This chapter provides a brief account of the cell biology of skin with particular relevance to skin cancer. I would suggest watching the two videos first, before reading the text.
This chapter in one minute
An introduction to skin biology (13 minutes)
A quick primer of skin anatomy
With the index finger and the thumb of your left hand pinch a fold of skin on the lower inner forearm of your right arm. If you are careful, you can roll your finger and thumb such that the underlying fat (subcutis) is not included. If you measure this fold of skin with some callipers, it will measure close to 2-2.5mm. This fold is of course twice the thickness of a single layer of skin so, at this anatomical site, skin measures around 1.25mm thick.
As the schematic above shows, two anatomical components contribute to this single layer of skin at this site. The epidermis is the outermost layer, and is very thin but highly cellular, measuring around 50-100 microns (i.e. 50/1000 of one mm), extending as far as the basement membrane. Underneath the epidermis, and separated from it by the basement membrane, is the dermis which comprises the remaining bulk of the skin thickness (~1.25mm). Skin cancer is almost entirely a disease of the outer 50-100 micron epidermis.
Note, that the schematic above is highly stylised (like most skin images in books). In reality, most of the volume of the skin is taken up by the dermis. The image below shows a histological section through normal skin. The blue arrow shows the contribution of the dermis. The epidermis is shown as the outer darker layer (black arrow).
The epidermis sits on, and is separated from the dermis, by the acellular basement membrane. Most cells within the epidermis are either:
- Keratinocytes: Most (>90%) of the cells in the epidermis are keratinocytes, ectodermal derived cells, so named because they produce a range of proteins called keratins. Most common skin cancers are derived from keratinocytes
- Melanocytes: neural crest derived cells that produce melanin. Melanin protects against most types of skin cancer by reducing the harmful effects of ultraviolet radiation (UVR). Malignancy of melanocytes is known as melanoma (or malignant melanoma). Most fatal skin cancers are melanomas. Melanin and melanocytes are dealt with at length in the chapter on pigmentation.
- Langerhans’ cells: These are bone marrow derived antigen presenting cells. The immune system is important in skin carcinogenesis, although the exact contribution Langerhans’ cells make to this process is not clear. As we shall see later, some patients with grossly impaired immune systems have higher rates of skin cancer. An image of epidermal Langerhans’ cells is shown below.
The epidermis is a stratified squamous epithelium
The epidermis is a stratified squamous epithelium. Stratified, because it contains multiple layers and squamous, reflecting that most of the cells are wider than they are tall. It comprises the following layers (moving from deep to superficial):
- Basal layer (aka stratum basale)
- Spindle cell layer (aka prickle cell layer, or stratum spinosum)
- Granular cell layer (aka stratum granulosum)
- Stratum corneum (horny cell layer)
Basal cells are cuboidal keratinocytes that sit on the basement membrane that separates the epidermis from the dermis. The basal cell layer is only cell layer thick. Stem cells located in the basal layer undergo asymmetrical cell division, with one daughter cell being another stem cell, and the other a transient amplifying cell. Transient amplifying cells can undergo several rounds of division before they lose their ability to divide and differentiate into terminally differentiated keratinocytes. This stem cell pool is interfollicular, that is, it is located in the epidermis that lies between hair follicles.
There are two pools of keratinocyte stem cells in skin. The first has been discussed above (interfollicular stem cell pool). There is believed to be a secondary stem cell pool situated in the hair follicle close to where the sebaceous glands joins the follicle. These two pools are independent, but if the pool situated in the interfollicular skin is removed or damaged, stem cells from the hair follicle can repopulate the interfollicular stem cell pool. This seems to apply to both keratinocytes and melanocytes (i.e. there is also a melanocyte stem cell pool in the follicle).
The spindle cell layer is so named because of the spindle shape of the cells. It is also known as the prickle cell layer because the tight desmosomal attachments between cells tend to resemble spines, or prickles, under the microscope, after fixation (histopathological fixation shrinks tissues, so the cells pull away from each other, except where the desmosomes ‘stick’ them together). This spindle cell layer forms the bulk of the thickness of the epidermis, and has multiple layers (>4).
The layer above the spindle cell layer is called the granular cell layer (stratum granulosum). This is the outermost viable layer of skin that contains keratinocytes with nuclei. In this layer, a variety of granules made up of a range of protein products (e.g. keratins, profilaggrin, loricrin) form, as well as lamellar lipids. These products replace the plasma membrane with what is termed the cornified envelope, a composite of these covalently cross-linked proteins. Outside the cornified envelope, is the cornified lipid envelope.
The cells outermost to the granular cell layer, that have lost their nuclei and other cell organelles as a result of programmed cell death and have a cornified envelope, are known as corneocytes. These corneocytes make up the stratum corneum (horny cell layer). This is the outermost layer of skin, the layer you can see and feel, and is made up of a variable number of dead layers of keratinocytes. Although dead, the stratum corneum is not metabolically inert and, as we shall see, this layer plays an important role in the response of skin to ultraviolet radiation (UVR).
The basement membrane and the dermis
Most skin cancers are derived from cells within the epidermis, and whereas the dermis makes up the physical bulk of skin, and may play important roles in carcinogenesis, we can get by without delving any further into its biology for present purposes. Similarly, I have not discussed the formation of the epidermal appendages such as the eccrine sweat glands, sebaceous glands, or hair follicles. (see image below, with the white arrow pointing to the epidermis).
Knowledge of the skin appendages is not central to our understanding of most skin cancers, and where they are relevant they will be dealt with later in skincancer909. If you want to read further, ed.derm.101 and the accompanying videos provide more detail.
Questions: Skin Structure
- Name the four cell layers of the epidermis?
- What are the embryological origins of keratinocytes and melanocytes?
- What is the layer of anucleate cells called?
- What gives spindle cells their ‘prickles’?
- Where do you find keratinocyte stem cells?
- What is the cornified envelope?
- Which is thicker, the epidermis or the dermis?
- Which are more common: cancers derived from the epidermis or the dermis?
- Which layer within the epidermis is one cell thick?
- What compartment contributes most cells to skin: the epidermis or the dermis?
A PDF containing the above questions and the answers is here. The video talkover below goes through the questions and answers in greater depth: I talk around the answers providing a little perspective.
Skincancer909 by Jonathan Rees is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Where different rights apply for any figures, this is indicated in the text.