Cutaneous squamous cell carcinomas
(SCCs) are the second most common and potentially
deadly human cancers. SCCs are sustained
by tumor propagating cancer cells (TPCs) that reside within the basal layer of these tumors, which is located along the tumor stroma interface. 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,
TPCs from normal, adult skin epithelial
stem and progenitor cells. Within this signature we identified Oxidative
Stress Response as one the most significantly up-regulated Gene Ontology categories
in TPCs. Oxidative Stress Response is trigged by reactive oxygen species (ROS), which are generated as a natural, metabolic byproduct.
conditions, ROS levels are buffered by a complex detoxifying machinery,
which is dependent on glutathione production.
However, under certain situations,
stress, ROS levels can rise resulting
stress that can cause DNA damage and protein oxidation. Indeed, high ROS levels were found to promote tumor progression as they cause mutagenesis and transformation. However, once tumors are established,
cancer stem cells (TPCs) must reduce ROS levels, to sustain their long-term self-renewing capacity and to avoid their differentiation. The transcription factor Nrf2 is a master regulator of oxidative stress response in cells. It is induced by high ROS levels, and it can trigger the expression
of a variety of enzymes responsible
for NADPH production, glutathione
synthesis, detoxification of glutathione production.
It also reduces proteins that are oxidized by ROS species. Still, how Nrf2 and target gene transcription are controlled in TPCs remains elusive. We hypothesize, based on our preliminary data, that the transcription factors Sox2 and Pitx1 can directly regulate the expression
of Nrf2 and antioxidant
signaling genes in an Nrf2 independent
way, to increase the self-renewal capacity of TPCs. Once these regulatory
mechanisms have been defined, we can begin to develop novel, pharmacological approaches
that restrict self-renewal and accelerate
TPC differentiation for a more effective treatment
of SCC patients in the clinic.