Cellular Intrinsic Factors Involved in the Resistance of Squamous Cell Carcinoma to Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) is widely used to treat non-melanoma skin cancer. However, some patients affected with squamous cell carcinoma (SCC) do not respond adequately to PDT with methyl-δ-aminolevulinic acid (MAL-PDT) and the tumors acquire an infiltrative phenotype and became histologically more aggressive, less differentiated, and more fibroblastic. To search for potential factors implicated in SCC resistance to PDT, we have used the SCC-13 cell line (parental) and resistant SCC-13 cells obtained by repeated MAL-PDT treatments (5th and 10th PDT-resistant generations). Xenografts assays in immunodeficient mice showed that the tumors generated by resistant cells were bigger than those induced by parental cells. Comparative genomic hybridization array (aCGH) showed that the three cell types presented amplicons in 3p12.1 CADM2, 7p11.2 EFGR, and 11q13.3 CCND1 genes. The 5th and 10th PDT-resistant cells showed an amplicon in 5q11.2 MAP3K1, which was not present in parental cells. The changes detected by aCGH on CCND1, EFGR, and MAP3K1 were confirmed in extracts of SCC-13 cells by reverse-transcriptase PCR and by western blot, and by immunohistochemistry in human biopsies from persistent tumors after MAL-PDT. Our data suggest that genomic imbalances related to CCND1, EFGR, and particularly MAP3K1 seem to be involved in the development of the resistance of SCC to PDT.

The role of photodynamic therapy in overcoming cancer drug resistance

“…BPD-PDT complements the cytostatic effects of cetuximab by photochemically triggering apoptosis, in part by inducing mitochondria-mediated apoptosis (Figure 1). Furthermore, a study by Gilaberte et al 87 found that EGFR expression is correlated with the resistance to PDT with methyl-aminolevulinic acid (MAL-PDT) in analyses of PDT-resistant squamous cell carcinoma (SCC) cells and tumor biopsies from patients with persistent SCC following MAL-PDT.…”

Photodynamic Therapy and Skin Cancer

“…Gilaberte et al [106] postulated that chromosomal instability is the reasonable factor through the induction of overexpression of CCND1 and aberration of the MAPK/ ERK signal pathway, as previously shown in immunodeficient mice.…”

Tumor Microenvironment as a Determinant of Photodynamic Therapy Resistance

“…These signaling changes may counteract the therapeutic benefit of treatment, and even make a tumor more aggressive, thus, it is necessary to consider the impact of PDT on the molecular microenvironment. Several reports have highlighted "resistance" to PDT as a result of treatmentinduced changes to tumor and endothelial cell biology [68,69]. The most common molecules known to impair PDT response due to alteration in their expression or signaling following light treatment include the epidermal growth factor receptor (EGFR) [70][71][72], ERKs [73,74], signal transducer and activator of transcription 3 (STAT3) [70], cyclooxygenase 2 (COX-2) [75,76], heat shock proteins (Hsp) [67,68,77], matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) [78][79][80].…”

“…This resistance is related to several molecular alterations in resistant tumor cells, specifically in expression of the EGFR, Cyclin D1, and ERK1/2 genes. These genes were observed to increase following PDT, thus rendering the SCC tumor cells more tumorigenic and attenuating the PDT response [69].…”