title: CYP genes in osteosarcoma: Their role in tumorigenesis, pulmonary metastatic microenvironment and treatment response.
abstract: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The present study investigated the expression of Cytochrome P-450 (CYP) genes: CYP1A2, CYP3A4 and CYP3A5 by qRT-PCR in 135 specimens obtained from OS patients, including biopsy (pre-chemotherapy), tumor resected in surgery (post-chemotherapy), adjacent bone to tumor (nonmalignant tissue), pulmonary metastasis and adjacent lung to metastasis (nonmalignant tissue). Normal bone and normal lung tissues were used as control. We also investigated in five OS cell lines the modulation of CYPs expression by cisplatin, doxorubicin and methotrexate. As result, the adjacent lung specimens presented CYP1A2 overexpression compared to the normal lung (p=0.0256). Biopsy specimens presented lower CYP3A4 expression than normal bone (p=0.0314). The overexpression of both CYP1A2 and CYP3A4 in post-chemotherapy specimens were correlated with better event free-survival (p=0.0244) and good response (p=0.0484), respectively. Furthermore, in vitro assays revealed that CYP1A2 was upregulated by doxorubicin (p=0.0034); CYP3A4 was upregulated by cisplatin, doxorubicin and methotrexate (p=0.0004, p=0.0024, p<0.0001, respectively); and CYP3A5 was downregulated by doxorubicin (p=0.0285) and upregulated in time-dependent manner by methotrexate (p=0.0239). In conclusion, our findings suggest that CYP genes play an important role in OS tumorigenesis, at primary and metastatic sites, as well in treatment response.
authors.affiliation: Genetics Laboratory, Pediatric Oncology Institute (IOP/GRAACC), Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04023-062, Brazil.|Department of Clinical and Experimental Oncology, Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04037-003, Brazil.
authors.forename: Alini
authors.initials: A
authors.lastname: Trujillo-Paolillo
authors.affiliation: Genetics Laboratory, Pediatric Oncology Institute (IOP/GRAACC), Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04023-062, Brazil.
authors.forename: Francine
authors.initials: F
authors.lastname: Tesser-Gamba
authors.affiliation: Pediatric Oncology Institute (IOP/GRAACC), Department of Pediatrics, Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04023-062, Brazil.
authors.forename: Antonio Sergio
authors.initials: AS
authors.lastname: Petrilli
authors.affiliation: Department of Pathology, Federal University of Sao Paulo, Sao Paulo SP, 04023-062, Brazil.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: de Seixas Alves
authors.affiliation: Department of Orthopedic Surgery and Traumatology, Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04038-031, Brazil.
authors.forename: Reynaldo Jesus
authors.initials: RJ
authors.lastname: Garcia Filho
authors.affiliation: Department of Thoracic Surgery, Federal University of Sao Paulo, Vila Clementino SP, 04024-002, Brazil.
authors.forename: Renato
authors.initials: R
authors.lastname: de Oliveira
authors.affiliation: Genetics Laboratory, Pediatric Oncology Institute (IOP/GRAACC), Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04023-062, Brazil.|Department of Clinical and Experimental Oncology, Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04037-003, Brazil.|Department of Morphology and Genetics, Federal University of Sao Paulo, Vila Clementino, Sao Paulo SP, 04023-062, Brazil.
authors.forename: Silvia Regina Caminada
authors.initials: SRC
authors.lastname: de Toledo
mesh_terms: D000293:Adolescent; D001859:Bone Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002648:Child; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D012516:Osteosarcoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome; D059016:Tumor Microenvironment
chemical_list: C504573:CYP1A2 protein, human; C510164:CYP3A5 protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: cytochrome P-450; osteosarcoma; osteosarcoma cell line; treatment response; tumor microenvironment