Mutant stem cells can cause skin cancer at cuts

Cells meant to fix injuries can trigger tumours in cancer-prone mice.

an enhanced scanning electron microscopic image of a stem cell and its processes
Injuries can allow mutated stem cells to trigger the growth of cancers in mice.

Wounds could allow certain types of mutated cell to migrate to the surface of the skin, triggering tumours in people predisposed to cancer, according to a study.

A variety of cancers have been associated with wounds — for instance, battlefield injuries can lead to a type of tumour called Marjolin’s ulcer, and ‘kangri cancer’ afflicts some people from Kashmir at the site of burns caused by personal heaters carried under the clothes. But until now, no one has shown how skin tumours could arise when the skin is damaged by a physical injury.

A study published today in Proceedings of the National Academy of Sciences1 by Sunny Wong and Jeremy Reiter, biochemists at the University of California, San Francisco, suggests that the mechanism could involve the migration of mutated stem cells.

“We know that chronic wounding can contribute to cancer development,” said Anthony Oro, a dermatologist at Stanford University School of Medicine in California. “This work says that if you have a predisposition to getting cancer, wounding might enhance the chance it will develop.”

Wound worries

Wong and Reiter looked at a mouse model for basal cell carcinoma — the most common type of skin cancer. The tumours are thought to be caused by sun damage to the epidermis, the outer layer of skin. But some features of basal cell carcinomas mimic those of the stem cells that mend damage to the skin; for example, the cancers grow slowly and can sometimes differentiate into other types of cells. That has led researchers to speculate that stem cells might contribute to the formation of such cancers.

“This work says that if you have a predisposition to getting cancer, wounding might enhance the chance it will develop.”

To test this, the researchers investigated an oncogene — a gene that, when mutated, can cause cancer — called Smoothened — which is sometimes mutated in people with basal cell carcinomas. They activated a mutated version of the gene in the skin stem cells near hair follicles in mice, but this alone did not cause the rate of cancers to increase. So the team conducted a second experiment, activating the gene and then wounding the mice by punching out a small disc of skin from their backs. This time, the mice developed tumours resembling basal cell carcinomas at the wound sites.

Wong and Reiter found that the stem cells with mutated genes stayed near the follicles, in the lower layers of skin — until the mice were wounded. Once the animals had been cut, the cells migrated to the upper layers of skin to fix the damage, but while there, they disrupted a biochemical signalling pathway that has been linked to basal cell carcinoma development — and thus seeded cancer growth.

What’s more, the cells were able to seed cancers for up to five weeks after the oncogene was activated, and even when the wounds were no more severe than a paper cut.

In fact, Reiter says that when he first found that injuries could trigger cancer, he “started to get worried about shaving”.

Dormant danger

The study suggests that, after DNA in the skin’s stem cells is damaged to create a mutation in an oncogene, the mutated cells might rest for years without causing cancer, and might cause problems only when a wound prompts them to act.

But other researchers say that most basal cell carcinomas do not develop at the sites of injury, so the finding is of limited significance. “This is certainly not a major mechanism underlying basal cell carcinoma formation in humans,” says Sabine Werner, a cell biologist at the Swiss Federal Institute of Technology in Zurich.

But Werner acknowledges that the study does demonstrate a note-worthy principle. “It may well be that mobilization of cells with oncogenic mutations to other sites — in particular to sites with a pro-tumorigenic micro-environment, such as wounds — could trigger tumorigenesis. This is the most interesting finding of this manuscript,” she says.

Reiter says that his paper holds a hopeful message: that the niches in which stem cells are normally found — such as the area surrounding hair follicles in mice — are good at suppressing cancers.

“It’s surprising that activating oncogenes in a stem-cell population doesn’t cause tumours,” he says. “This gives us a glimpse of a way in which our bodies protect us.”

source: nature

Ischemic Stroke Recurrence in Young Adults

A large study of stroke recurrence rates in young-adult patients

Young adults with stroke have different risk factors and etiologies than older stroke patients and, therefore, may have different rates of stroke recurrence. However, epidemiologic data regarding recurrent ischemic events in younger patients have been limited. This study’s aim was to determine recurrence rates and risk factors for ischemic events after a first ischemic stroke. Participants were 807 consecutive patients aged 15 to 49 with a first ischemic stroke treated at one hospital in Finland. The hospital provides exclusive neurological emergency care for 1.5 million people, and few patients were lost to follow-up or declined to participate. Primary endpoints were recurrent ischemic stroke, myocardial infarction, other arterial thrombotic events, and revascularization during 5 years of follow-up.

The 5-year cumulative incidence rate of recurrent stroke was 9%; the rate of the composite outcome of any ischemic event was 12%. Annual recurrence rates for stroke and the composite outcome were highest during the first year after the index stroke. Independent predictors of recurrent stroke included histories of type 1 diabetes, large-artery atherosclerosis, or transient ischemic attack. The risk for recurrent stroke was three times higher in patients with large-artery atherosclerosis by TOAST criteria than in patients with other or undetermined etiologies.

Comment: This study demonstrates that younger stroke patients are at moderate risk for recurrent stroke or other ischemic events and that stroke etiology is important in stratifying recurrence rates. The strengths of the study are its large sample size and well-defined population base, which decreases referral bias in estimating incidence rates. Although the reported 5-year cumulative incidence rate for recurrent stroke in this population is about half that reported in the general stroke population, these findings are clinically important because the lifetime cumulative risk in younger stroke patients may be substantial.

— Christine Fox, MD

Dr. Fox is a Vascular Neurology Fellow, University of California, San Francisco.

Published in Journal Watch Neurology February 15, 2011

A Genetic, Lipid-Independent Contribution to Coronary Artery Disease?

A specific LDLR gene polymorphism was associated with increased factor VIII coagulant activity, possibly leading to atherogenesis.

The low-density lipoprotein receptor (LDLR) regulates plasma levels of LDL cholesterol. Genetic mutations at the LDLR locus are associated with familial hypercholesterolemia and coronary artery disease (CAD). The LDLR also mediates the cellular uptake and degradation of coagulation factor VIII (FVIII). To determine whether three specific LDLR polymorphisms (rs688, rs2228671, and rs1122608) are associated with increased FVIII coagulant activity and CAD, investigators in Italy analyzed data from 692 patients with angiographically confirmed CAD and from 291 controls without CAD.

FVIII levels were higher in CAD patients than in controls (mean, 172 IU/dL vs. 149 IU/dL; P<0.001); this difference persisted after adjustment for traditional CAD risk factors. FVIII levels did not correlate with plasma lipid concentrations.

The mean FVIII level was significantly higher among carriers of the LDLR-rs688 T allele than among CC-homozygotes, and carrying the allele was significantly associated with CAD (multivariable-adjusted odds ratio, 1.48; 95% confidence interval, 1.01–2.16). Carriers of the LDLR-rs2228671 T allele also had a significantly higher mean FVIII level than CC-homozygotes, but this allele was associated with significantly lower LDL cholesterol levels and no higher risk for CAD. Carrying the third T allele, LDLR-rs1122608, was not associated with elevated FVIII levels, and carriers tended to have a favorable lipid profile; a significantly lower risk for CAD associated with this third allele did not persist in the multivariable analysis.

Comment: Elevated FVIII levels have been observed in patients with venous and arterial thrombosis, and this study confirms an association between FVIII elevation and CAD that is independent of lipid levels. FVIII is a potent procoagulant that enhances thrombin generation and fibrin deposition in vulnerable vessels. The observation that a specific polymorphism at the LDLR locus is associated with increased FVIII levels — possibly contributing to atherogenesis by a lipid-independent mechanism — is a novel finding that awaits confirmation.

David Green, MD, PhD

Published in Journal Watch Oncology and Hematology February 15, 2011

electronic contact lenses


A new generation of contact lenses built with tiny circuits and LEDs could make bionic eyesight a reality.

Researchers at the University of Washington in Seattle have created contact lenses with built-in electronics and an LED, powered wirelessly by RF.

“These lenses don’t give us the vision of an eagle or the benefit of running subtitles on our surroundings yet,” University of Washington professor Babak Parviz writes in IEEE Spectrum. “What we’ve done so far barely hints at what will soon be possible with this technology.”

While conventional contact lenses are polymers formed in various shapes to correct faulty vision, electronic contact lenses are far more “engineered.”

Parviz writes:

To turn such a lens into a functional system, we integrate control circuits, communication circuits, and miniature antennas into the lens using custom-built optoelectronic components. Those components will eventually include hundreds of LEDs, which will form images in front of the eye, such as words, charts, and photographs. Much of the hardware is semitransparent so that wearers can navigate their surroundings without crashing into them or becoming disoriented. In all likelihood, a separate, portable device will relay displayable information to the lens’s control circuit, which will operate the optoelectronics in the lens.

The potential for the development is far-reaching, from healthcare (noninvasive health indicators, such as reporting blood sugar levels for diabetic users) to computer gaming, translation to navigation.

Even the Internet is possible, Parviz writes:

“With basic image processing and Internet access, a contact-lens display could unlock whole new worlds of visual information, unfettered by the constraints of a physical display.”

But the initial road is for health purposes, such as the aformentioned biosensors:

Contact lenses are worn daily by more than a hundred million people, and they are one of the only disposable, mass-market products that remain in contact, through fluids, with the interior of the body for an extended period of time. When you get a blood test, your doctor is probably measuring many of the same biomarkers that are found in the live cells on the surface of your eye—and in concentrations that correlate closely with the levels in your bloodstream. An appropriately configured contact lens could monitor cholesterol, sodium, and potassium levels, to name a few potential targets. Coupled with a wireless data transmitter, the lens could relay information to medics or nurses instantly, without needles or laboratory chemistry, and with a much lower chance of mix-ups.

There are still hurdles. First, mass production has proved difficult, since the processes for building individual systems for the electronic contact lens are incompatible — they can’t be manufactured directly on the lens.

Second, all the key components of the lens need to be miniaturized and integrated onto just 1.5 square centimeters of a flexible, transparent polymer.

Finally, the entire device needs to be safe for the eye — difficult, since most red LEDs are made of a toxic material.

The team has produced lenses that can accommodate an 8-by-8 array of LED, but Parviz writes that the team is already looking into using passive pixels, which would significantly reduce power draw.

source: smartplanet