Some of the most deadly skin cancers may start in stem cells that lend color to hair, and originate in hair follicles rather than in skin layers, a new study finds.
Hair follicles are complex organs that reside within skin layers.
It is there that immature pigment-making cells develop cancer-causing genetic changes – and in a second step – are exposed to normal hair growth signals, say the study authors.
Past models of the disease had argued that sunlight (e.g., ultraviolet radiation) was a major risk factor for melanoma – but current work argues that the triggers are always there in normal follicles.
The new study, published online November 4 in Nature Communications, found that unlike their normal counterparts, newly cancerous pigment stem cells then migrate up and out of the follicles to establish melanomas in nearby surface skin before spreading deeper.
The study was conducted in genetically engineered mice, with the results confirmed in human tissue samples.
“By confirming that oncogenic pigment cells in hair follicles are a bona fide source of melanoma, we have a better understanding of this cancer’s biology and new ideas about how to counter it,” says corresponding study author Mayumi Ito Suzuki, Ph.D., associate professor in the Ronald O. Perelman Department of Dermatology at NYU School of Medicine and Perlmutter Cancer Center.
Invisible Trail Revealed
The study results reflect development, in which a human starts as a single stem cell, the embryo, and becomes a fetus made up of hundreds of cell types.
Along the way, stem cells divide, multiply and specialize, until, finally, they become cells capable of playing a single role (e.g., nerves, skin, etc.).
Complicating matters, stem cells can become more than one cell type, and can shift between them.
This flexibility is useful during development, but can be dangerous in adults, in whom cancer cells are thought to re-acquire aspects of early embryonic cells.
Because of this malleability, researchers have theorized that melanomas might arise from several stem cell types, making them hard to treat and their origins difficult to track.
The new study addresses the stem cells that mature into melanocytes, cells that make the protein pigment melanin, which protects skin by absorbing some of the sun’s ultraviolet, DNA-damaging rays.
By absorbing some wavelengths of visible light, but reflecting others, pigments “create” hair color.
In a series of elegant steps, the research team established a new mouse model for the study of melanoma, one engineered such that the team could edit genes in follicular melanocyte stem cells only (the c-Kit-CreER mouse).
This capability enabled researchers to introduce genetic changes that made only melanoctye stem cells—and their descendants destined to form melanomas—glow no matter where they traveled.
Able to accurately track a key stem cell type for the first time, the authors confirmed that melanoma cells can arise from melanocyte stem cells, which abnormally migrate up and out of hair follicles to enter the epidermis, the outermost layer of skin.
The team then tracked the same cells as they multiplied there, and then moved deeper into the skin layer called the dermis.
Once there, the cells shed the markers and pigment that went with their follicular origins, presumably in response to local signals.
They also acquired signatures similar to nerve cells (neurons) and skin cells (mesenchymal), molecular characteristics “almost exactly like” those noted in examinations of human melanoma tissue.
Knowing where to look for the original, cancer-causing event, the researchers temporarily eliminated signals one by one in the follicular environment to see if cancer still formed in their absences.
In this way, the team confirmed that follicular melanocyte stem cells, even though they had cancer-causing genetic mutations, did not multiply or migrate to cause melanomas unless also exposed to endothelin (EDN) and WNT.
These signaling proteins normally cause hairs to become longer and pigment cells to multiply in follicles.
“Our mouse model is the first to demonstrate that follicular oncogenic melanocyte stem cells can establish melanomas, which promises to make it useful in identifying new diagnostics and treatments for melanoma,” says first study author Qi Sun, Ph.D., a postdoctoral fellow in Ito’s lab.
“While our findings will require confirmation in further human testing, they argue that melanoma can arise in pigment stem cells originating both in follicles and in skin layers, such that some melanomas have multiple stem cells of origin.”
Skin cancer is the most common malignancy in the world, affecting men and women of every skin color [1].
The incidence of cancers of all kinds is increasing; among newly diagnosed cancers, one in three is a skin cancer [2] (Figure 1).
Individuals in white- or light-skinned populations bear the brunt of skin cancer; the most common cancers in these populations are melanoma and non-melanoma skin cancer (including squamous cell carcinoma, basal cell carcinoma, Bowen’s disease, keratoacanthoma, and actinic keratosis).
Huge amounts of time and money are spent on research worldwide in an effort to address cancer; as a result, the associated mortality rates are stable and possibly decreasing [3]. That said, the World Health Organization still estimates that, each year, between 2 and 3 million non-melanoma skin cancers and ~132,000 melanomas occur globally [4].
The progression and general characteristics of melanomas are far more severe than those of non-melanoma skin cancers; the incidence of the latter varies widely, with the highest rates reported in Australia [5] and the lowest rates in parts of Africa [6].
This pattern results from both skin color and exposure to sunlight in these areas. With an incidence of ~80%, basal cell carcinomas comprise the bulk of non-melanoma skin cancers [7].
Basal cell and squamous cell skin cancers are easier to treat and grow more slowly than melanomas, which is good, as they occur more often. On the other hand, melanoma, which is highly metastatic, drug-resistant, and aggressive, is responsible for 75% of all deaths from skin cancer, even though it comprises only 5–10% of the cases diagnosed.
The burden imposed by melanoma is borne primarily by Australasian, North American, and European populations, as well as individuals from all populations who are elderly and/or male [8].
Incidence of different types of skin cancer.
Two unusual skin cancers are Merkel cell carcinoma and dermatofibrosarcoma protuberans, both of which occur rarely. While the incidence of Merkel cell carcinoma is ~4.5- to 5.5-fold lower than that of melanoma, it is particularly aggressive and metastasizes at an early stage. Within 2 years of diagnosis, it has a relative mortality of approximately 30%, which reaches 50% within 5 years of diagnosis [9].
Merkel cell carcinoma is the second leading cause of skin cancer death after melanoma, even though it is responsible for less than 1% of malignant tumors of the skin [10]. Dermatofibrosarcoma protuberans, which occurs ~1.3–7.5 times less often than even Merkel cell carcinoma, rarely metastasizes [11] and in general has a much better prognosis. Unfortunately, without early detection and treatment, this invasive cancer can insert itself deeply into a variety of tissues, including fat, muscle, and even bone.
A simple Google search for ‘melanoma’ (>34,300,000 results) demonstrates the importance of this cancer to human populations, as does the related search for ‘life expectancy’ (>34,400,000 results). One of the main goals of this review is to help increase the life expectancy of patients with skin cancer, resulting in causing the number of results for Google searches for ‘melanoma’ to plummet, as happened for ‘smallpox’ (>8,340,000 results), which was declared eradicated in 1980 [12].
Skin: Where One-Third of New Cancers Are Born
Skin, the human body’s largest organ, is complex. An adult has between 1.5 and 2 square meters of skin, responsible for about 15–17% of total body mass. In the skin, there are several distinct types of tissue organized by cell type into four primary layers. The stratum corneum, which forms a barrier against the environment, consists of dead keratinized cells. The subcutaneous tissue (subcutis) contains fibroblasts, adipose cells, and macrophages. The epidermis and dermis are both made up of epithelial, mesenchymal, glandular, and neurovascular components. As the outermost layer of skin, the epidermis, of ectodermal origin, is the body’s first point of contact with bacteria, viruses, chemicals, radiation, and humidity. The particular characteristics of the epidermis, both biological and physical, determine how it responds to and resists stressful environmental factors such as infectious pathogens, harmful chemicals, and UV light [13,14,15,16,17]. Constantly exposed to UV radiation from sunlight and other sources, the epidermis is highly susceptible to DNA damage. UVB radiation (280–315 nm), which makes up less than 2% of the UV rays in sunlight, is considered the major environmental cause of skin cancer. UVB is involved in both tumor initiation and promotion [18]. UVB completely penetrates the epidermis (0.03–0.13 mm thick) and is able to penetrate slightly below it into the dermis (1.1 mm thick). When this happens, the caused damage allows this area to become the focal point of a new cancer.
Malignant melanoma is the deadliest form of skin cancer. Over the last few decades, the incidence of this cancer, which is prone to metastasis and often difficult to treat, has increased steadily and significantly [19], so much so that globally, melanoma cases are increasing faster than those of any other cancer. Unlike cells that give rise to squamous cell and basal cell carcinomas, it is unknown where melanoma cells originate. There are several theories: dedifferentiated melanocytes may give rise to the precursors of melanoma, or these cells may develop from melanocyte progenitors in the bulge region of hair follicles or from Schwann cell precursors that derive from the neural crest [20,21,22,23]. On the other hand, squamous cell carcinoma is known to originate in the basal cell layer of the epidermis from progenitor/stem cells. While both squamous cell carcinoma and melanoma frequently metastasize, basal cell carcinoma does not [21,22]. The origins of basal cell carcinoma (the most common malignant skin cancer worldwide) are harder to pin down. It has been proposed that they develop either from cells in the bulge region of the hair follicle (an area rich in keratinocyte stem cells) or, like squamous cell carcinoma, in the basal cell layer of the epidermis from progenitor/stem cells [24]. Controversy surrounds the exact cellular origin of basal cell carcinoma. Evidence from studies points strongly at an origin in the stem cells within hair follicles and mechanosensory niches [25].
Determining the identity of cancer cells in solid tumors has always been a challenge and remains so even now [26]. Fortunately, this is not the case with skin cancer. Indeed, as an organ, the skin lends itself to experimental investigation; it is much more accessible than the internal organs and is constructed of well-defined cellular compartments. In addition, genetically engineered mouse models that mimic the progression of melanocytic and epithelial skin cancers in humans have now been developed. This is important because we need a starting point from which to begin our assault on these aggressive cancers. For example, dermatofibrosarcoma protuberans, one of the unusual skin cancers mentioned previously, is known to be a mesenchymal tumor that originates in fibroblasts [27]. It is the most common of all the dermal sarcomas [28], usually affecting the dermis and subcutaneous tissue. Even though it is unusual, knowing the tissues that give rise to it and nourish it provide us with vital information about how to defeat it. Since the precise origins of some cancers remain elusive, there is still room for new and sometimes unexpected discoveries [29]. The origin of another unusual cancer, Merkel cell carcinoma, has been strongly linked to the Merkel cell polyomavirus. In a large number of cases (>80%), this cancer has been found to occur concomitantly with Merkel cell polyomavirus, a member of the normal human viral flora [30]. While it is most commonly believed that Merkel cell carcinoma derives from cutaneous Merkel cells or from some common precursor, its true origin is still a matter of debate [31,32,33] (Figure 2).
The origins of various types of skin cancer. 1—Merkel cell (Merkel cell carcinoma); 2—melanocytes (melanoma); 3—basal cells (basal cell carcinoma and squamous cell carcinoma); 4—keratinocytes (basal cell carcinoma); 5—fibroblasts (dermatofibrosarcoma protuberans).
Ultraviolet Light Illuminates the Path of Skin Cancer
We tend to think of sunlight as visible light from the sun; white light made up of the different wavelengths of light that, with a prism, we can separate into a rainbow. However, solar radiation is the combination of this visible light and ultraviolet radiation (UVR), which comprises different wavelengths classified into three groups. The shortest and most dangerous wavelengths, <295 nm, are classified as UVC. Fortunately, the majority of UVC radiation is absorbed by the atmosphere before it reaches the Earth’s surface and our skin. Solar UVR, the radiation that does penetrate the atmosphere and reach the surface, has wavelengths >295 nm and is classified as UVA and UVB. While UVB (280–315 nm) represents only 5% of solar radiation, it is much more effective than UVA at damaging DNA. It causes cancer and sunburn in both humans and other animals, even though it only penetrates the upper layers of the skin. UVA radiation (315–400 nm), which represents 95% of solar radiation, penetrates deeper into the tissues. For the most part, it was believed that UVA caused little harm other than wrinkles and the cosmetically distressing signs of ageing of the skin. However, in epidemiological studies, it is difficult to separate the effects caused by UVB, UVA, and visible light. Therefore, these wavelengths are typically grouped together and treated as a unit [34]. Generally, UVR is an important risk factor for all skin cancers and is considered as a ‘complete carcinogen’ because it causes both general (nonspecific) skin damage and mutations and functions both as an initiator and as a promoter of tumors [35]. UVR is responsible for damage to the DNA (where it causes cyclobutane pyrimidine dimers to form) and gene mutations, including mutations to the p53 tumor suppressor genes involved in DNA repair and/or in the apoptosis of cells disabled by extensive DNA damage. By inducing the immunosuppressive cytokines interleukin-1 and tumor necrosis factor-alpha (TNF-α), UVR increases the levels of oxidative stress and related inflammatory responses. All of these negative effects play an important role in the photoaging of the skin and greatly increase the likelihood of initiation of skin cancer [36,37,38].
The amount of UVR that actually reaches the Earth’s surface is affected by many factors, including ozone depletion, UV light elevation, latitude, altitude, and weather conditions [39]. South America receives the greatest amount of ultraviolet radiation, particularly in the Peruvian Andes and throughout the west–central Altiplano region [40]. The following countries/cities have the highest UV levels: Australia (Darwin), Brazil (Rio de Janeiro), Cuba (Havana), Kenya (Nairobi), Madagascar (Tananarive), Mozambique (Maputo), Panama (Panama), Singapore (Singapore), Sri Lanka (Colombo), Thailand (Bangkok), and Vietnam (Hanoi) [41]. In 1992, Canada introduced the use of the UV Index (which ranges from 0 to 11+) as a way to address growing concerns about ozone depletion and how this might increase ultraviolet (UV) radiation. For example, between March and September, the UV Index in Vancouver (Canada) can be 3 or higher. When the UV Index is 3 or higher, the skin should be protected as much as possible [41]. It has been estimated that UV exposure, and thus a high UV Index, is one of the primary causes of 65% of melanomas and 90% of non-melanoma skin cancers [42]. Artificial UV rays are as dangerous as their natural counterparts; cosmetic tanning using indoor UVR predisposes its practitioners to skin cancer [39]. The soaring popularity of outdoor activities, in addition to indoor tanning devices, as well as the rapid depletion of the ozone layer, have all contributed to increased UVR exposure [43]. At the same time, it is important to remember there are significant positive effects that moderate doses of ultraviolet light contribute to all living creatures on the Earth, including humans. One of the best known and most positive effects of human exposure to both solar and artificial radiation is UVB-induced production of vitamin D in the skin. Vitamin D deficiency (≤20 ng/mL) is associated with increased incidence and worse prognosis of various types of cancer, including melanoma [44]. Successful treatments for several human skin diseases, such as psoriasis, vitiligo, atopic dermatitis, and localized scleroderma, include solar radiation (heliotherapy) or artificial UV radiation (phototherapy). UV also generates nitric oxide (NO), which research has shown may reduce blood pressure and generally improve cardiovascular health [45].
Different patterns of UV exposure, as well as different intracellular molecular pathways, affect the development of melanomas versus non-melanoma cancers. Squamous cell carcinoma can occur in the absence of UVR exposure; its occurrence has also been associated with scarring, nonhealing wounds, or chronic lesions caused by active or previous chronic immuno-inflammatory processes. This is not the case with basal cell carcinoma or melanoma [46]. However, when it comes to certain humans, these cancers are in agreement: squamous cell carcinoma, basal cell carcinoma, and melanoma all more frequently affect those who are elderly, red-haired, blue-eyed, and fair-complexioned [47]. Over the last few hundred years, European colonization and the emigration caused by wars and political unrest have led to humans with these vulnerable phenotypes moving to the areas with some of the highest rates of UV radiation exposure. Studies of the occurrence of melanoma across the South American continent have shown a strong correlation between white-skinned European ancestry and the risk of melanoma [48]. An increased risk of these malignancies has consistently been linked with variants of the melanocortin 1 receptor (MC1R) gene [49]. The MC1R, a melanocytic G protein-coupled receptor, has been shown to regulate skin pigmentation and the response to UV radiation, two factors heavily involved with the risk of melanoma. It is a highly polymorphic gene, frequently found in fair, UV-sensitive individuals (such as those described above) who are prone to melanoma as the result of defective epidermal melanization and the suboptimal DNA repair that occurs when the gene becomes dysfunctional. This is important because MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin [50]. This protects the skin against UV damage in two different ways. First, MC1R signaling increases the production and accumulation of eumelanin in the epidermis by inducing increased synthesis of melanocytic pigments. The resulting epidermal melanization blocks skin penetration by UV rays. When UV radiation cannot enter, the risks of superficial skin damage, mutagenesis, and the development of cancer are lessened. Second, MC1R signaling makes melanocytes more resistant to UV radiation by ramping up nucleotide excision DNA repair and oxidative resistance. The melanocyte stimulating hormone (MSH)–MC1R signaling axis plays a key role in determining both the type and the amount of melanin produced by melanocytes. As such, it represents a critical UV protective mechanism innate to the skin [35,50].
Exposure to UV radiation is one of the risk factors linked to the immunosuppression associated with Merkel cell carcinoma [51]. The mRNA transcript of Merkel cell polyomavirus (strongly linked to Merkel cell carcinoma) small t antigen had a dose-dependent increase after UV radiation (in the form of solar-simulated radiation) [52]. Moreover, Merkel cell carcinomas that are not associated with Merkel cell polyomavirus develop directly from UV-associated mutations [53]. There is a greatly increased incidence of Merkel cell carcinoma among fair-skinned individuals compared to its incidence in those with darker skin [54]. The lesions are most likely to develop on areas of the skin most frequently exposed to the sun, such as the head, scalp, neck, ears, and arms [55,56]. Unlike so many of the other skin cancers, the literature confirms that dermatofibrosarcoma protuberans is the only one without any obvious direct link to UV radiation. This unusual skin cancer tends to form lesions on the trunk (shoulders, chest, abdomen, back, buttocks), an area of the body not exposed to the sun with the same relentless frequency as the head and arms (Figure 3). It is also imperative to mention the important role of immunosupression in favouring the development of squamous cell carcinoma, which is extremely frequent in organ transplant recipients and represents a major cause of morbidity after organ transplantation [57]. Moreover, the role of certain viruses in promoting non-melanoma skin cancer is shown. The basis of such theory is represented by the genodermatosis epidermodisplasia verruciformis (EV), in which pathogenetic factors such as infection by beta human papillomaviruses as well as sun exposure are considered responsible for the malignant transformation of EV lesions to skin cancer within decades [58].
The effect of UV radiation on skin cells.
Journal information: Nature Communications
Provided by NYU Langone Health
