title: Irradiation-induced angiosarcoma and anti-angiogenic therapy: a therapeutic hope?
abstract: Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin. They can be sporadic or caused by therapeutic radiation, hence secondary breast angiosarcomas are an important subgroup of patients. Assessing the molecular biology of angiosarcomas and identify specific targets for treatment is challenging. There is currently great interest in the role of angiogenesis and of angiogenic factors associated with tumor pathogenesis and as targets for treatment of angiosarcomas. A primary cell line derived from a skin fragment of a irradiation-induced angiosarcoma patient was obtained and utilized to evaluate cell biomarkers CD31, CD34, HIF-1 alpha and VEGFRs expression by immunocytochemistry and immunofluorescence, drugs cytotoxicity by cell counting and VEGF release by ELISA immunoassay. In addition to previous biomarkers, FVIII and VEGF were also evaluated on tumor specimens by immunohistochemistry to further confirm the diagnosis. We targeted the VEGF-VEGFR-2 axis of tumor angiogenesis with two different class of vascular targeted drugs; caprelsa, the VEGFR-2/EGFR/RET inhibitor and bevacizumab the anti-VEGF monoclonal antibody. We found the same biomarkers expression either in tumor specimens and in the cell line derived from tumor. In vitro experiments demonstrated that angiogenesis plays a pivotal role in the progression of this tumor as cells displayed high level of VEGFR-2, HIF-1 alpha strongly accumulated into the nucleus and the pro-angiogenic factor VEGF was released by cells in culture medium. The evaluation of caprelsa and bevacizumab cytotoxicity demonstrated that both drugs were effective in inhibiting tumor proliferation. Due to these results, we started to treat the patient with pazopanib, which was the unique tyrosine kinase inhibitor available in Italy through a compassionate supply program, obtaining a long lasting partial response. Our data suggest that the study of the primary cell line could help physicians in choosing a therapeutic approach for patient that almost in vitro shows chances of success and that the anti-angiogenetic agents are a reliable therapeutic opportunity for angiosarcomas patients.
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy. Electronic address: a.azzariti@oncologico.bari.it.
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.affiliation: Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Saponaro
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Quatrale
authors.affiliation: Department of Pathology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Ondina S
authors.initials: OS
authors.lastname: Popescu
authors.affiliation: Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: Strippoli
authors.affiliation: Department of Pathology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Simone
authors.affiliation: Experimental Medical Oncology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.affiliation: Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Guida
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D006394:Hemangiosarcoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy* / Q000473:pathology; D061251:Primary Cell Culture
chemical_list: D020533:Angiogenesis Inhibitors
keywords: Angiosarcoma; Bevacizumab; Caprelsa; Citotoxicity; VEGF; VEGFR