Positive Health Online

Assessing the Invasive and Metastatic Potential of Cancer Cells from a Tissue Section

Hokkaido University

There are many proteins involved in the spread of cancer. However, some of them are notably difficult to observe in patient tissue samples. Now, to tackle this challenge, a research group from the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD) of Hokkaido University has developed an unprecedented technique. Their method allows the use of cancer tissue removed from colorectal cancer patients to evaluate the ability of cancer cells to move on a tissue section.

Rac and Cdc42* are well-studied low molecular weight G proteins that regulate the ability of cancer cells to move, which is called their motility and invasive capacity. The more active these molecules are, the greater the ability of cancer cells to move. This also makes it more likely that diseased cells will invade and metastasize in blood and lymph vessels.

Until now, the motility and invasive capacity of cancer cells had only been assessed biochemically with a method called Rac/Cdc42 pull-down assay. However, when using this approach, the positional information within the cancer tissue is completely lost, and it is also impossible to evaluate the heterogenicity of the cells (how different they are from each other).

Fortunately, and for the first time ever, a research group including Professor Shinya Tanaka and Associate Professor Masumi Tsuda of the Department of Cancer Pathology, Faculty of Medicine, Hokkaido University/Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), managed to successfully evaluate the motility and invasive capacity of cancer cells in cancer tissue sections removed from colorectal cancer patients. The study has been published in Scientific Reports.[1]

The researchers used a recently developed non-contact agitation technology in which alternating electrical fields are used to ‘stir’ liquid droplets at extremely high speeds. With this approach, the group found that they were able to rapidly and specifically evaluate the motility and invasive ability of colon cancer cells by agitating a solution containing molecular probes that bind to activated Rac/Cdc42 on cancer tissue sections. Such sections are called formalin-fixed paraffin-embedded (FFPE) specimens and are routinely used for physical diagnosis.

Their evaluations revealed many insights about the Rac/Cdc42 activity of cells. (a) First, that it was significantly higher in the tumour area than in the normal mucosa of the colon. (b) Moreover, the more advanced the cancer cell stage, the greater the increase in Rac/Cdc42 activity. (c) This increase was particularly high at the leading edges of the tumour, where cancer cells infiltrate the surrounding healthy tissue. (d) Additionally, in cases where Rac1/Cdc42 activity was high, there was a strong tendency for lymphatic invasion.

According to Associate Professor Masumi Tsuda, "While developing this technique, we found it difficult at first to suppress the staining background and detect specific signals. This technology is effective for breast cancer and brain tumors as well as colorectal cancer, and it promises to provide useful information for predicting lymph node metastasis and for the assessment of Rac inhibitor-based therapies in the future."

Footnote

*Rac/Cdc42: Major members of the Rho family of low molecular weight G proteins. They become active upon binding with GTP (guanosine triphosphate), and are inactivated upon binding with GDP (guanosine diphosphate). The motility and invasive ability of cancer cells are increased by activated Rac/Cdc42.

References

1. Tsuda, M., Horio, R., Wang, L. et al. Novel rapid immunohistochemistry using an alternating current electric field identifies Rac and Cdc42 activation in human colon cancer FFPE tissues. Sci Rep 12: 1733. 2022. https://doi.org/10.1038/s41598-022-05892-7

Original Japanese article published in the March 4^th edition of the Science News
https://sci-news.co.jp/     https://sj.jst.go.jp/news/202203/n0324-04k.html

About Science Japan

Science Japan is a science news site that provides recent news and stories from Japan’s leading research institutes. It is run by the Asia Pacific Research Centre as part of the Japan Science and Technology Agency (JST), one of Japan’s largest funding agencies, with a focus on information and collaboration within the Asia and Pacific regions. 

Science Japan’s goal is to deliver news and information to English speakers around the world with an interest in Japan and its science and technology industries. Daily updates include the latest research news from Japan, and interviews and stories from leading scientists in the region. https://sj.jst.go.jp/

Media Contact and Further Information

Indrani Das,  indrani.das@cactusglobal.com
Public Relations Japan Science and Technology Agency (JST)
Name: Matthew Drum sciencejapan@jst.go.jp
Japan Science and Technology Agency

­­Scientists Create Antibodies to Target a Secretory Protein for Anti-cancer Therapy

By identifying how the cancer-promoting protein chitinase-3-like-1 is released by cells, a team of researchers has succeeded in creating antibodies to neutralize it and stop cancer growth. The secretory glycoprotein, chitinase-3-like-1 (CHI3L1), is associated with many signaling pathways in the development of cancer. However, the precise mechanism of its transport and regulation has remained elusive so far. Researchers from Taiwan’s National Cheng Kung University have now unearthed how CHI3L1 is secreted by cells, identified a new protein biomarker for cancer progression, and developed CHI3L1-neutralizing antibodies that can arrest the growth of cancers and supplement existing standard chemotherapies.  

Lung, colorectal, and pancreatic cancer are three cancers with a poor prognosis. Lung and colorectal cancers are the leading causes of cancer-related deaths worldwide and pancreatic cancer is one of the most aggressive cancers – patients with pancreatic cancer generally do not survive for more than five years post-detection. Common to these three cancers is the non-enzymatic chitinase-3-like-1 (CHI3L1) – a soluble protein containing carbohydrate groups – which demonstrates an increased expression in the plasma or serum and tumors of patients with these cancers, hinting at its role in their progression. This makes it an attractive target for cancer therapy.

Researchers from National Cheng Kung University, Taiwan, have recently been successful in identifying more details on how CHI3L1 promotes tumorigenesis (the development of cancer). The group successfully described CHI3L1’s possible secretory and immunosuppressive mechanisms and developed and validated the efficacy of anti-CHI3L1 antibodies in solid tumors. They have published their findings in Theranostics. This paper was made available online and published in Volume 12 Issue 1 of the journal on January 1, 2022.[1]

The team used a variety of experimental approaches and cutting-edge techniques, such as vesicle isolation, fluorescence microscopy, and immunohistochemistry to come to their conclusions. For instance, the team monitored the real-time movement of the CHI3L1 protein inside cells using light-emitting fluorescent “trackers.” To further validate their findings, the researchers also conducted experiments using laboratory mice.

We spoke to Dr. Yi-Ching Wang, Chair Professor at the National Cheng Kung University, Taiwan, who explained their experiments in more detail.

“CHI3L1 is typically secreted by a variety of cells, including macrophages, T cells, neutrophils, epithelial cells, smooth muscle cells, fibroblasts, and cancer cells. We found that a protein called Rab37 mediated the transport of CHI3L1 out of these cells via a pathway that was dependent on guanosine triphosphate (GTP) for energy. This was evidenced by the fact that CHI3L1 secretion was attenuated in mice, which were genetically modified to not produce Rab37.”

Once outside the cell, CHI3L1 activated a series of sub-cellular signaling pathways, resulting in the rapid development of pro-tumor microenvironments. This finding led the team to focus its attention on the development of novel antibodies to counter subsequent cancer progression.      

“CHI3L1 blockage by neutralizing antibodies may shift tumor microenvironments towards an immunostimulatory phenotype, therefore reducing cancer progression,’ said Dr Wang. ‘Hence, we developed CHI3L1-neutralizing antibodies, which we tested on cancer models in mice and on cancer cell lines.”

As expected, the neutralizing antibodies reduced tumour growth. They also reduced metastases – the spread of cancer from its original location to one or more nearby/distant body organs. Moreover, they triggered a significant “biological reversal” by creating physiological conditions that facilitate the identification and elimination of cancer cells by the immune system. The researchers observed this reversal in lung, pancreatic, and colon tumour models.   

Dr Yan-Shen Shan, senior author and Distinguished Professor, and Dr Wu-Chou Su, Professor and Director at the Department of Internal Medicine (both from the National Cheng Kung University), educate us about the advantages of their experimental findings,

“Our CHI3L1-neutralizing antibodies appear to be non-toxic and safe in the short-term. Furthermore, combining them with current chemotherapies used in cancer treatment could lessen adverse effects and shorten patients’ hospital stay.”

After observing the great efficacy of these antibodies, for further clinical application, the team recently developed fully human monoclonal antibodies against CHI3L1 with AP Biosciences, Inc. Two out of eleven candidate clones will be validated with more in vivo examinations to determine which has the best antitumor efficacy and lowest toxicity.

Let us hope that these laboratory experiments pave the way for the successful development of new cancer therapies. Meanwhile, let us also thank the researchers for their groundbreaking contribution to cancer research!

Reference

1. 1. Pei-Shan Yang¹, Min-Hua Yu¹, Ya-Chin Hou^2,3, Chih-Peng Chang^4,5, Shao-Chieh Lin⁶, I-Ying Kuo^1,5, Pei-Chia Su⁵, Hung-Chi Cheng⁵, Wu-Chou Su⁷, Yan-Shen Shan^2,3,8, Yi-Ching Wang^1,5  Targeting protumor factor chitinase-3-like-1 secreted by Rab37 vesicles for cancer immunotherapy. Theranostics 12(1):340-361. DOI: https://doi.org/10.7150/thno.65522.

¹Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ²Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ³Department of Clinical Medical Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ⁴Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ⁵Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ⁶Colorectal Division, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ⁷Division of Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ⁸Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

About National Cheng-Kung University, Taiwan

Established first in 1931 under the name of Tainan Technical College, National Cheng Kung University (NCKU) is a public university in Tainan, Taiwan. Currently spread over a total area of approximately 186 hectares, including 8 main campuses and 3 satellite campuses, NCKU has come a long way since its inception 90 years ago. With 9 colleges, 44 departments, and 15 university-level research centers, NCKU aims to cultivate critical thinking, empathy, and imagination, and strives to improve the wellbeing of humankind and become a university of excellence in education,

research, and social responsibility. “Seek for Truth; Toil for Good” is the university’s motto.
https://www.ncku.edu.tw/  

About Professor Yi-Ching Wang

Dr Yi-Ching Wang is a Chair Professor at the National Cheng Kung University, Taiwan, where she researches cancer genomics, epigenomics, genome-scanning approaches, anti-cancer drugs, tumorigenesis, and tumor microenvironments. She has published around 150 peer-reviewed articles on lung cancer in prestigious journals and is a recipient of the Taiwan Ministry of Science’s Excellent Research Award.

About Professor Yan-Shen Shan

Dr Yan-Shen Shan is a Distinguished Professor and Dean at the National Cheng Kung University, Taiwan, where he primarily conducts research on gastrointestinal physiology and clinical oncology, tumor microenvironments of pancreatic and gastric cancers, hepatopancreatic regeneration and fibrosis, as well as surgical infections and nutrition metabolism.

About Professor Wu-Chou Su

Dr Wu-Chou Su is a Professor at and Director of the Department of Internal Medicine at National Cheng Kung University, Taiwan. A senior physician and medical researcher, Prof. Su attained his MD from the National Taiwan University College of Medicine in 1983. Prof. Su possesses immense expertise in the areas of cell signaling & transduction, nanomedicine, oncology, and clinical trials, and has more than 260 research publications to his credit.

Media Contact and Further Information

Brijesh Manek brijesh.manek@cactusglobal.com

Leading Food-Integrity Researchers Question Influential Data Around Red Meat

An international team of experts, including Professor Chris Elliott of the Institute for Global Food Security (IGFS) at Queen’s University Belfast, has called on the influential Global Burden of Diseases, Injuries and Risk Factors Study (GBD) to publish the evidence behind its most recent report linking the consumption of unprocessed red meat to certain diseases.

In a letter published in The Lancet, six leading academics raise concerns about the dramatic differences in estimates of disease burden attributable to unprocessed red meat cited in GBD 2019 compared to the GBD 2017 study.[1]

In writing the letter, the researchers are seeking to emphasize the importance of making research data publicly available so that guidelines and policies can be developed, based on a full understanding of the evidence.

The letter states: “The 2019 estimates of deaths attributable to unprocessed red-meat intake have increased 36-fold and estimates of DALYs  attributable to unprocessed red meat intake have increased 18-fold.”

DALYs [disability-adjusted life year] are an internationally recognized measure of the impact of diseases on populations.

Based on these findings, the GBD 2019 reported that red-meat intake contributes to the causation of a range of diseases including heart disease, breast cancer and stroke, in addition to diabetes and colon cancer. It appears that the marked increase in the 2019 estimates is dependent on two assumptions: that the optimal intake of red meat is zero; and that risk rises sharply even with moderate consumption of red meat.

The authors of the letter are led by Prof Alice Stanton, of RCSI [Royal College of Surgeons in Ireland] University of Medicine and Health Sciences, Dublin. The co-authors are: Prof Chris Elliott (Queen’s University Belfast); Prof Frederic Lerory (Vrije Universiteit Brussels); Prof Neil Mann (University of Melbourne); Prof Patrick Wall (University College Dublin); and Prof Stefaan De Smet (Ghent University).

Commenting, Prof Stanton said: “It is of considerable concern that the GBD 2019 study provides little or no evidence regarding the scientific basis for the assumption that moderate consumption of red meat results in sharp increases in risk of cancers, heart attacks and strokes.

“Given the substantial influence of GBD reports on worldwide, nutritional-policy decision making, it is of considerable importance that the GBD estimates are subject to critical scrutiny, and that they continue to be rigorously and transparently evidence-based.

“If the current public-health message advising moderate consumption of red meat as part of a healthy balanced diet is replaced by the message that any intake of red meat is harmful, then childhood malnutrition, iron-deficiency anaemia in women of child-bearing age and elderly fragility will greatly increase.”

Prof Elliott of IGFS said: “It is of huge importance that the evidence supporting the negative health impacts around red-meat consumption is made available. It is hard to understand how such conclusions could have been published without a strong evidence base that can be subjected to scientific scrutiny.”

Prof Nigel Scollan, Director of IGFS added: “Such a jump from the 2017 to the 2019 GBD estimates raises questions around the evidence behind the data. It’s immensely important that this kind of evidence is transparent and publicly available, especially when it will have a major bearing on international public health.”

The letter further recommends that the GBD 2019 dietary-risk estimates are not used in any national or international policy documents until comprehensive independent peer reviews have been conducted of the evidence underpinning the revised estimates.

The letter can be read here: 36-fold higher estimate of deaths attributable to red meat intake in GBD 2019: is this reliable? - The Lancet

Reference

1. Alice V Stanton, Frédéric Leroy, Christopher Elliott, Neil Mann, Patrick Wall, Stefaan De Smet. 36-fold higher estimate of deaths attributable to red meat intake in GBD 2019: is this reliable? The Lancet February 25, 2022. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00311-7/fulltext DOI:https://doi.org/10.1016/S0140-6736(22)00311-7

Media Contact and Further Information

For further information, please contact IGFS Communications Officer Una Bradley on u.bradley@qub.ac.uk  or +44 7920 088450

Insomnia Could Increase People’s Risk of Type 2 Diabetes

People who have difficulty getting to sleep or staying asleep had higher blood sugar levels than people who rarely had sleep issues, new research has found. The findings suggest insomnia could increase people’s risk of type 2 diabetes, and that lifestyle or pharmacological treatments that improve insomnia could help to prevent or treat the condition.

The study, led by the University of Bristol, supported by the universities of Manchester, Exeter, and Harvard, and funded by Diabetes UK, is published in Diabetes Care.[1]

Insomnia, not getting enough sleep, and having a later bedtime, have been linked in previous studies to a greater risk of type 2 diabetes. In this study, the research team assessed whether these associations are explained by causal effects of sleep traits on blood sugar levels.

The researchers used a statistical technique called Mendelian Randomization to see how five sleep measures - insomnia, sleep duration, daytime sleepiness, napping and morning or evening preference (chronotype) - were related to average blood sugar levels assessed by a measure called HbA1c levels. Using Mendelian Randomization, which groups people according to a genetic code randomly assigned at birth, allowed the researchers to remove any bias from the results.

The study of over 336,999 adults living in the UK, showed that people who reported that they often had difficulty getting to sleep or staying asleep had higher blood sugar levels than people who said they never, rarely, or only sometimes had these difficulties. The research team found no clear evidence for an effect of other sleep traits on blood sugar levels.

The findings could improve researchers understanding of how sleep disturbance influences type 2 diabetes risk. The study also suggests that lifestyle and/or pharmacological interventions that improve insomnia might help to prevent or treat diabetes.

James Liu, Senior Research Associate in the Bristol Medical School (PHS) and MRC Integrative Epidemiology Unit (IEU) and corresponding author on the paper, said: “We estimated that an effective insomnia treatment could result in more glucose lowering than an equivalent intervention, which reduces body weight by 14kg in a person of average height. This means around 27,300 UK adults, aged between 40- and 70-years-old, with frequent insomnia symptoms would be free from having diabetes if their insomnia was treated.”

Currently, there are some treatments for insomnia. For example, UK guidelines to doctors recommend cognitive behavioural therapy (CBT) for insomnia, and short-term treatment of sleeping tablets or treatment with a hormone called melatonin if CBT does not work.

Dr Faye Riley is Research Communications Manager at Diabetes UK. She said: “We know from past research that there’s a link between sleep and a person’s risk of type 2 diabetes, but  it hasn’t been clear which comes first, bad sleep or higher blood sugars, or if other factors are at play.

“This new study, funded by Diabetes UK, gives us important insights into the direction of the relationship between sleep and type 2 diabetes, suggesting that insufficient sleep can cause higher blood sugars levels and could play a direct role in the development of type 2 diabetes. Knowing this could open up new approaches to help prevent or manage the condition.

“However, it’s important to remember that type 2 diabetes is a complex condition, with multiple risk factors. Eating a healthy balanced diet, being active, along with getting enough sleep, are all essential components of good health for everyone – including those at risk of, or living with, type 2 diabetes.”

Future studies to assess the impact of these insomnia treatments on glucose levels in people with and without diabetes could establish potential new treatments for the prevention and treatment of diabetes.

The study was supported by the Medical Research Council, British Heart Foundation, National Institute of Health Research, Wellcome Trust, US National Institute of Health and a de Pass Vice Chancellors Fellowship from the University of Bristol.

Reference

1. James Liu, Rebecca C Richmond, Martin K Rutter et al. Assessing the causal role of sleep traits on glycated haemoglobin: a Mendelian randomization study. Diabetes Care: 45(4): 772–781. 2022. Junxi Liu, ieu_james.liu@bristol.ac.uk.   https://doi.org/10.2337/dc21-0089    https://diabetesjournals.org/care/article/45/4/772/144928/Assessing-the-Causal-Role-of-Sleep-Traits-on

About Mendelian Randomization

Mendelian Randomization is a study that uses genetic variants as instrumental variables to test the causal effect of a (non-genetic) risk factor on a disease or health-related outcome.

About MRC Integrative Epidemiology Unit

The MRC Integrative Epidemiology Unit (IEU) is a research unit based at the University of Bristol with funding from the Medical Research Council. It uses genetics, population data and experimental interventions to look for the underlying causes of chronic disease.

About Diabetes UK

1. Diabetes UK’s aim is creating a world where diabetes can do no harm. Diabetes is the most devastating and fastest growing health crisis of our time, affecting more people than any other serious health condition in the UK - more than dementia and cancer combined. There is currently no known cure for any type of diabetes. With the right treatment, knowledge and support people living with diabetes can lead a long, full and healthy life. For more information about diabetes and the charity’s work, visit diabetes.org.uk
2. Diabetes is a condition where there is too much glucose in the blood because the body cannot use it properly. If not managed well, both type 1 and type 2 diabetes can lead to devastating complications. Diabetes is one of the leading causes of preventable sight loss in people of working age in the UK and is a major cause of lower limb amputation, kidney failure and stroke. 
3. People with type 1 diabetes cannot produce insulin. About 10 per cent of people with diabetes have type 1. No one knows exactly what causes it, but it’s not to do with being overweight and it isn’t currently preventable. It’s the most common type of diabetes in children and young adults, starting suddenly and getting worse quickly. Type 1 diabetes is treated by daily insulin doses – taken either by injections or via an insulin pump. It is also recommended to follow a healthy diet and take regular physical activity.
4. People with type 2 diabetes don’t produce enough insulin or the insulin they produce doesn’t work properly (known as insulin resistance). Around 90 per cent of people with diabetes have type 2. They might get type 2 diabetes because of their family history, age and ethnic background puts them at increased risk. They are also more likely to get type 2 diabetes if they are overweight. It starts gradually, usually later in life, and it can be years before they realise they have it. Type 2 diabetes is treated with a healthy diet and increased physical activity. In addition, tablets and/or insulin can be required. 

For more information on reporting on diabetes, download our journalists’ guide: Diabetes in the News: A Guide for Journalists on Reporting on Diabetes (PDF, 3MB)

About The University of Manchester

The University of Manchester, a member of the prestigious Russell Group, is one of the UK’s largest single-site university with more than 40,000 students – including more than 10,000 from overseas. It is consistently ranked among the world’s elite for graduate employability. The University is also one of the country’s major research institutions, rated fifth in the UK in terms of ‘research power’ (REF 2014). World-class research is carried out across a diverse range of fields including cancer, advanced materials, global inequalities, energy and industrial biotechnology.

Further Information

For further information or to interview James Liu and Martin K Rutter, please contact Mon/Tuesday press-office@bristol.ac.uk  or Caroline Clancy-Cottle [Weds to Fri], email: caroline.clancy@bristol.ac.uk  in the University of Bristol Media & PR Team.