For a Healthier 2018!

Dancing together is good for your health!

 

By Jesica Levingston Mac leod, PhD

 

Social dancers know the amazing feeling that a synchronized dance could bring. When your follower or leader is connected and it feels like you are one mind and body following the music, it is mystical and magical… Well, it turns out that synchronized dancing is also good for your health. I started dancing salsa because a good friend was going crazy about it and she recommended it, this inspired me to join a class. At this point I was a solitary belly dancer only following in team dances where you have choreography and if you are coordinated enough you feel this celestial connection with the other dancers…but without any physical contact.

On the other hand, in social dances like salsa, bachata, tango, zouk or swing, the connection is the base of a good dance. Nobody wants to be the person stepping to the left when 5 other dancers moved to the right while performing in a stage in front of hundreds of people, as well as nobody enjoys turning to the wrong side for misreading your dance partner lead, or watching how a follower does a completely different step that the one the leader indicated. Furthermore, being “in sync” with the group or your direct dance partner may help to improve your health, science says. In a nutshell, a recent study found that synchronizing with others while dancing raised pain tolerance and encouraged people to feel closer to others.

This year, Dr. Burzynska et al., at Colorado State University, separated 174 healthy adults, 60s to 79 years old, who had no signs of memory loss or impairment, into 3 activity groups: walking, stretching and balance training, or dance classes. The activities were carry on for 6 months and three times a week, those in the dance group practiced and learned a country dance choreography. Brain scans were done on all participants and compared with scans taken before the activities began. Not surprisingly, the participants in the dancing group performed better and had less deterioration in their brains than the other groups. Their most recent study published in November: “The Dancing Brain: Structural and Functional Signatures of Expert Dance Training” showed that dancers’ brains differed from non-dancers’ at both functional- and structural-levels. Most of the group differences were skill-relevant and correlated with objective laboratory measures of dance skill and balance. Their results are promising in that long-term, versatile, combined motor and coordination training may induce neural alterations that support performance demands.” (link 2)

Moreover, It is well established that dancing-based therapies are providing outstanding results in the treatment of dementia, autism and Parkinson’s. Indeed, dance therapy improves motor and cognitive functions in patients with Parkinson’s disease. Dancing was suggested to be a powerful tool to improve motor-cognitive dual-task performance in adults. Dance movement therapy has known benefits for cancer patients’ physical and psychological health and quality of lifeAnother study by Domane and collaborators, working with a cohort of overweight and physically inactive women, showed that Zumba fitness is indeed an efficacious health-enhancing activity for adults. Park also concluded that “a 12-week low- to moderate-intensity exercise program appears to be beneficial for obese elderly women by improving risk factors for cardiovascular disease”.

Dancing helps generate positive connections with others and this is one of the evolutionary reasons you are “called” to the dance floor when a song you like starts playing, and probably you will start your dance by coordinating with or copying others. Probably this behavior signaled tribe membership for early humans and also got couples together in a more romantic way, creating emotional bonds. Coordinated dances are as old as music, and distributed in a lot of different cultures, for example, the nowadays Hakka, used by rugby players, was a native group dance that intimidates rival tribes.

Talking about the chemistry of dancing, as any other exercise, it releases endorphins (the hormones of happiness and pain relief). For example, a study from the University of London were anxiety-sufferers enrolled in one of four settings: exercise class, a music class, a math class and a dance class, showed that only the last group displayed “significantly reduced anxiety.”

In the most recent study done in the same London University by Tarr and collaborators, the researchers used pain thresholds as an indirect measure of endorphin realize (more endorphins mean we tolerate pain better) for 264 young people in Brazil. The volunteers were divided into groups of three, and they did either high or low-exertion dancing that was either synchronized or unsynchronized. The high exertion moves were standing, full-bodied movements, on the other hand, in the low-exertion groups did small hand movements sitting down. They measured the before and after feelings of closeness to each other via a questionnaire and their pain threshold by attaching and inflating a blood pressure cuff on their arm, and determining how much pressure they could stand.

Most of the volunteers who did full-bodied exertive dancing had higher pain thresholds compared with those who were in the low-exertion groups. Most importantly, synchronization led to higher pain thresholds, even if the synchronized movements were not exertive. Therefore when the volunteers saw that others were doing the equivalent movement at the same time, their pain thresholds increased.

The results also showed that synchronized activity encouraged bonding and closeness feelings more than unsynchronized dancing. Therefore, “Dance which combined high energy and synchrony had the greatest effects. So the next time you find yourself in an awkward Christmas party or at a wedding wondering whether or not to get up and groove, just do it”, claims Dr. Tarr.

Coming back to the dance floor, I had reached out for an opinion about the wellness of dancing to the best Bachata DJ: Brian el Matatan: “I enjoy the dancing for a few reasons. There’s the enjoyment & challenge of using what I’ve learned; socially as well as choreographed performance. Also, there is the rush of endorphins similar to “runner’s high”. There’s also the socializing aspect of dancing. It’s like having a conversation without speaking.” Well said DJ!
He also offered some advice for followers: dance with many different types of leaders if you’d like to improve your following. There are many different leads, and there is an experience to be gained in social dancing that would not be gained via dance class. Also, feel free to ask a leader to dance, & be courteous in how you decline a dance. Most importantly- communicate. Don’t “lead” a leader into thinking their lead is better than what it really is- for your sake & that of your fellow followers. For example, if he almost ended your life with that risky move, let him know so that he doesn’t try it on you or anyone else again (at least not without figuring out how to do the move properly). And some advice for leaders: be VERY  courteous in how you ask for a dance, try to not take rejection personally, be patient with follows who may not be on the same skill level as you, & don’t almost end her life with risky moves.

Lastly, I asked for the most sensual dancer, scientist, and project manager –  Debbie McCabe – for her advice for followers. She commented “The lady’s job is to surrender and connect to her partner…it is a 3-minute love affair and energy exchange. I love Bachata because I can get out of my head and just feel, express my sensuality, be playful and connect… it balances out my left brained day job.”

More than 20 years ago, scientists found a connection between music and enhancement of performance or changing of neuropsychological activity involving Mozart’s music from which the theory of “The Mozart Effect” was derived. The basis of The Mozart Effect lies at the super-organization of the cerebral cortex that might resonate with the superior architecture of Mozart’s music. Basically listening to Mozart K.448 enhances performance on spatial tasks for a period of approximately 20 min.

So dear reader, please stop complaining and making excuses and just dance! Or at least listen to music, as the outstanding jazz singer Tamar Korn once told me when I was in distress “music heals”.

 

This post was originally published on Dec 30, 2015 and was updated with new research on Dec 12, 2016 and on Dec 19, 2017.

Is Your Deodorant Bad For Your Health?

 

By Jesica Levingston Mac Leod, PhD

Body odors (BO) are part of our evolution, and the ability to smell has evolved with us, making people fall in love or run away from a smelly person. Sweat has an initial effect to cool our body down and avoid overheating. Sweat can also be trigger by stress, anxiety or other hormonal changes. Sweat by itself doesn’t smell, but the bacteria located near the glands, for example, the armpits, breakdown the sweat generating the “BO”. How do we deal with the stinky fact? We apply deodorants and/or antiperspirants. Deodorants have ingredients like triclosan, which make the skin more salty or acidic for the bacteria to grow in those areas. Therefore deodorants don’t stop you from sweating, but antiperspirants will do the trick, as they contain ingredients like aluminum and zirconium, which are taken up through the pores and they react with water and swell, forming a gel that blocks the sweat.

Last year, Mandriota and collaborators demonstrated that in a cancer mouse model, concentrations of aluminum in the amount of those measured in the human breast are able to transform cultured mammary epithelial cells, allowing them to form tumors and to metastasize. Moreover, aluminum salts have been linked with DNA damage, oxidative stress, and estrogen action. In 2004, a woman reported aluminum poisoning after using antiperspirants for four years, and after stopping the use of these products the aluminum levels dropped and she recovered.

Breast cancer develops after cells with mutations in their DNA start growing uncontrolled, generating a tumor. Most breast cancers develop in the upper outer quadrant of the breast, near to the lymph nodes that are exposed to antiperspirants. This fact was the starting point for the theories that the underarm cosmetic products could be carcinogenic. One of the first publications on this subject dates from 2002; it was population-based (ages 20-74, 1606 patients) and found no correlation between breast cancer and antiperspirant use. A second article found a relationship between an earlier age of breast cancer diagnosis to more frequent regular use of antiperspirants/deodorants and underarm shaving.

Aluminum salts have been linked to increased risk of developing breast cancer, but so far the research on this has been quite inconsistent. Last month, a new research study of 418 women (ages 20 to 85) examined their self-reported history of use of underarm cosmetic products and health status, in order to unveil a bit more about the link between antiperspirants and breast cancer. Linhart and col. from Austria, studied the relationship of the use of underarm cosmetic products and the risk of breast cancer. They divided the group in two: half of the women were breast cancer patients and the other half healthy controls. Then, they measured the concentration of aluminum in the breast tissue of some of the women. The results showed that the risk of breast cancer increased by an odd ratio of 3.88 in females who described using the underarm products multiple times per day starting before their 30th birthday. Importantly: “aluminum traces were found in the breast tissue in both cancer patients and healthy controls and it was significantly associated to self-reported underarm cosmetic products use”. In fact, the median concentrations of aluminum were 5.8 (2.3-12.9) nmol/g in the tissues from breast cancer patients versus 3.8 (2.5-5.8) nmol/g in controls. The conclusion is that more than daily use of these cosmetic products at younger ages may lead to the accumulation of aluminum in breast tissue and increase the risk of breast cancer.

Although the American Cancer Society claims that “there are no strong epidemiologic studies in the medical literature that link breast cancer risk and antiperspirant use”, after the Linhart investigation, and knowing that 1 in 8 women will be diagnosed with breast cancer in her lifetime, I will avoid antiperspirants with aluminum. Nobody wants to be called “stinky”, so some actions to take are to wash your clothes after working out, take showers regularly and/or clean your armpits with water and soap as soon as you “smell something”, apply deodorant, and consult with your doctor about the best way to keep your body odors under control. The last resource: perfume. If you can’t win the fight… hide.

HeLa, the VIP of cell lines

By  Gesa Junge, PhD

A month ago, The Immortal Life of Henrietta Lacks was released on HBO, an adaptation of Rebecca Skloot’s 2010 book of the same title. The book, and the movie, tell the story of Henrietta Lacks, the woman behind the first cell line ever generated, the famous HeLa cell line. From a biologist’s standpoint, this is a really unique thing, as we don’t usually know who is behind the cell lines we grow in the lab. Which, incidentally, is at the centre of the controversy around HeLa cells. HeLa was the first cell line ever made over 60 years ago and today a PubMed search for “HeLa” return 93274 search results.

Cell lines are an integral part to research in many fields, and these days there are probably thousands of cell lines. Usually, they are generated from patient samples which are immortalised and then can be grown in dishes, put under the microscope, frozen down, thawed and revived, have their DNA sequenced, their protein levels measured, be genetically modified, treated with drugs, and generally make biomedical research possible. As a general rule, work with cancer cell lines is an easy and cheap way to investigate biological concepts, test drugs and validate methods, mainly because cell lines are cheap compared to animal research, readily available, easy to grow, and there are few concerns around ethics and informed consent. This is because although they originate from patients, the cell lines are not considered living beings in the sense that they have feelings and lives and rights; they are for the most part considered research tools. This is an easy argument to make, as almost all cell lines are immortalised and therefore different from the original tissues patients donated, and most importantly they are anonymous, so that any data generated cannot be related back to the person.

But this is exactly what did not happen with HeLa cells. Henrietta Lack’s cells were taken without her knowledge nor consent after she was treated for cervical cancer at Johns Hopkins in 1951. At this point, nobody had managed to grow cells outside the human body, so when Henrietta Lack’s cells started to divide and grow, the researchers were excited, and yet nobody ever told her, or her family. Henrietta Lacks died of her cancer later that year, but her cells survived. For more on this, there is a great Radiolab episode that features interviews with the scientists, as well as Rebecca Skloot and Henrietta Lack’s youngest daughter Deborah Lacks Pullum.

In the 1970s, some researchers did reach out to the Lacks family, not because of ethical concerns or gratitude, but to request blood samples. This naturally led to confusion amongst family members around how Henrietta Lack’s cells could be alive, and be used in labs everywhere, even go to space, while Henrietta herself had been dead for twenty years. Nobody had told them, let alone explained the concept of cell lines to them.

The lack of consent and information are one side, but in addition to being an invaluable research tool, cell lines are also big business: The global market for cell lines development (which includes cell lines and the media they grow in, and other reagents) is worth around 3 billion dollars, and it’s growing fast. There are companies that specialise in making cell lines of certain genotypes that are sold for hundreds of dollars, and different cell types need different growth media and additives in order to grow. This adds a dimension of financial interest, and whether the family should share in the profit derived from research involving HeLa cells.

We have a lot to be grateful for to HeLa cells, and not just biomedical advances. The history of HeLa brought up a plethora of ethical issues around privacy, information, communication and consent that arguably were overdue for discussion. Innovation usually outruns ethics, but while nowadays informed consent is standard for all research involving humans, and patient data is anonymised (or at least pseudonomised and kept confidential), there were no such rules in 1951. There was also apparently no attempt to explain scientific concept and research to non-scientists.

And clearly we still have not fully grasped the issues at hand, as in 2013 researchers sequenced the HeLa cell genome – and published it. Again, without the family’s consent. The main argument in defence of publishing the HeLa genome was that the cell line was too different from the original cells to provide any information on Henrietta Lack’s living relatives. There may some truth in that; cell lines change a lot over time, but even after all these years there will still be information about Henrietta Lack’s and her family in there, and genetic information is still personal and should be kept private.

HeLa cells have gotten around to research labs around the world and even gone to space and on deep sea dives. And they are now even contaminating other cell lines (which could perhaps be interpreted as just karma). Sadly, the spotlight on Henrietta Lack’s life has sparked arguments amongst the family members around the use and distribution of profits and benefits from the book and movie, and the portrayal of Henrietta Lack’s in the story. Johns Hopkins say they have no rights to the cell line, and have not profited from them, and they have established symposiums, scholarships and awards in Henrietta Lack’s honour.

The NIH has established the HeLa Genome Data Access Working Group, which includes members of Henrietta Lack’s family. Any researcher wanting to use the HeLa cell genome in their research has to request the data from this committee, and explain their research plans, and any potential commercialisation. The data may only be used in biomedical research, not ancestry research, and no researcher is allowed to contact the Lacks family directly.

Immunotherapy: Using Your Own Cells to Fight Cancer – Part 2

 

By Gesa Junge, PhD

 

Part 1 of this post described passive immunotherapies like antibodies and cytokines, but there are also active immunotherapies, which re-target our immune system towards cancer cells, for example cancer vaccines. These can be preventative vaccines, offering protection against cancer-associated viruses such as Hepatitis B (liver cancer) or Human Papilloma Virus (HPV, cervical cancer). The link between HPV and cervical cancer was first described in 1983, and a vaccine was approved in 2006. By 2015, the incidence of HPV infections in women under 20 had decreased as much as 60% in countries that had 50% vaccination coverage, although it may still be too early to tell what the impact on HPV-associated cancer incidence is. There are also other factors to consider, for example screening programmes are also likely to have a positive impact on HPV-associated cancers.

Vaccines can also be therapeutic vaccines, which stimulate the immune system to attack cancer cells. To date, the only cancer vaccine approved in the US is Provenge, used for the treatment of metastatic prostate cancer. For this therapy, a patient’s white blood cells are extracted from the blood, incubated with prostatic acid phosphatase (PAP, a prostate-specific enzyme) and granulocyte macrophage colony stimulating factor (GM-CSF) in order to produce mature antigen presenting cells which are then returned to the patient and search and destroy tumour cells.

Many other therapeutic cancer vaccines are in development, for example OncoVax, which is an autologous vaccine made from a patient’s resected tumour cells. OncoVax has been in development since the 1990s and is currently in phase III trials. Another example is GVAX, an allogenic whole-cell tumour vaccine currently being studied in phase I and II trials or pancreatic and colorectal cancer. As an allogenic vaccine, it is not made from the patient’s own blood cells (like an autologous vaccine), and it does not target specific antigens but rather increases the production of cytokines and GM-CSF.

Another therapy which is based on re-programming the patient’s immune system is adoptive T-cell transfer. As with some cancer vaccines, a patient’s T-cells are isolated from the blood, and the cells with the greatest affinity for tumour cells are expanded in the lab and the re-infused in the patient. A recent modification of this technique is the use of chimeric antigen receptor (CAR) T-cells, where the T-cell receptors are genetically engineered to be more tumour-specific before re-infusion. This approached was especially promising in chronic lymphocytic leukaemia, where some patients experienced remissions of a year and longer. Later, CAR T-cells were also tested in acute lymphocytic leukaemia, where response rates were as high as 89%.

Finally, a new class of cancer drugs called immune checkpoint inhibitors has been making headlines recently, some of which are now approved for the treatment of cancer. Immune checkpoints are part of the mechanism by which human cells, including cancer cells, can evade the immune system. For example, the programmed cell death (PD) 1 receptor on immune cells interacts with PD1 ligand (PDL1) on cancer cells, which inhibits the killing of the cancer cell by the immune cell. Similarly, CTLA-4 is a receptor on activated T-cells which downregulates the immune response.

The first checkpoint inhibitor was an antibody to CTLA-4, ipilimumab, which was approved for the treatment of melanoma in 2011. PD1 antibodies such as pembrolizumab and nivolumab were only approved in 2014, and the only PDL1 antibody (atezolizumab) in 2016, so it is difficult to tell what the long-term effects of checkpoint inhibitor treatment will be. Numerous checkpoint inhibitors are still undergoing trials, most of the advanced (phase III) ones being targeted to PD1 or PDL1. However, there are other compounds in early trials (phase I or II) that target KIR (killer-cell immunoglobulin-like receptor) which are primarily being studied in myeloma, or LAG3 (lymphocyte activation gene 3), in trials for various solid tumours and leukaemias.

Immunotherapies all come under the umbrella of biological therapies. Biologics are produced by organisms, usually cells in a dish, unlike synthetic drugs, which are manufactured using a chemical process in the lab. This makes biologicals more expensive to manufacture. Ipilimumab therapy, for example, can cost about $100 000 per patient, with pembrolizumab and nivolumab being only slightly less expensive at $48 000 – $67 000. This puts considerable financial strain on patients and insurance companies. From a safety perspective, biologicals can cause the immune system to overreact. This sounds odd, as the whole point of immunotherapy is to activate the immune system in order to fight tumour cells, but if this response gets out of control, it can lead to potentially serious side effects as the immune system attacks the body’s organs and tissues.

All of these therapeutic approaches (antibodies, interleukins, vaccines, and checkpoint inhibitors) are usually not used alone but in combination with each other or other chemotherapy, which makes it difficult to definitively say which drug works best. But it is safe to say that collectively they have improved the lives of a lot of cancer patients. If you are interested in finding out more about the fascinating history of immunotherapy, from the discovery of the immune system to checkpoint inhibitors, check out the CRI’s timeline of progress on immunology and immunotherapy here.

 

Immunotherapy: Using Your Own Cells to Fight Cancer – Part 1

 

By Gesa Junge, PhD

 

Our immune system’s job is to recognize foreign, unfamiliar and potentially dangerous cells and molecules. On the one hand, it helps us fight infections by bacteria and viruses, while on the other hand it can leave us with annoying and potentially dangerous allergic reactions to harmless things like peanuts, pollen or pets. Tumor cells are arguably very harmful to our health, and yet the immune system does not always eliminate them. This is partially because cancer cells are our own cells, and not a foreign, unfamiliar intruder.

The immune system can recognize cancer cells; this was first postulated in 1909 by Paul Ehrlich and subsequently found by several others. However, detecting cancer cells may not be enough to prevent tumor growth. Recent research has shown that while detection can lead to elimination of cancer cells, some cells are not killed but enter an equilibrium stage, where they can exist undisturbed and undergo changes, and finally the cells can escape, if they have changed in a way that allows them to grow undetected by the immune system. This process of elimination, equilibrium and escape is referred to as “cancer immunoediting” and is one of the most active research areas in cancer, particularly in regard to cancer therapy.

Immunotherapy is a form of cancer therapy that harnesses our immune system to kill cancer cells, and there are various approaches to this. Probably the most established forms of immunotherapy are antibodies, which have been used for almost two decades. They generally target surface markers of cancer cells; for example, rituximab is an antibody to CD20, or trastuzumab, which targets HER2. CD20 and HER2 are cell surface proteins highly expressed by leukaemia and breast cancer cells, respectively, while normal, healthy cells have lower expression, making the cancer cells more susceptible. Rituximab was approved for Non-Hodgkins Lymphoma in 1997, the first of now nearly 20 antibodies to be routinely used in cancer therapy. In addition to this, there are several new antibodies undergoing clinical trials for most cancers. These are mainly antibodies to tumour-specific antigens (proteins that may only be expressed by e.g. prostate or lung cancer), and checkpoint inhibitors such as PD1 (more on that in part 2).

Initially, antibodies were usually generated in mice; however, giving murine antibodies to humans can lead to an immune response and resistance to the mouse antibodies when they are administered again later. Therefore, antibodies had to be “humanised”, i.e. made more like human antibodies, without losing the target affinity, and this was only made possible by advances in biotechnology. The first clinically used antibodies, such as rituximab, were chimeric antibodies, in which the variable region (which binds the target) is murine and the constant region is human, making them much better tolerated. Trastuzumab is an example of a humanised antibody, where only the very end of the variable region (the complementarity-determining region, CDR) is murine, and the rest of the molecule is human). And then there are fully human antibodies, such as panitumumab, an anti-EGFR antibody used to treat colorectal cancer. There is actually a system to labeling therapeutic antibodies: -ximab is chimeric, -zumab is humanised and –umab is human.

Antibodies can also be conjugated to drugs, which should make the drug more selective to its target and the antibody more effective in cell-killing. So far there are only very few antibody-drug conjugates in clinical use, but one example is Kadcyla, which consists of trastuzumab conjugated to emtansine, a cytotoxic agent.

Other examples of immunotherapy are cytokines such as interferons and interleukins. These are mediators of the immune response secreted by immune cells which can be given intravenously to help attack cancer cells, and they are used for example in the treatment of skin cancer. Interleukin 2 (IL-2) was the first interleukin to be approved, for the treatment of advanced melanoma and renal cancer, and research into new interleukins and their therapeutic potential is still going strong. Especially IL-2 and IL-12, but also several others are currently in clinical studies for both and various other indications, such as viral infections and autoimmune diseases.

In addition to passive immunotherapies like antibodies and cytokines, there are also active immunotherapies which re-target our immune system towards cancer cells, for example cancer vaccines. More on this, and on new drugs and their issues in part 2.

 

 

 

RESIDENT LYMPHOCYTES KEEP A LOOKOUT FOR NASCENT CANCER CELLS

 

By Sophie Balmer, PhD

One of the first questions that comes to my mind when discussing the emergence of cancer cells is how my immune system recognizes that my own cells have been transformed? This process is commonly termed cancer immunosurveillance. In the prevalent model, the adaptive immune system composed of lymphocytes circulating in the blood stream plays the main function. However, recent findings describe specific immune cells already present within the tissue, a.k.a. tissue-resident lymphocytes, and how they trigger the first immune response against cancer cells, allowing a much faster reaction in an attempt to eradicate transformed cells.

 

The cancer immunosurveillance concept hypothesizes that sentinel thymus-derived immune cells constantly survey tissues for the presence of nascent transformed cells. Cancer immunosurveillance was first suggested in the early 1900’s by Dr. Erlich but it took another fifty years for Dr. Thomas and Dr. Burnet to revisit this model and speculate about the presence of transformed cells induced inflammation and antigen-specific lymphocyte responses. Additionally, Dr. Prehn and Dr. Main estimated that chemically-induced tumor triggered the synthesis of antigen at the surface of cancerous cells that could be recognized by the immune system. Countless studies arose from these hypotheses and either validated or disproved these models. The latest attempt was published a little over a month ago, in a paper by Dr. Dadi and colleagues, describing a new mechanism for the immune system to respond to nascent cancer lesions by activating specific resident lymphocytes.

 

In this study, the authors used a genetically-induced tumor model (the MMTV-PyMT spontaneous mammary cancer mouse model) to analyze the in vivo response of the immune system to nascent transformed cells. Most studies have been performed using chemically-induced tumors or tumor transplantation into a healthy host but these do not account for the initial environment of the nascent tumor. The spontaneous model the authors use rapidly exhibits developing cancer lesion (in 8-week old mice), allowing the analysis of cellular populations present near transformed cells.

 

To analyze which immune cell types are present near cancer lesions, the authors performed several analyses. First, they measure the levels of granzyme B, a serine protease found in granules synthesized by cytotoxic lymphocytes to generate apoptosis of targeted cells, and show that PyMT mice have elevated levels of granzyme B when compared to wild-type mouse. Moreover, similar analysis of PyMT secondary lymphoid organs show that this response was restricted to the transformed tissue.

During the first steps of immune responses, conventional natural killer (cNK) cells as well as innate lymphoid cells (ILC) are found in tumor microenvironments. In this model however, sorting of cells located in the vicinity of the lesion identified unconventional populations of immune cells, derived from innate, TCRab and TCRgd lineages. Indeed, their RNA-seq profiling reveal a specific gene signature characterized by high expression of the NK receptor NK1.1 but also the integrins CD49a and CD103. As these newly identified cells share part of their transcriptome with type 1 ILCs, the authors named them type 1-like ILCs (ILC1ls) and type 1 innate-like T cells (ILTC1s). In addition, transcripts encoding several immune effectors as well as apoptosis-inducing factors are upregulated in these cells, likely indicating that they trigger several pathways to eliminate transformed cells.

The authors also suggest that cNK cells are not required for immunosurveillance in this model and the unconventional lymphocytes described in this paper are regulated by the interleukine-15 (IL-15) in a dose-dependent way. Mice overexpressing IL-15 exhibit higher proliferation of these resident lymphocytes and tumor regression. Secretion of IL-15 in the tumor microenvironment might therefore promote cancer immunosurveillance.

 

In contradiction with the conventional view that recirculating populations of immune cells survey tissues for cellular transformation, ILC1ls and ILTC1s are tissue-resident lymphocytes. Their gene signature indicates that transcripts encoding motility-related genes are downregulated in these cells. Moreover, parabiosis experiments, during which two congenically marked mice are surgically united and share their blood stream, are performed to determine whether they are resident or circulating cells. The amounts of non-host ILC1s and ILTC1s are much reduced when compared to other recirculating immune cell type demonstrating that these cells are tissue-resident lymphocytes. Single-cell killing assays also determine that ILC1ls and ILTC1s are highly efficient at inducing apoptosis of tumor cells, which is more likely dependent on the lytic granules pathway.

 

Although the cancer immunosurveillance concept has been around for decades, it is still highly debated. Overall, these results shed light on this confusing field and bring up several questions. The signals recognized by this immune response are still unknown. Although the authors suggest that IL-15 might regulate the proliferation and/or activation of these cells, the source of IL-15 remains to be found. In addition, these cells might promote cancer immunosurveillance but are not sufficient to eradicate tumor cells and determining the cascade of signals induced by these resident lymphocytes will be required to ascertain their role. Establishing the limit of their efficiency as well as the mechanisms activated by transformed cell to escape their surveillance will also be crucial. Finally, one of the most important question to consider is how one could manipulate the activity of tissue-resident lymphocytes in cancer immunotherapy.

Tumor-Suppressive microRNAs

 

By Thalyana Smith-Vikos

MicroRNAs (miRNAs) are short, noncoding RNAs that inhibit the expression of specific target genes. Certain classes of miRNAs have been identified as tumor suppressors, most notably miR-34. Studies have shown that miR-34 can be delivered as a tumor-static agent, including a 2012 report by Kasinski and Slack in Cancer Research. This report identifies miR-34 as a tumor suppressor in a Kras;p53 mouse model of lung cancer, the most potent cause of cancer deaths around the world. Tumors harvested from these mice had elevated levels of miR-34 targets, including Met and Bcl-2, indicating that miR-34 expression was inhibited. By adding exogenous miR-34, both tumor formation and progression of preformed tumors were prevented in the mice, and proliferation and invasion of lung tumor-derived epithelial cells were inhibited. This and other studies show promise for the use of miRNAs, especially miR-34, in clinical trials for cancer treatment and prevention.

Backdoor Targeting of the Cancer Causing Protein K-Ras

 

Elaine To

When targeting a specific protein with a small molecule drug in order to treat a disease, scientists often use a molecule that mimics the natural substrate of the enzyme and targets the active site. However, this approach has met with limited success in the case of the oncogenic GTPase K-Ras. GTPases are regulatory proteins that act like binary switches for cellular pathways. In its “on” state, K-Ras is bound to GTP and activates signaling cascades responsible for cell growth, survival, and differentiation. When GTP gets hydrolyzed to GDP, K-Ras is turned “off.” Mutations that prolong the lifetime of GTP when bound to K-Ras, such as the G12C (glycine at position 12 is changed to cysteine) mutant, are highly oncogenic and lead to cancer. The high affinity of K-Ras for GTP and GDP makes drug targeting of the K-Ras active site difficult, but researchers Ostrem, Peters, et al. have discovered an alternate site on K-Ras that can be targeted for cancer therapies.

The researchers set out to find a small molecule that could specifically bind to the oncogenic G12C mutant protein while avoiding the wild type K-Ras by screening a disulfide library, which would be expected to react with the thiol group of the cysteine. Intact protein mass spectrometry revealed which compounds bound to the G12C mutant without targeting the wild type. The two strongest binders were unaffected by the presence of excess GDP, indicating that they do not compete with GDP for binding. X-ray crystallography showed that one of the strong binders was binding in a previously allosteric pocket of K-Ras.

In order to further characterize the novel allosteric site, the researchers examined libraries containing electrophiles, acrylamides, and vinyl sulphonamides for G12C K-Ras binding. Co-crystals of potent binders with K-Ras revealed that the switch-I and switch-II domains of the protein are disrupted, which also disturbs magnesium ion binding. Previously studied mutations in the residues that coordinate the magnesium ion result in a preference for GDP over GTP, thus the researchers tested the compounds for this activity as well. Indeed, exchange assays reveal a shift in K-Ras’s preference from GTP to GDP when the potent electrophiles are bound. Additionally, the compounds can block nucleotide exchange by exchange factors, though EDTA still effectively catalyzes the exchange of GDP for GTP.

It was also noted that the potent compounds occupied a position normally reserved for G60 when K-Ras is active. Known mutants of G60 have impaired binding to partner effector proteins such as Raf. Studies in cell lines show that compound binding impairs the association of K-Ras with Raf. Lastly, in order to show the effectiveness of the identified compounds as chemotherapeutic drugs, the researchers treat various cancer cell lines, some of which contain the G12C mutation. As expected, the cells with the mutation demonstrated significantly decreased viability in the presence of the compounds.

Overall, this is an elegant approach to small molecule drug development that fortuitously revealed a novel regulatory site of K-Ras. Drugs that target this site can be designed specifically for oncogenic mutations, and do not have to overcome the significant barrier of trying to out compete GDP and GTP for binding. The extensive crystal structure and enzymatic characterizations lay the groundwork for further drug development on K-Ras and may open up a whole new class of chemotherapeutic drugs.

A Marvellous Month of Science

 

Stephanie Swift

Fungal extracts prevent hepatitis C virus infection

Credit: ti-wago (Flickr)
Credit: Tiwago (Flickr)

Hepatitis C virus (HCV) is a huge cause of liver cancer, but current treatments are very expensive and not that great. Since HCV is a cunning little virus capable of quickly evolving drug resistance, simultaneously attacking it at several key points during its life cycle has the best chance of resolving infection. Researchers in Japan have now created and screened a library of 300 natural drugs isolated from fungi found on seaweed, mosses and other plants, and tested their ability to shut down HCV infection. One of their best hits, sulochrin, repelled several strains of hepatitis C virus, and was free from any toxic side effects. When they combined sulochrin with the traditional HCV drug, telaprevir, results were even better. Although any potential off-target effects of sulochrin still have to be ruled out, this research highlights that the natural world is a tremendously rich source of new drugs that should continue to be mined.

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Unwinding shielded DNA attacks the root cause of prostate cancer

Credit: axshuzaifa (Flickr)
Credit: Huzaifa Das (Flickr)

Most organs in the human body, including the prostate gland, contain a tiny population of stem cells that replace old defunct cells with shiny new ones. If these stem cells get damaged, they can become carcinogenic machines, dividing uncontrollably to form a tumor. Such cancer stem cells are thought to be the driving force that creates prostate tumors. Cancer stem cells are very difficult to kill, since they have excellent inbuilt safety features, one of which is very tightly coiled DNA that rebuffs normal treatments. Researchers at the University of York have now shown that treating prostate cancer stem cells with drugs that unwind and relax DNA sensitizes them to common chemotherapies, allowing them to be destroyed and ultimately preventing tumor relapse.

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Chilly temperatures help cancers to grow

Credit: ssoosay (Flickr)
Credit: Surian Soosay (Flickr)

At low temperatures the human body has a hard time, entering a state of thermal stress where only the most vital systems, like the brain, are left switched on. Now, a paper published in PNAS suggests that cold has yet another disadvantage – it changes the way cancer cells grow and spread, at least in mice. Mice living in a relatively cold environment (around 22°C) had cancers that grew more quickly and aggressively than mice living at a nice thermally comfortable temperature (around 30°C). Both the cold and the comfortable mice had the same numbers of potential cancer-fighting immune T cells when they were healthy, but when they got sick, the T cells in the comfortable mice were quicker and better at burrowing into the tumour to attack it. They also secreted more cancer-fighting substances than the cells from cold mice. In the tumors of cold mice, there were greater numbers of suppressive cells capable of shutting down normal immune responses. Cold temperatures, then, shifted the body’s response from fighting the tumor to accepting it. This suggests that the benefits of heat therapy for cancer may have been largely overlooked. Adapted from an article originally published on The Conversation.

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Common chemotherapy drug helps oncolytic viruses kill tumors

Credit: Bryan Brandenburg (Flickr)
Credit: Bryan Brandenburg (http://bryanbrandenburg.net)

There is a lot of excitement in the world of cancer immunotherapy over the potential utility of oncolytic viruses – that is, viruses that specifically infect and destroy cancer cells with the help of the immune system. Since a tumor is essentially a big chunk of overgrown tissue, the immune system often continues to see it as a normal part of the body (although sometimes, the sneaky tumor simply makes itself invisible to the immune system). Even after immune-activating oncolytic virus treatment, properly re-educating the immune system to see the tumor as a malignant intruder is a very difficult process. Researchers at McMaster Immunology Research Centre now show that administering an oncolytic virus together with a chemotherapy drug that triggers the immune system as it kills cancer cells finally allows the tumor to be recognized as a threat. Once that biological brake has been removed, cancer-fighting immune cells can pour into the tumor and secrete cancer-busting substances. Such exciting new combination therapies can help retrain the immune system to identify developing