Biologists Find The Cause Of Pain In The Treatment Of Fair Skin Cancer

Pain caused by 2 different mechanisms

Apply the ointment, light on, light off - that's how easy it is to cure various forms of non-melanoma skin cancer. However, the majority of patients suffer severe pain during the so-called photodynamic therapy. Why the treatment with ointment and red light can be so painful has now been uncovered by researchers from the RUB. They identified the ion channels involved and signalling molecules secreted by the cancer cells. "The results may provide a starting point for suppressing the pain", says Dr. Ben Novak of the Department of Animal Physiology.

How the photodynamic therapy works

In contrast to normal cells, cancer cells are equipped with different enzymes and have a much higher metabolism. If you apply a molecule called aminolevulinic acid to the skin in the form of a gel, cancer cells take up considerably more of this substance than healthy cells. If aminolevulinic acid accumulates in the cells, the mitochondria - the power plants of the cells - form the molecule protoporphyrin IX. When irradiated with red light, protoporphyrin IX reacts with oxygen. This produces highly reactive oxygen species, free radicals, which destroy the cancer cells. Approximately ten minutes of red light irradiation is sufficient to successfully treat superficial forms of non-melanoma skin cancers such as actinic keratosis. Doctors also remove warts in this way.

Painful therapy

"The catch is: it's terribly painful", says Ben Novak. Forty percent of those treated experience pain during the light irradiation, which they assess on a scale of 0 to 10 (whereby 10 corresponds to an excruciating pain like a heart attack) as 7 to 8. Using injections, like at the dentist, it is possible to numb the nerves involved. "But that also always involves a risk", says the Bochum biologist. The scientists led by the RUB professor Dr. Hermann Lübbert have now solved the mystery as to why the treatment hurts at all.

Pain-sensitive cells in the skin are stimulated

The pain is generated by two mechanisms. In a cell culture experiment, the team showed that not only cancer cells but also pain-sensitive nerve cells in the skin take up aminolevulinic acid - and its derivative methyl aminolevulinic acid - from the ointment. Using calcium imaging, the animal physiologists followed the activity of nerve cells which they had treated with aminolevulinic acid and cells that were not exposed to the substance. Treated nerve cells fired when the researchers exposed them to light. In a living organism, this would mean that the cells would send a pain stimulus to the brain. Without the aminolevulinic acid, the pain-sensitive cells remained inactive under red light. In further experiments, the scientists showed that the activity of the nerve cells is caused by sodium channels and voltage-gated calcium channels in the cell membrane. "A drug that targets these channels would, conceivably, be able to suppress the pain - but that's still in the future", says Ben Novak.

Tumour cells alert nerve cells

Lübbert's team found that pain is generated in the nerve cells themselves, but also in another way. The affected tumour cells secrete a molecule - namely acetylcholine. "This is how they pass the message to other cells: something is wrong, my mitochondria are collapsing right now", Novak illustrates. Acetylcholine acts as a neurotransmitter in the nervous system, where it is harmless. "Previous studies have shown though, that it is very painful when it is injected into the skin". Some of the results have already been published. The researchers are currently preparing the data on the mechanisms of pain generation for publication. This attracted a great deal of interest at the 12th Congress of the European Society for Photodynamic Therapy in Dermatology (Euro-PDT) in Copenhagen in May 2012.

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Gene Therapy Drugs Topically Delivered Via Commercial Moisturizers For Skin Disease Treatment

"Getting under your skin" takes on a brave new meaning thanks to Northwestern University research that could transform gene regulation.

A team led by a physician-scientist and a chemist - from the fields of dermatology and nanotechnology - is the first to demonstrate the use of commercial moisturizers to deliver gene regulation technology that has great potential for life-saving therapies for skin cancers.

The topical delivery of gene regulation technology to cells deep in the skin is extremely difficult because of the formidable defenses skin provides for the body. The Northwestern approach takes advantage of drugs consisting of novel spherical arrangements of nucleic acids. These structures, each about 1,000 times smaller than the diameter of a human hair, have the unique ability to recruit and bind to natural proteins that allow them to traverse the skin and enter cells.

Applied directly to the skin, the drug penetrates all of the skin's layers and can selectively target disease-causing genes while sparing normal genes. Once in cells, the drug simply flips the switch of the troublesome genes to "off."

A detailed study of a method that could dramatically redefine the field of gene regulation will be published online during the week of July 2 by the Proceedings of the National Academy of Sciences (PNAS).

Early targets of the novel treatment are melanoma and squamous cell carcinoma (two of the most common types of skin cancer), the common inflammatory skin disorder psoriasis, diabetic wound healing and a rare genetic skin disorder that has no effective treatment (epidermolytic ichthyosis). Other targets could even include wrinkles that come with aging skin.

"The technology developed by my collaborator Chad Mirkin and his lab is incredibly exciting because it can break through the skin barrier," said co-senior author Amy S. Paller, M.D., the Walter J. Hamlin Professor, chair of dermatology and professor of pediatrics at Northwestern University Feinberg School of Medicine. She also is director of Northwestern's Skin Disease Research Center.

"This allows us to treat a skin problem precisely where it is manifesting - on the skin," she said. "We can target our therapy to the drivers of disease, at a level so minute that it can distinguish mutant genes from normal genes. Risks are minimized, and side effects have not been seen to date in our human skin and mouse models."

A co-senior author of the paper, Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences and professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering. He also is the director of Northwestern's International Institute for Nanotechnology.

Mirkin first developed the nanostructure platform used in this study in 1996 at Northwestern, and the FDA-cleared technology now is the basis of powerful commercialized medical diagnostic tools. This, however, is the first realization that the nanostructures naturally enter skin and that they can deliver a large payload of therapeutics.

"The field of medicine needs new constructs and strategies for treating disease," Mirkin said. "Many of the ways we treat disease are based on old methods and materials. Nanotechnology offers the ability to very rapidly create new structures with properties that are very different from conventional forms of matter. This collaborative study is a case in point."

The key is the nanostructure's spherical shape and nucleic acid density. Normal (linear) nucleic acids cannot get into cells, but these spherical nucleic acids can. Small interfering RNA (siRNA) surrounds a gold nanoparticle like a shell; the nucleic acids are highly oriented, densely packed and form a tiny sphere. The RNA's sequence is programmed to target the disease-causing gene.

"We now can go after a whole new set of diseases," Mirkin said. "Thanks to the Human Genome Project and all of the genomics research over the last two decades, we have an enormous number of known targets. And we can use the same tool for each, the spherical nucleic acid. We simply change the sequence to match the target gene. That's the power of gene regulation technology."

The nanostructures were developed in Mirkin's lab on the Evanston campus and then combined with a commercial moisturizer. Next, down in Paller's Chicago lab, the researchers applied the therapeutic ointment to the skin of mice and to human epidermis. The nanostructures were designed to target epidermal growth factor receptor (EGFR), a biomarker associated with a number of cancers.

In both cases, the drug broke through the epidermal layer and penetrated the skin very deeply, with cells taking up 100 percent of the nanostructures. They selectively knocked down the EGFR gene, decreasing the production of the problem proteins.

After a month of continued application of the ointment, there was no evidence of side effects, inappropriate triggering of the immune system or accumulation of the particles in organs. The treatment is skin specific and doesn't interfere with other cells.

Interdisciplinary research is a hallmark of Northwestern. Paller and Mirkin said their work highlights the power of physician-scientists and scientists and engineers from other fields coming together to address a difficult medical problem.

"This all happened because of our world-class presence in both cancer nanotechnology and skin disease research," Paller said. "In putting together the Skin Disease Research Center proposal, I reached out to Chad to see if his nanostructures might be applied to skin disease. We initially worked together through a pilot project of the center, and now the rest is history."

Northwestern has one of nine Centers of Cancer Nanotechnology Excellence funded by the National Cancer Institute and one of six Skin Disease Research Centers funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

"This study is a landmark achievement in the area of gene regulation - I believe our work has a chance to positively and irreversibly change the field," Mirkin said. "The skin is a very tough barrier to go through, which is why this effective gene knockdown has not been accomplished before. The power and elegance of this system are in its simplicity."

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Treatment Of Tumors Based On Differentiation Therapies, A Novel Strategy For The Treatment Of An Aggressive Type Of Skin Cancer

Skin squamous cell carcinoma (SCC) is a subtype of very aggressive skin cancers that usually develops in sunexposed body regions, but can also affect a large number of organs such as the bladder, esophagus, lungs etc. However, little is known about the biology of these cells, which consequently makes difficult the generation of new specific therapies; actually, the standard treatments are based on surgery and subsequent radiotherapy.

Researchers at the Spanish National Cancer Research Centre (CNIO) led by Erwin Wagner, vice-director of Basic Research and director of BBVA Foundation-CNIO Cancer Cell Biology Programme, have discovered a molecular mechanism that favours the disappearance and inhibition of SCC development. The authors propose that these mechanisms could be crucial for the development of targeted therapies that could potentially overcome drug resistance.

The study, which also involves the participation of medical researchers at the Medical University of Vienna, Austria, is published in the online edition of The Journal of Clinical Investigation.

"The guardian of the genome" p53, decreases cell division in favour of cell differentiation

Using in vitro models, mouse genetic models and human tumors, researchers have uncovered the molecular signals by which the p53 protein, also called "the guardian of the genome", prevents the formation of skin SCC tumors.

"We demonstrate for the first time that p53 promotes differentiation

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