Introduction
Cutaneous squamous cell carcinoma (cSCC) is the second most common
cancer in the United States, behind basal cell carcinoma
(BCC).1-4 cSCC is also the second most likely skin
cancer to metastasize, following melanoma.1-4Globally, 2.4 million cases and 56,100 deaths were attributable to
cutaneous cSCC in 2019.5 Actinic keratoses (AKs) are
precancerous skin lesions that can potentially progress to SCC. AKs and
cSCC represent aberrant keratinocytes, with AKs characterized by a less
aggressive phenotype. AKs are the most commonly diagnosed pathology in
dermatology and have an estimated prevalence of 11.5 to 26% in the
United States.6,7 Treating AKs is important as
progression to SCC represents a significant public health
risk.1-4,8 From 2007 to 2011, the cost of treating
nonmelanoma skin cancer, including SCC and BCC, totaled over 4.5 billion
US dollars.8
5-Aminolevulinic acid (5-ALA) photodynamic therapy (PDT) is a Federal
Drug Administration (FDA) approved treatment for AK and has been studied
in the management of non-invasive SCC and BCC
tumors.9-12 During PDT, 5-ALA is either applied to
single lesions or to a field of skin that includes aberrant and
surrounding normal cells. 5-ALA is then metabolized to photosensitive
protoporphyrin IX (PP-IX).13,14 Cancerous cell types
have decreased metabolization of PP-IX compared to normal cells,
resulting in preferential accumulation.13-16 PP-IX
absorbs blue light (~417 nm) from 1000 seconds of
phototherapy, producing reactive oxygen species and subsequent cell
death.14
PDT leads to the targeted destruction of cSCC cells by inducing
apoptosis and necrosis.13,14,17 However, a residual
population of cells may not undergo cell death.18 In
these cells, 5-ALA blue light PDT may induce favorable changes in gene
expression to a more benign profile. Previous research has shown that
PDT treatment of AKs with methyl-aminolevulinic acid (MAL) and red light
may beneficially alter the expression of cancer
genes.19-22 MAL PDT has been shown to downregulate
genes and pathways related to cellular proliferation while upregulating
keratinocyte differentiation markers and
autophagy.19-22 The present study investigates whether
5-ALA blue light PDT similarly modulates gene expression and pathways
related to proliferation and cancer pathogenesis in cSCC cells that
survived PDT. Differential gene expression and pathway analysis of cSCC
and human dermal fibroblasts (HDFs) were compared before and after 5-ALA
blue light PDT using RNA-Sequencing (RNA-Seq).