Cellular intrinsic factors involved in the resistance of squamous cell carcinoma to photodynamic therapy.
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.
Unidad de Dermatología, Hospital de San Jorge de Huesca, and Institute of Health Science of Aragón, Zaragoza, Spain.
Yolanda
Y
Gilaberte
Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Córdoba, Argentina.
Laura
L
Milla
Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
Nerea
N
Salazar
Departamento de Patología, Hospital de San Jorge de Huesca, Huesca, Spain.
Jesús
J
Vera-Alvarez
Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
Omar
O
Kourani
Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
Alejandra
A
Damian
Departamento de Biología Molecular, Facultad de Ciencias Exactas, Físico-Químicas y Naturales, Universidad Nacional de Río Cuarto, Córdoba, Argentina.
Viviana
V
Rivarola
Departamento de Patología, Hospital de San Jorge de Huesca, Huesca, Spain.
Maria José
MJ
Roca
Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
Jesús
J
Espada
Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Salvador
S
González
Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: angeles.juarranz@uam.es.
Angeles
A
Juarranz
D000369:Aged, 80 and over; D000622:Aminolevulinic Acid / Q000008:administration & dosage*; D000818:Animals; D001706:Biopsy; D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D019938:Cyclin D1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
C530104:CCND1 protein, human; D017319:Photosensitizing Agents; D019938:Cyclin D1; D000622:Aminolevulinic Acid; D066246:ErbB Receptors; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human