ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach
Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent T...
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/11/2592 |
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| author | Iacopo Petrini Martina Sollini Francesco Bartoli Serena Barachini Marina Montali Eleonora Pardini Irene Sofia Burzi Paola Anna Erba |
| author_facet | Iacopo Petrini Martina Sollini Francesco Bartoli Serena Barachini Marina Montali Eleonora Pardini Irene Sofia Burzi Paola Anna Erba |
| author_sort | Iacopo Petrini |
| collection | DOAJ |
| description | Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled in prospective theragnostic phase I/II trials with Radretumab, an ED-B FN specific recombinant human antibody. Radretumab radioimmunotherapy (R-RIT) was offered to patients who exhibited the target expression. Experiments included immunochemical analysis (ICH), cell cultures, immunophenotypic analysis, Western blot, slot-blot assay, and quantitative RT-PCR of two primary thymoma cultures we obtained from patients’ samples and in the Ty82 cell line. Results: The in vivo scintigraphic demonstration of ED-B FN expression resulted in R-RIT eligibility in 8/11 patients, of which seven were treated. The best observed response was disease stabilization (<i>n =</i> 5/7) with a duration of 4.3 months (range 3–5 months). IHC data confirmed high ED-B FN expression in the peripherical microenvironment rather than in the center of the tumor, which was more abundant in B3 thymomas. Further, there was a predominant expression of ED-B FN by the stromal cells of the thymoma microenvironment rather than the epithelial cells. Conclusions: Our data support the hypothesis that thymomas induce stromal cells to shift FN production to the ED-B subtype, likely representing a favorable hallmark for tumor progression and metastasis. Collectively, results derived from clinical experience and molecular insights of the in vitro experiments suggested that R-RIT inefficacy is unlikely related to low target expression in TET, being the mechanism of R-RIT resistance eventually related to patients’ susceptibility (i.e., inherent characteristics), the pattern expression of the target (i.e., at periphery), the biological characteristics of the tumor (i.e., aggressive and resistant phenotypes), and/or to format of the target agent (i.e., 131I-L19-SIP). |
| first_indexed | 2024-03-10T01:27:23Z |
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| id | doaj.art-084736f483a24a00aac67f7d1728fd67 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:27:23Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-084736f483a24a00aac67f7d1728fd672023-11-23T13:47:51ZengMDPI AGCancers2072-66942022-05-011411259210.3390/cancers14112592ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic ApproachIacopo Petrini0Martina Sollini1Francesco Bartoli2Serena Barachini3Marina Montali4Eleonora Pardini5Irene Sofia Burzi6Paola Anna Erba7General Pathology, Department of Translational Research & New Technologies in Surgery and Medicine, University of Pisa and Azienda Ospedaliero Universitaria Pisana, 56100 Pisa, ItalyDepartment of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, ItalyRegional Center of Nuclear Medicine, Department of Translational Research and New Technology in Medicine, University of Pisa and Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, ItalyLaboratory of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyLaboratory of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyLaboratory of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyLaboratory of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, ItalyRegional Center of Nuclear Medicine, Department of Translational Research and New Technology in Medicine, University of Pisa and Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, ItalyAim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled in prospective theragnostic phase I/II trials with Radretumab, an ED-B FN specific recombinant human antibody. Radretumab radioimmunotherapy (R-RIT) was offered to patients who exhibited the target expression. Experiments included immunochemical analysis (ICH), cell cultures, immunophenotypic analysis, Western blot, slot-blot assay, and quantitative RT-PCR of two primary thymoma cultures we obtained from patients’ samples and in the Ty82 cell line. Results: The in vivo scintigraphic demonstration of ED-B FN expression resulted in R-RIT eligibility in 8/11 patients, of which seven were treated. The best observed response was disease stabilization (<i>n =</i> 5/7) with a duration of 4.3 months (range 3–5 months). IHC data confirmed high ED-B FN expression in the peripherical microenvironment rather than in the center of the tumor, which was more abundant in B3 thymomas. Further, there was a predominant expression of ED-B FN by the stromal cells of the thymoma microenvironment rather than the epithelial cells. Conclusions: Our data support the hypothesis that thymomas induce stromal cells to shift FN production to the ED-B subtype, likely representing a favorable hallmark for tumor progression and metastasis. Collectively, results derived from clinical experience and molecular insights of the in vitro experiments suggested that R-RIT inefficacy is unlikely related to low target expression in TET, being the mechanism of R-RIT resistance eventually related to patients’ susceptibility (i.e., inherent characteristics), the pattern expression of the target (i.e., at periphery), the biological characteristics of the tumor (i.e., aggressive and resistant phenotypes), and/or to format of the target agent (i.e., 131I-L19-SIP).https://www.mdpi.com/2072-6694/14/11/2592thymic epithelial tumorstumor microenvironmentfibronectintarget therapytheragnostic |
| spellingShingle | Iacopo Petrini Martina Sollini Francesco Bartoli Serena Barachini Marina Montali Eleonora Pardini Irene Sofia Burzi Paola Anna Erba ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach Cancers thymic epithelial tumors tumor microenvironment fibronectin target therapy theragnostic |
| title | ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach |
| title_full | ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach |
| title_fullStr | ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach |
| title_full_unstemmed | ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach |
| title_short | ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach |
| title_sort | ed b containing isoform of fibronectin in tumor microenvironment of thymomas a target for a theragnostic approach |
| topic | thymic epithelial tumors tumor microenvironment fibronectin target therapy theragnostic |
| url | https://www.mdpi.com/2072-6694/14/11/2592 |
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