The skin is the
largest organ in the body. It protects the body against physical injuries,
temperature regulation, sunlight, infection, stores water, fat, and plays a key
role in metabolism including vitamin D, among other functions. The skin
consists of three main layers, epidermis (upper or outer layer), dermis (lower
or inner layer) and subcutaneous tissue.


Skin cancer begins in
the epidermis, which is made up of three kinds of cells: keratinocytes, Melanocytes & Langerhans cells. Keratinocyte cells are found in the deepest
basal layer of the stratified epithelium that comprises the epidermis. They are in charge of producing the protein keratin
and making the skin waterproof and tough. Keratins form the cytoskeleton of
keratinocytes and are what makes up our hair and nails. So, if defects occur in
keratin expression, it would result in numerous diseases of the epidermis, hair
and nails. As they mature, divide and differentiate, they lose water, flatten
and move to the uppermost layer of the epidermis, the stratum corneum, which
mainly accumulates dead keratinocytes, keratins and lipids. This is the tough
outer layer of the skin. The skin completely
renews itself every 3-5 weeks replacing the accumulated dead keratinocytes by
other ones. Keratinocytes also play an immune system role as inmunomodulators,
activating Langerhans cells in response to injury, preventing unwanted
substances from penetrating the skin and secreting inhibitory cytokines in the
absence of injury. Other significant cells in the epidermis are melanocytes,
cells that produce melanin, the pigment responsible for skin tone and color and
found in the lower part of the epidermis.


Dermis is undoubtedly the
layer most important for skin maintenance and hair follicle. It contains cells
for the immune system, collagen, elastin, fibronectin which maintains it soft
and stretchy and proteins that allow water absorbance for keeping the skin
hydrated and with a good texture. The dermis also contains capillaries (tiny
blood vessels) and lymph nodes (depots of immune cells) the blood vessels carry
oxygen and nutrients and lymph nodes for protecting it from microorganisms
Dermis receives blood and distributes it to the epidermis, regulates
temperature, wound and removes toxins.


Subcutaneous tissue is the innermost
layer of the skin located under the dermis consisting of connective tissue and
fat molecules. It connects, along with the connective tissue, the dermis with
the muscles and bones.

It also helps the
dermis function by providing support to the blood vessels, lymphatic vessels,
nerves, and gland caps that pass through it to reach the dermis. Subcutaneous
fat acts as a shock absorber and heat insulator protecting underlying tissues
from cold and mechanical trauma.


Cutaneous squamous cell carcinomas
(SCCs) are the second most common and potentially
deadly human cancers. A
significant lifetime ultraviolet radiation exposure is the principal
determinant of squamous cell carcinoma (SCC) and the disease appears most
frequently in the areas more exposed by natural or artificial sunlight, head
and neck among others, such as the edges of the ears, lips, face and scalp.

Ultraviolet radiation produces mutations in DNA, usually the formation of
thymidine dimers in the p53 tumor-suppressor gene. Failure to repair these
mutations may result in tumor formation. The solar exposure that a person
receives throughout his life becomes a cumulative damage that can lead to SCCs;
the older, the higher the incidence. Chronic skin ulceration and an
immunosuppressed state are also predisposing factors for this malignant
disease. These facts seem to be related by favoring the spread of atypical
keratinocytes through the epidermis and its subsequent dermal invasion.


These solid tumors are complex structures composed of
multiple cell types in unique microenvironments. Actively proliferating cancer
cells in SCCs reside in the basal layer of the tumor propagating cancer cells
(TPCs), which is located along the tumor stroma interface. In Squamous cell
Carcinoma, cells tumor propagating cells are located in the basal layer, in
contact with the stroma. In adult skin, stem cells are located in two different
compartments, one in the inter-follicullar epidermis (Epi) and the second one
in the bulge from the hair follicle (Hair follicle stem cells; HFSC), which are
the most prominent cell population in skin epithelium. TPCs can self-renew to sustain their own identity and differentiate into post-mitotic progeny without tumor propagating
potential. Differential
gene expression
analyses uncovered
a transcriptional signature,
which distinguishes
TPCs from normal, adult skin epithelial
stem and progenitor cells.


Here is where we identify the Oxidative Stress
Response as one of the most significantly up-regulated Gene Ontology categories
in TPCs. This stress response is triggered by reactive oxygen species (ROS).

ROS species are normal byproducts generated through metabolic reactions
essential for eukaryotic organisms. They are associated to aerobic organisms
and related to cellular processes such as metabolism, proliferation,
differentiation and immune system regulation. These components come from redox reactions generated
principally in the mitochondria electronic chain, using oxygen as the principal
pathway for ATP production in the process known as oxidative
phosphorylation.  Nevertheless, they can
also be generated in other cell organelles like peroxisomes, apoplasts and
chloroplasts. These oxygen species are composed specially by hydrogen peroxide
(H2O2) and free radical’s superoxide
anion (O2).


It has been
demonstrated that in cancer cells: at low levels of ROS, they act as signaling molecules to
activate proliferation and survival pathways. A moderate increase in ROS levels
is caused because of genetic, metabolic and microenvironment-associated
alteration. This leads to DNA damage and promotes mutagenesis in cells. High
ROS levels causes oxidative stress that can lately result in cell senescence or
death. It is known to cause cell toxicity.  


Intracellular ROS
accumulation is associated to high toxicity at cellular and tissue levels and
it is responsible of oxidative stress and harm in biomolecules such as lipids,
proteins and nucleic acids. Due to this fact, it is necessary to eradicate the
additional ROS, avoiding it´s negative consequences. Aerobic organisms
mentioned before, own enzymatic mechanisms to remove in an efficient way this
additional ROS, by generating H2O and O2. By doing this, we can
avoid the extra ROS accumulation in cells. Once tumors are established, tumor propagating cancer stem cells (TPCs) must reduce ROS levels, to sustain their long-term self-renewing capacity and to avoid their differentiation. To prevent excessive oxidative stress, tumor cells
adjust antioxidant enzymes using their metabolic pathway to provide an adequate
supply of antioxidant molecules. The most relevant antioxidant enzymes within the cells is
glutathione (GSH) which uses glutathione peroxidases that eliminate H2O2
to H2O. Another important defensive mechanism is the one known as
Thioredoxin. Superoxide dismutases (SODs) that convert superoxide O2-
to less reactive H2O2.


For countering the impact of ROS species, cells
develop antioxidant response strategies. Nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway is
one of the pathways that has been very well studied. NRF2 is a transcription
factor known as the master regulator of the antioxidant response in cancer. It
is induced by ROS and can regulate the expression of enzymes that control NADPH
production, the glutathione synthesis, detoxification of glutathione production
as well as the mechanism that reduces the proteins that are oxidized by ROS species.

Still, how Nrf2 and target gene transcription are controlled in TPCs remains elusive.

What is trying to be understood is how a
normal stem cell that is self-renewing and differentiating keeping homeostasis
in the tissue is going to get transformed and being in a situation where the
cell renewing process has increased while the differentiation is being


SOX2 and PITX1 are transcription factors that are only
expressed in the cell that have the tumor initiating potential and self-renewal
capacity while they are not expressing the differentiation of SCCs. They are
co-expressed in the nuclei of the tumor propagating cells in hSCC grafts. These
transcription factors are expressed in mouse and human SCCs, while they are not
detectable in normal skin epithelial cells. They are essential to maintain
self-renewal and restrict differentiation on those cells. The expansion of
tumour initiating SCC cells along the stroma interface, is known to be
dependent on SOX2 expression critical for tumor initiation and growth. 


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