Melanoma: Taming a migratory menace

Richard Neubig, Michigan State University

The deadliest cancer of the skin is cutaneous melanoma. In 2017 over 160,000 Americans are expected to be diagnosed with melanoma, and over half will have invasive disease, or one that has gone beyond the skin and which carries greater risk of recurrence. About 9,700 people are expected to die from melanoma this year.

Unlike most common cancers, such as breast and lung cancer, the incidence of melanoma continues to increase, mainly in young people below the age of 30. There has been a more than 50 percent increase in melanoma in young women since 1980.

The vast majority of melanomas are caused by exposure to UV light from sun or indoor tanning. Reducing these exposures by changing habits or using sun protection – sun screens and clothing coverage – is the best way to avoid melanoma and other skin cancers.

As a researcher who studies what makes melanoma spread, or metastasize, I’m acutely aware of how hard this deadly cancer is to tame. To be sure, advances have been made. Former President Jimmy Carter – probably the most high-profile melanoma survivor in history – benefited from new treatments resulting from immunotherapy, a technique my lab and many others are using to combat cancer.

A challenging cancer

For reasons that aren’t fully understood, even quite small melanomas can spread in the body, or metastasize. Detection very early, when the tumor is less than 1 millimeter thick, allows surgery that provides a near cure.

Survival with the earliest Stage 0 or 1A melanomas, or local disease, is greater than 95 percent at ten years after diagnosis. This fact has prompted the Melanoma Research Foundation to promote its #GETNAKED campaign for monthly skin checks to identify new moles or skin changes that might be an early indication of melanoma. Catching it early is critical because once it spreads, melanoma can become a monster.

Let’s consider the process of cancer metastasis, which involves at least four distinct steps.

First the cancer cells have to leave the vicinity of the primary tumor. They do this by invading through tissue barriers that sustain the normal tissue architecture.

Second, they need to invade through the blood vessel wall to get into the bloodstream.

These two steps are called intravasation, which means “into the blood stream.” Once there, the cancer cells need to survive.

Most cells in normal tissues require cell attachment, or contact with surfaces or other cells, to survive. When normal cells are detached from those contacts, they usually undergo a type of cell suicide called anoikis. This process of cell suicide is lost in many cancers.

The cancer cells then need to leave the bloodstream by invading through the wall of the blood vessel in a process called extravasation. This third step allows the cancer cells to spread to other parts of the body.

Finally, the cancer cells need to adapt and grow in the new environment, such as in the lung or brain.

One unique characteristic of melanoma is that it is not uncommon to have melanoma metastases show up after 10 or more years with no evidence of disease.

These late recurrences may be due to several underlying mechanisms, but one explanation is a process called cellular dormancy. While in this dormant state, cells can not be detected, and it is thought that the patient may have been cured.

Finding a way to prevent dormancy could reduce the chances of a late recurrence of metastatic disease.

Recent advances bring hope

Beyond prevention of the cancer in the first place, which is the best approach, there have been tremendous advances in the treatment of cutaneous melanoma. A critical development was the discovery in 2002 that over half of cutaneous melanomas have a mutation in the BRAF gene.

The mutation of this gene plays a key role in melanoma cell growth and proliferation. The BRAF protein is a member of the protein kinase family which has become a major target class for drug development in the pharmaceutical sector.

In 2010, remarkable results were presented on clinical benefits of a BRAF inhibitor, vemurafenib.

In the same year, a major advance in immune therapy for melanoma was reported where ipilimumab, an antibody that enhances the body’s immune responses, showed a significant survival benefit in patients with diffuse metastatic melanoma. These were the first breakthroughs in melanoma treatment in more than a decade.

In addition to these two early developments, other drugs acting like vemurafenib as well as improved immunotherapies have been developed. These have further improved therapy of cutaneous melanoma. Immune modulation has even resulted in long-term survival in a fraction (10-20 percent) of patients.

Limits to new treatments

Despite these advances, however, there are still key problems with current therapies. Many rapidly lose effectiveness; drugs like vemurafenib that were controlling the tumor stop working through the development of resistant cancer cells, often within less than one year.

Also, the immune therapies only benefit a fraction of patients. When combinations of two immune therapy drugs are used to give a better effect on the cancer, the patients’ immune systems begin attacking normal tissues, which leads to autoimmune side effects.

Consequently, we need new approaches to prevent or treat the progression of melanoma and especially the development of metastases.

Work in our lab and that of others has identified a cellular mechanism similar to the BRAF pathway that appears to play a role in the migration and metastasis of melanoma. A pathway is a series of biological steps that lead to changes in cell function, such as growth or migration.

If we could confirm this new pathway as a possible drug target, we may be able to develop a therapy to prevent metastasis.

A protein to examine

In the BRAF pathway, a small protein called Ras works upstream of BRAF to activate it. Ras is one of the most commonly mutated genes in all of cancer biology. The particular version in melanoma is called NRAS. It is mutated and activated in about 20 percent of melanomas. Combined, mutations in BRAF and NRAS are found in 80-90 percent of melanomas. This is why the BRAF pathway is a prime target for therapy.

The new pathway we have identified starts with something called the Rho protein, which is very closely related to Ras.

When this Rho mechanism is activated, cancer cells move more actively and will invade the tissue that surrounds a tumor.

Along with Rho, a second critical player is a protein called MRTF that turns on gene expression (i.e. the production of RNA and proteins) when it is activated. Rho activates MRTF by driving it into the nucleus of the cell, where it can turn on gene expression.

We found that this Rho/MRTF pathway is activated in some melanoma tumors but not others. When it is turned on, the MRTF protein is in the nucleus and the cells migrate very quickly and form large lung metastases when injected into mice.

Our lab, in collaboration with Dr. Scott Larsen at the University of Michigan, has developed some chemical inhibitors of the Rho/MRTF pathway. In our recent publication, we showed that one of these compounds was able to reduce melanoma cell migration and invasion in lab studies and to reduce metastasis of a human melanoma to the lung in a mouse model. We observed a remarkable decrease in the number and size of lung metastases in this study.

Our current studies are trying to determine whether measurements of Rho/MRTF pathway activity can be used to predict which melanoma tumors will metastasize and which early-stage melanomas are more likely to recur. If so, identification of high activity would trigger the need for very close clinical monitoring after surgery or possible drug treatment with existing drugs, or our compounds if they become available for clinical use.

We are also trying to determine whether we can prevent metastases only before the cancer cells have arrived in the lung, for example. Alternatively, if we prevent dormancy so that the cells die before setting up shop in the distant tissue or prevent the reactivation of the dormant cells in their new environment, the compounds might work even after the earliest stage of tumor spread.

The road from studies in mice to the clinic is long and full of pitfalls. We are continuing efforts to demonstrate that these compounds are safe enough for human studies in a few years. There are still many questions, but this approach could add a new arrow in the quiver of cancer treatment specialists.

The Conversation

Richard Neubig, Professor of Pharmacology and Toxicology, Michigan State University

This article was originally published on The Conversation. Read the original article.

Life Review

Every so often I feel an urge to review my life, not that which has been, though I am sure there is merit in doing so from time to time – especially from a Christian perspective (and I have done that and do do that – more regularly than many other things I do I expect). What I mean is life as a daily thing, that which I do, etc. What are my daily habits and are they profitable or useful? Do I need to tweak things or even completely do away with certain aspects of my daily life and replace them with something else? So that in brief purview is the sort of thing I’m on about.

So having said all that, I am currently in the process of doing this again and that in some detail. My approach on this occasion is to view everything from the start of the day through to the end of the day, applying my focus to one or two areas at a time, so that I can apply some useful changes with applied resilience that will stand the test of life and time – at least until the next review.

So that is what I am currently up to and seeking to sort out. There are useful tools in this digital age to assist and I am using such things as Evernote, One Calendar, Amazon Kindle reading app on my Samsung tablet, my Windows 10 PC, etc. All very modern tools to do a very long established practice throughout the ages.

The science is in: gardening is good for you

Chris Williams, University of Melbourne

As the weather warms and days lengthen, your attention may be turning to that forgotten patch of your backyard. This week we’ve asked our experts to share the science behind gardening. So grab a trowel and your green thumbs, and dig in.

“That’s all very well put,” says Candide, in the final line of Voltaire’s novel of the same name, “but we must go and work our garden.”

I studied this text at high school before I became a gardener and professional horticulturist. We were taught that Candide’s gardening imperative was metaphorical not literal; a command for finding an authentic vocation, not a call to take up trowels and secateurs.

In fact, Voltaire himself really believed that active gardening was a great way to stay sane, healthy and free from stress. That was 300 years ago.

As it turns out, the science suggests he was right.

The science of therapeutic horticulture

Gardens and landscapes have long been designed as sanctuaries and retreats from the stresses of life – from great urban green spaces such as Central Park in New York to the humblest suburban backyard. But beyond the passive enjoyment of a garden or of being in nature more generally, researchers have also studied the role of actively caring for plants as a therapeutic and educational tool.

“Therapeutic horticulture” and “horticultural therapy” have become recognised treatments for stress and depression, which have served as a healing aid in settings ranging from prisons and mental health treatment facilities to schools and hospitals.

Gardening and school

Studies of school gardening programs – which usually centre on growing food – show that students who have worked on designing, creating and maintaining gardens develop more positive attitudes about health, nutrition and the consumption of vegetables.

They also score better on science achievement, have better attitudes about school, and improve their interpersonal skills and classroom behaviour.

Research on students confirms that gardening leads to higher levels of self-esteem and responsibility. Research suggests that incorporating gardening into a school setting can boost group cohesiveness.

Gardening and mental health

Tailored gardening programs have been shown to increase quality of life for people with chronic mental illnesses, including anxiety and depression.

Another study on the use of therapeutic horticulture for patients with clinical depression sought to understand why gardening programs were effective in lessening patient experience of depression. They found that structured gardening activities gave patients existential purpose. Put simply, it gave their lives meaning.

In jails and corrective programs, horticultural therapy programs have been used to give inmates positive, purposeful activities that lessen aggression and hostility during and after incarceration.

In one detailed study from a San Francisco program, involvement in therapeutic horticulture was particularly effective in improving psychosocial functioning across prison populations (although the benefits were not necessarily sustained after release.)

Gardening has been shown to help improve the lives of military veterans and homeless people. Various therapeutic horticulture programs have been used to help people with learning difficulties, asylum seekers, refugees and victims of torture.

Gardening and older people

As populations in the West age, hands-on gardening programs have been used for older people in nursing homes and related facilities.

A systematic review of 22 studies of gardening programs for older adults found that gardening was a powerful health-promoting activity across diverse populations.

One study sought to understand if patients recovering from heart attack might benefit from a horticultural therapy program. It concluded:

[Our] findings indicate that horticultural therapy improves mood state, suggesting that it may be a useful tool in reducing stress. Therefore, to the extent that stress contributes to coronary heart disease, these findings support the role of horticultural therapy as an effective component of cardiac rehabilitation.

Horticulturist and nurse Steven Wells talks about his work at Austin Health.

While the literature on the positive effects of gardening, reflecting both qualitative and quantitative studies, is large, most of these studies are from overseas.

Investment in horticultural therapy programs in Australia is piecemeal. That said, there are some standout success stories such as the Stephanie Alexander Kitchen Garden Foundation and the work of nurse Steven Wells at the Royal Talbot Rehabilitation Centre and beyond.

Finally, without professionally trained horticulturists none of these programs – in Australia or internationally – can take place.

The Conversation

Chris Williams, Lecturer in urban horticulture, University of Melbourne

This article was originally published on The Conversation. Read the original article.

Red Centre Holiday 2016: Day 11 – Watarrka National Park, Northern Territory

Kevin's Walk on the Wild Side

It was a fairly easy day for my last day at Watarrka National Park. All I had left to do was walk the very short Kathleen Springs Walk, which only took about 1 hour to complete. It was a reasonably short drive to this section of Watarrka National Park and the walk itself was also very easy. Still, it was an early start considering just how little I had to do.

Having returned to camp following the walk, I once again had a very early main meal for the day while the campsite was quiet and found that again there was no water for a lengthy period, and once again no communication from site management that the water was being turned off. Eventually I was able to clean up my gear and settle down for a lazy afternoon reading and chatting. I also made sure I had ready everything I…

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A Wonderful Time We Live In

At the BookShelf

What a wonderful time we live in. Sure, there are always things to lament and probably in this day and age there may be more than in any time in the past. Yet there is still much to be excited about and to be thankful for. It may seem incongruous to both lament the current times, while still being excited and thankful for them. That this is a paradox is a given, but I can live inside it without feeling any contradiction. Now this may all seem a little heavy for late on a Saturday night (in Australia it is approaching 11.00 pm at this moment and is sure to be later when I actually upload this post), however I am not really looking for a philosophical debate – far from it. In fact, my purpose is to talk books.

OK, so that seems a rather strange jumping off point…

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Red Centre Holiday 2016: Day 10 – Watarrka National Park, Northern Territory

Kevin's Walk on the Wild Side

It was a fairly straight-forward type of day today. It was an early, short drive to Watarrka National Park from Kings Canyon Resort, where I did the Kings Canyon Rim Walk. The Kings Canyon Rim Walk is a spectacular exploration of the the area above the gorge and also descendsinto the gorge to an area known as ‘The Garden of Eden.’ It is a 6km return walk, with some moderate to difficult sections, especially at the beginning with the climb to the gorge rim. Surprisingly the walk was completed in about 3 hours, even allowing for a bit of sightseeing along the way.

Having completed the walk and once again not being able to use the free wifi point at Watarrka National Park I travelled back to Kings Canyon Resort for a very early main meal (while the resort was fairly quiet) and to spend a relaxing afternoon chatting with…

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Red Centre Holiday 2016: Day 9 – Yulara to Watarrka National Park, Northern Territory

Kevin's Walk on the Wild Side

It was an early start as I headed of for Watarrka National Park, for a morning that was going to be spent driving and then hopefullly setting up my campsite, before heading off for a quick walk at Watarrka National Park. My first stop was at Curtain Springs for a quick top up of the fuel, knowing that fuel was going to be expensive at Kings Canyon Resort. So after that stop it was basically nothing but driving straight to Watarrka National Park and the Kings Canyon Resort.

When I arrived there were no powered campsites available as the place was pretty busy and booked out. It turned out that the Variety Bash was in the area and staying at the resort that night. It was a very crowded scene and somewhat chaotic. I managed to grab a campsite without power, set up and decided to escape to the national…

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Red Centre Holiday 2016: Day 8 – Uluru-Kata Tjuta National Park, Northern Territory

Kevin's Walk on the Wild Side

It was a much later start today, with just some short walks to knock over before a fairly relaxing afternoon. Before I started the walks I stopped at the Uluru Sunset Viewing Area to collect a couple of shots of Uluru.

The first of the two walks for this morning was the Liru Walk. The Liru Walk connects Uluru with the Cultural Centre and can be walked from either location. I started at Uluru because it would also be the starting point for the Mala Walk, the second walk I would be doing this morning. The Liru Walk is a 4 km return walk which is flat and easy, making its way through the low woodland and wildflower covered region between the Rock and the Cultural Centre. It was a visual feast of wildflowers during my visit.

With the Liru Walk completed, I headed off to repeat the Mala Walk…

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