Can Skin Cells Protect Themselves Against Stress?

The skin is our largest organ, and, among other things, it provides protection against mechanical impacts. To ensure this protection, skin cells have to be connected to one another especially closely. Exactly how this mechanical stability is provided on the molecular level was unclear for a long time.

Researchers in the team led by Professor Carsten Grashoff from the Institute of Molecular Cell Biology at the University of Münster and the Max Planck Institute of Biochemistry have been collaborating with colleagues at Ludwig Maximilian University of Munich and Stanford University, and they are now able to demonstrate how mechanical stress on specialized adhesion points, so-called desmosomes, is processed. They designed a mini-measuring device, which can determine forces along individual components of the desmosomes. In the study, published in Nature Communications, they show how mechanical forces propagate along these structures.

Our skin acts as a protective shield against external influences and has to withstand very different stresses. It has to be able to stretch but must not tear when exposed to great strains. To fulfill this mechanical function, skin cells form specialized adhesion points, so-called desmosomes, which strengthen the adhesion between cells. Patients with deficient desmosomes suffer from severe skin disorders, which arise after the exposure to mechanical stress. What was hitherto barely understood, however, was how mechanical forces impact on the individual components of the desmosomes.

The international group of researchers has developed a method for analyzing the molecular forces at these adhesion points. "This technique functions in way that is similar to a miniature spring scale," says Anna-Lena Cost from the Max Planck Institute, who is one of the lead authors of the study. The force sensor consists of two fluorescent dyes, which are connected with an extensible peptide. The peptide acts as a spring, which is stretched by just a few piconewtons, which in turn leads to a change in the dyes' radiance.”

The researchers are able to read this change with a microscope so that mechanical differences at individual binding points can be determined. In their experiments, the researchers discovered that desmosomes are not exposed to any mechanical stress as long as external forces are absent. If cells are pulled - as it frequently happens in the skin - then mechanical stress becomes apparent in the desmosomes. These forms of stress depend on the force magnitude and its orientation. "When there is only a low level of mechanical stress, other structures in the cell can carry the burden. But if a high degree of stress occurs, then desmosomes come to the rescue," Anna-Lena Cost said.

What's On Your Skin?

It turns out your skin is crawling with single-celled microorganisms – ­and they’re not just bacteria. A study by the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) and the Medical University of Graz found that the skin microbiome also contains archaea, a type of extreme-loving microbe, and that the amount of it varies with age. The researchers conducted both genetic and chemical analyses of samples collected from human volunteers ranging in age from one to 75. They found that archaea were most abundant in subjects younger than 12 and older than 60.

Their study was published in Scientific Reports (a Nature journal) in an article titled, “Human age and skin physiology shape diversity and abundance of Archaea on skin.”  “The skin microbiome is usually dominated by bacteria,” said Hoi-Ying Holman, director of the Berkeley Synchrotron Infrared Structural Biology (BSISB) Program and a senior author on the paper. “Most of the scientific attention has been on bacteria, because it’s easier to detect. Based on the literature, six years ago we didn’t even know that archaea existed on human skin. Now we’ve found they’re part of the core microbiome and are an important player on human skin.”

 The study was a joint effort of Holman, Berkeley Lab postdoctoral fellow Giovanni Birarda (now a scientist at Elettra Sincrotrone Trieste in Italy), UC Berkeley postdoctoral fellow Alexander Probst (now associate professor at the University of Duisburg-Essen in Germany), and Christine Moissl-Eichinger, the corresponding author of the study. Moissl-Eichinger and her team at the Medical University of Graz in Austria and at the University of Regensburg in Germany analyzed the genetic features of the skin microbiomes.

In addition to the influence of age, they found that gender was not a factor but that people with dry skin have more archaea. “Archaea might be important for the cleanup process under dry skin conditions,” said Moissl-Eichinger. “The results of our genetic analysis - DNA-based quantitative PCR and next-generation sequencing - together with results obtained from infrared spectroscopy imaging, allowed us to link lower levels of sebum - the oily secretion of sebaceous glands - and thus reduced skin moisture with an increase of archaeal signatures.”

Three Branches Of Life

It was not until the 1970s that scientists realized how different archaea were from bacteria, and they became a separate branch on the tree of life. The three branches being Bacteria, Archaea, and Eukarya, which includes all plants and animals. Archaea are commonly found in extreme environments, such as hot springs and Antarctic ice. Nowadays it is known that archaea exist in sediments and in the Earth’s subsurface as well, but they have only recently been found in the human gut and linked with the human microbiome.

Holman’s focus is on developing synchrotron infrared spectroscopy techniques to look at biological or ecological systems. Using Berkeley Lab’s Advanced Light Source (ALS), one of the world’s brightest sources of infrared beams, the Holman Group developed a rapid and label-free method to screen cells and immediately tell if they’re bacteria or archaea. “The challenges in microbial profiling are speed, throughput, and sample integrity,” she said. “We spent years developing this technique and could not have done it without the unique resources of the ALS.” 

But the dearth of studies on skin archaea is not just because of technical limitations. The researchers assert that the lack of age diversity in the sampling in previous studies was also a factor. “Sampling criteria and methods matter,” Holman said. “We found middle-aged human subjects have less archaea; therefore, the archaeal signatures have been overlooked in other skin microbiome studies.” This study stemmed from a planetary protection project for NASA and the European Space Agency.

 “We were checking spacecraft and their clean rooms for the presence of archaea, as they are suspected to be possible critical contaminants during space exploration – certain methane-producing archaea, the so-called methanogens, could possibly survive on Mars,” Moissl-Eichinger said. “We did not find many signatures from methanogens, but we found loads of Thaumarchaeota, a very different type of archaea that survives with oxygen.”

Clinical Relevance

At first it was thought the Thaumarchaeota were from the outside, but after finding them in hospitals and other clean rooms, the researchers suspected they were from human skin. So they conducted a pilot study of 13 volunteers and found they all had these archaea on their skin. As a follow-up, which is the current study, they tested 51 volunteers and decided to get a large range in ages to test the age-dependency of the archaeal signatures. Samples were taken from the chest area. The variations in archaeal abundance among the age groups were statistically significant and unexpected. “It was surprising,” Holman said. “There’s a five to eightfold difference between middle-aged people and the elderly – that’s a lot.”

Their study focused on Thaumarchaeota, one of the many phyla of archaea, as little evidence of the others was found in the pilot study. “We know that Thaumarchaeota are supposed to be an ammonia-oxidizing microorganism, and ammonia is a major component of sweat, which means they might play a role in nitrogen turnover and skin health,” Holman said. In collaboration with Peter Wolf of the Medical University of Graz, the team also correlated archaeal abundance with skin dryness, as middle-aged persons have higher sebum levels and thus moister skin than the elderly. 

So far, most archaea are known to be beneficial rather than harmful to human health. They may be important for reducing skin pH or keeping it at low levels, and lower pH is associated with lower susceptibility to infections. “The detected archaea are probably involved in nitrogen turnover on skin, and are capable of lowering the skin pH, supporting the suppression of pathogens,” said Moissl-Eichinger. “Bacteria with the same capacities are already used as skin probiotics, potentially improving skin moisture and reducing body odors. Nevertheless, the clinical relevance of Thaumarchaeota remains unclear and awaits further studies.” 

Holman listed several avenues of inquiry for future studies with Moissl-Eichinger. “We would like to investigate the physiological role of human skin archaea and how they differ from environmental archaea,” she said. “We would like to find out which niches they prefer on or in the human body. We also want to know whether they might be involved in pathogenic processes, such as neurodermatitis or psoriasis. So far, there is little evidence of the pathogenicity of archaea.”

Ensuring The Accurate Diagnosis Of Skin Cancer 

The visual inspection of a suspicious skin lesion using the naked eye alone is not enough to ensure the accurate diagnosis of skin cancer, a group of experts concluded following a largescale systematic review of research. The review - published in The Cochrane Library - brings together a large body of research on the accuracy of tests used to diagnose skin cancer. The review was led by Dr. Jac Dinnes at the University of Birmingham and supported by the Cochrane Skin Group and a team of over 30 researchers and expert advisors. The reviews summarize research evidence assessing the accuracy of different diagnostic tests to support clinical and policy-related decision making in the diagnosis of all types of skin cancer.

"Early and accurate detection of all skin cancer types is essential to manage the disease and to improve survival rates in melanoma, especially given the rate of skin cancer world-wide is rising,” Dinnes said. "The visual nature of skin cancer means that it can be detected and treated in many different ways and by a number of different types of specialists, therefore the aim of these reviews is to provide the world's best evidence for how this endemic type of cancer should be identified and treated. We have found that careful consideration should be given of the technologies that could be used to make sure that skin cancers are not missed, at the same time ensuring that inappropriate referrals for specialist assessment and inappropriate excision of benign skin lesions are kept to a minimum."

There are three main forms of skin cancer. Melanoma and cutaneous squamous cell carcinoma (cSCC), are high-risk skin cancers with the potential to spread and cause death. A basal cell carcinoma (BCC) rarely spreads, usually remaining localized with potential to infiltrate and damage surrounding tissue.

Key findings were:

  • Visual inspection using the naked eye alone is not good enough and melanomas may be missed.
  • Smartphone applications used by people with concerns about new or changing moles or other skin lesions have a high chance of missing melanomas.
  • When used by specialists, dermoscopy - a technique using a handheld device to zoom in on a mole and the underlying skin - is better at diagnosing melanoma than visual inspection alone, and may also help in the diagnosis of BCCs.
  • Dermoscopy might also help GPs to correctly identify people with suspicious lesions who need to be seen by a specialist.
  • Dermoscopy is already widely used by dermatologists to diagnose melanoma but its use in primary care has not been widely evaluated therefore more specific research is needed.
  • Checklists to help interpret dermoscopy might improve the accuracy of diagnosis for practitioners with less expertise and training.
  • Teledermatology - remote specialist assessment of skin lesions using dermoscopic images and photographs - is likely to be a good way of helping GPs to decide which skin lesions need to be seen by a skin specialist but future research needs to be better designed.
  • Artificial intelligence techniques, such as computer-assisted diagnosis (CAD), can identify more melanomas than doctors using dermoscopy images. However, CAD systems also produce far more false positive diagnoses than dermoscopy and could lead to considerable increases in unnecessary surgery.
  • Further research is needed on the use of specialist tests such as reflectance confocal microscopy (RCM), which is a non-invasive imaging technique allowing a clinician to do a 'virtual biopsy' of the skin and obtain diagnostic clues while minimizing unnecessary skin biopsies. RCM is not currently widely used in the UK but the evidence suggests that RCM may be better than dermoscopy for the diagnosis of melanoma in lesions that are difficult to diagnose.
  • Other tests such as using high frequency ultrasound have some promise, particularly for the diagnosis of BCCs, but the evidence base is small and more work is needed.

"Completing this broad suite of detailed reviews was a real marathon,” says Cochrane Skin Group founder Professor Hywel Williams, of the Centre of Evidence-Based Dermatology at the University of Nottingham. "Apart from a few exceptions, I was surprised by how poor the overall study designs were, especially in terms of accurately documenting where on the clinical pathway patients were tested. Although some useful conclusions have emerged, for example, on the role of dermoscopy, the greatest value of the research is to serve as a yardstick for designing future studies evaluating skin cancer diagnosis techniques on patients who are typically seen in GP and specialist settings."

Future studies evaluating diagnostic skin cancer tests should recruit patients with suspicious skin lesions at the point on the clinical pathway where the test under evaluation will be used in practice. Further research is also needed to evaluate whether checklists to assist diagnosis by visual inspection alone can improve accuracy and to identify how much accuracy varies according to the level of expertise of the clinician carrying out the assessment. Well-designed studies of dermoscopy in primary care are needed, and the best ways of delivering dermoscopy training need to be identified.

Detecting Skin Cancer Early

Although melanoma is the deadliest form of skin cancer, it’s not the only form of skin cancer that can be deadly. Squamous cell carcinoma, a type of nonmelanoma skin cancer, is not only potentially fatal, but also more common than melanoma. Recent research indicates that SCC incidence has risen by more than 250 percent. “While other skin cancers may be more lethal, they’re less common than SCC,” says board-certified dermatologist M. Laurin Council, MD, FAAD, an assistant professor of dermatology at Washington University in St. Louis. “SCC is highly treatable when detected early, so it’s important for people to know the signs of this disease and keep a close eye on their skin.”

SCC may appear as a pink or white bump; a rough, scaly patch; or a sore that won’t heal. Everyone who notices any suspicious spots on their skin are advised to see a board-certified dermatologist for diagnosis and, if necessary, treatment. “The ABCDE warning signs of melanoma don’t usually apply to SCC, so it’s important to keep an eye out for any and all suspicious spots,” Council says. “Moles are not the only skin lesions that may indicate skin cancer. Any skin growth that is new, changing or won’t go away warrants a visit to the dermatologist.”

The vast majority of SCCs can be successfully treated with surgical or destructive methods. Without treatment, however, the cancer may grow larger, which could lead to disfigurement; in rare cases, SCC may metastasize and spread, making it more difficult to treat. Current treatment options for advanced SCC, which include traditional chemotherapy and radiation, do not have high success rates and may cause negative side effects. She says doctors may be able to provide improved treatment by utilizing targeted therapies, drugs that hone in on patients’ specific tumors, allowing for more effective treatment with fewer side effects.

While these types of medications have not yet received U.S. Food and Drug Administration approval for treatment of cutaneous SCC, they have been approved for treatment of other cancers. “Targeted therapies have shown a lot of promise for SCC patients,” Council says. “A board-certified dermatologist can explain your treatment options and help determine the best possible treatment for you.”

Dermatologists also can identify patients who are at an increased risk for recurrent and advanced SCC and suggest preventive measures. Because unprotected exposure to natural and artificial ultraviolet light is a risk factor for all types of skin cancer, she advises everyone to stay out of tanning beds and protect themselves from the sun’s harmful UV rays. The American Academy of Dermatology recommends a comprehensive sun protection plan that includes seeking shade, wearing protective clothing and using a broad-spectrum, water-resistant sunscreen with an SPF of 30 or higher. “Prevention and early detection are both vital in the fight against skin cancer,” Council says. “Make sure you take steps to protect yourself, watch for changes on your skin, and see a board-certified dermatologist if you notice any suspicious spots.”


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