Non-melanoma skin cancers (NMSCs or Keratinocyte cancers-KC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), don’t receive the same level of attention as their melanoma counterpart. This is because they are perceived as causing fewer deaths, as only SCCs metastasise. However, the incidence of NMSC is very high (18-20 times higher than that of melanoma)– there were over 45,000 cases of SCC in 2015 in the UK alone, arising from mutations within the skin’s keratinocytes. Also, because these cancers are caused by excessive ultraviolet radiation, patients often end up having more than one skin cancer and many surgeries, so the disease burden for patients is high. Both types of carcinoma have excellent prognosis, are slow-growing and rarely metastasise, however in some cases they can develop into invasive skin cancers, with an aggressive nature. It is important to study NMSCs to produce diagnostic tests which identify high-risk tumours for metastasis and progression, and generate treatments which limit carcinoma recurrence, as this is more challenging to treat.
Ximbio spoke to Professor Leigh to find out more about her research career:
Professor Leigh and her team have contributed to various
streams of SCC and BCC research focusing mainly on keratinocyte biology;
ranging from epithelial differentiation and the cell biology of SCC to the
molecular machinery driving non-melanoma skin cancer. Leigh was a pioneer in
these fields, entering research at a time when keratinocyte growth was a new
technology, and was involved with producing various important antibodies and
cell lines, involved in BCC and SCC cancer identification.
One group of patients that are significantly affected by SCC
and BCC are the immunosuppressed. With over 40% of SCC mortalities occurring in
organ transplant receivers, understanding this group has an important impact on
immunotherapy treatment options and survivability. By working with this group
of patients, Professor Leigh and her team have established a unique panel of
patient derived cutaneous squamous cell carcinoma cell lines. One example from
this panel is the MET1
SCC cell line. This was derived from a primary lesion on the hand of an
immunosuppressed patient, which ultimately recurred (MET2 cell line) and metastasised
(MET4SCC line), representing crucial stages in SCC transformation. Understanding
the stages a squamous cell carcinoma takes in order to become increasingly
invasive helps dictate preventative and therapeutic measures for this cancer. This
cell line has also been used in a variety of research; from indicating HPV
isn’t essential for cancerous
phenotype maintenance, to furthering our understanding of epithelial-mesenchymal
transition within metastasis.
RDEB is a debilitating condition involving a deficiency in
anchoring fibrils - predominantly type VII collagen – between the epidermis
basement membrane and underlying connective tissue. This leads to extremely
fragile skin with severe blistering, with most patients developing SCC before
the age of 35. Irene and her team helped to uncover the genetic basis of this
condition through their research. They created LH7.2,
a monoclonal antibody, which binds to an epitope of type VII collagen, within
the basement membrane of stratified squamous epithelia. This antibody helps
diagnose RDEB, as LH7.2 binding is absent or significantly reduced in RDEB
patients. LH7.2 can also be used for differentiating invasive from non-invasive
melanoma by assessing the integrity of epidermal basement membranes. This
enables us to predict how aggressive SCC might be in RDEB patients.
Professor Leigh and her team also created a monoclonal antibody that could be used to diagnose SCC and BCC tumours. LP34 identifies tumours with an epithelial origin and is key in pathological diagnosis and understanding metastases. As this antibody binds to keratins 5,6 and 18, it can also be used to identify uncultured keratinocyte material. Polyspecific LP34 also has an uncommonly broad pattern of reactivity, staining all human epithelial cells (both stratified and simple epithelium).
Irene Leigh and her lab have made significant contributions
to the understanding and treatment of non-melanoma skin cancers and skin
diseases, generating a number of life science reagents (of which the above are
only a few) that can be used to diagnose these conditions. Despite the belief
that these cancers are not a danger due to their high treatability and low
mortality levels, investigating them can have far-reaching impacts. Understanding
the common pathways between NMSCs and keratinocytes can give insight into other
cancers and skin conditions. Alongside this, studying these skin cancers can
lead to new novel diagnostics and therapeutics to improve cancer survival rates
within at-risk populations.
Find out more about Prof. Irene Leigh's career in dermatology, her research tools and how you can access them through Ximbio