast cancer patients

Treatment approaches to reduce the risk of bone complications (metastasis) associated with breast cancer may be one step closer to becoming a reality. 

According to a study led by a team at the Research Institute of the McGill University Health Centre (RI-MUHC), findings show that medication used to treat bone deterioration in post-menopausal women may also slow skeletal metastasis caused from breast cancer. This study, published in this month’s issue of the Journal of the National Cancer Institute (JNCI), is among the first to link bisphosphonate (a common osteoporosis medication) use with improved survival in women with breast cancer.

Skeletal metastases develop in up to 70 percent of women who die from breast cancer,” says study co-lead author, Dr. Richard Kremer, director of the Bone and Mineral Unit at the MUHC and a professor in the Faculty of Medicine at McGill University. “This causes considerable suffering and is life-threatening. Preventing this could translate into saving a significant number of lives.”

Dr. Kremer and co-lead author, Dr. Nancy Mayo, worked with colleagues to evaluate data from more than 21,000 women diagnosed with breast cancer. The relationship between use of oral bisphosphonates and development of bone metastases after diagnosis with breast cancer was evaluated in two groups of women: those with early stage, localized, cancer and those whose cancer had spread to lymph nodes. Their findings showed that women with early stage breast cancer who had taken oral bisphosphonates, either before or after diagnosis of their cancer, had a reduced risk of bone metastasis. In addition, their study showed that women with later stage cancer, who took oral bisphosphonates post-diagnosis, also had a significantly reduced risk of bone metastasis.

The researchers also established a dose-response relationship with oral bisphophonate use in women with local disease: longer time spent on bisphophonate medication resulted in a greater reduction of bone metastases.

Our study is novel in that it mainly involved women who were post-menopausal and in whom bone-turnover is high due to osteoporosis,” says Dr. Richard Kremer who is also an RI-MUHC researcher. “We believe that this process results in an environment that is favorable for tumour cell growth and consequent metastasis. We know that bisphosphonates work by slowing down this bone-turnover. This will, in turn, make it harder for tumour cells to establish in the bone and may explain why we saw such a decline in metastasis.”

An association between bisphophonate use and improved survival was also observed and this merits further investigation,” Dr. Mayo, RI-MUHC researcher and James McGill professor in the Faculty of Medicine, School of Physical and Occupational Therapy at McGill. “Ours was an epidemiological study, involving a large number of women strengthening the importance of the findings. However, clinical interventional studies are needed before the results can be translated into standard clinical practice and guidelines.”

Kremer et al., (2014). Effect of Oral Bisphosphonates for Osteoporosis on Development of Skeletal Metastases in Women With Breast Cancer: Results From a Pharmaco-epidemiological Study. J. Natl. Cancer Inst., 106 (11): dju264 doi: 10.1093/jnci/dju264 [Abstract]

Novel immunotherapy vaccine decreases recurrence in HER2 positive breast cancer patients

Women who received trastuzumab, Herceptin, as part of standard treatment show greatest benefit

A new breast cancer vaccine candidate, (GP2), provides further evidence of the potential of immunotherapy in preventing disease recurrence. This is especially the case for high-risk patients when it is combined with a powerful immunotherapy drug. These findings are being presented by The University of Texas MD Anderson Cancer Center at the 2014 American Society of Clinical Oncology’s Breast Cancer Symposium in San Francisco.

One of only a few vaccines of its kind in development, GP2 has been shown to be safe and effective for breast cancer patients, reducing recurrence rates by 57%. Further, women with the highest overexpression of HER2 (known as HER2 +3) had no cancer recurrences when they were administered the vaccine after completing trastuzumab (Herceptin), a type of immunotherapy drug known as a monoclonal antibody. HER2 is an oncoprotein that promotes tumor growth and is expressed to some extent in 75-80% of breast cancers.

This is an important and different avenue in immunotherapy research, in that we are investigating ways to prevent cancer recurrence by stimulating the immune system to treat cancer,” says principal investigator Elizabeth Mittendorf, M.D., Ph.D., associate professor of Surgical Oncology. “The ultimate goal is to develop a preventative tool that will minimize the risk of recurrence in women who have already had breast cancer and for whom standard therapies have failed.”

The findings are the result of a phase II randomized trial that paired the GP2 vaccine, designed to stimulate the CD8+ cells, commonly known as “killer” or “toxic” T cells, with an immune stimulant known as granulocyte/macrophage colony stimulating factor (GM-CSF). The trial included 190 patients with varying levels of HER2; 89 women received the GP2 vaccine with a GM-CSF adjuvant and a control group of 91 patients received GM-CSF alone. Eight patients experienced early recurrence or developed a second malignancy and did not complete the vaccine trial. The vaccine is injected subcutaneously and the initial series consisted of monthly inoculations for six months, followed by four cycles of booster shots administered every six months thereafter. The patients were monitored for nearly three years.

For all 190 patients, including those who did not complete the trial, the disease-free survival (DFS) rate was 88% among those who received the vaccine and 81% in the control group – representing a 37% reduction in recurrence. Excluding the patients who did not complete the vaccine series, the results are higher – 94% DFS rate versus 85% who did not get GP2 – a 57% risk reduction.

Women with HER2 +3 who were administered trastuzumab as part of the standard of care prior to receiving the vaccine experienced no cases of cancer recurrence. According to Mittendorf, trastuzumab may act like a primer for the vaccine. Trastuzumab stimulates CD4+ T cells to release substances that fight cancer cells and initiates an antibody response. Thus, it may prepare the immune system, making the vaccine even more effective. MD Anderson is now testing this combination of immunotherapies in other clinical trials.

The GP2 study supports previous MD Anderson research on similar breast cancer vaccines, such as AE37, which showed a significant immune response and improved recurrence rates in triple-negative breast cancer patients. Another candidate, E75, known as NeuVax or nelipepimut-S, showed a 50% recurrence decrease in high-risk patients. Currently, NeuVax is being tested internationally in a phase III clinical trial.

We believe many more patients will benefit in some way from immunotherapy,” says Mittendorf. “The challenge will be identifying the right immunotherapeutic approach for each individual patient. When doctors are able to do that, cancer therapy, and immunotherapy specifically, will follow a more personalized approach.”

American Society of Clinical Oncology’s Breast Cancer Symposium, 2014, San Francisco.