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The roles of platelet-derived growth factors and their receptors in brain radiation necrosis.

Miyata T, Toho T, Nonoguchi N, Furuse M, Kuwabara H, Yoritsune E, Kawabata S, Kuroiwa T, Miyatake S - Radiat Oncol (2014)

Bottom Line: All PDGFs were expressed in macrophages, microglia, and endothelial cells in the boundary of the core of RN, namely, the perinecrotic area (PN), as well as in undamaged brain tissue (UB).PDGF-C, D and PDGFR-α were also expressed in reactive astrocytes in PN.PDGFs and PDGFR-α were scarcely detected in UB, but PDGFR-β was specifically expressed in endothelial cells not only in PN but also in UB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. neu070@poh.osaka-med.ac.jp.

ABSTRACT

Background: Brain radiation necrosis (RN) occurring after radiotherapy is a serious complication. We and others have performed several treatments for RN, using anticoagulants, corticosteroids, surgical resection and bevacizumab. However, the mechanisms underlying RN have not yet been completely elucidated. For more than a decade, platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been extensively studied in many biological processes. These proteins influence a wide range of biological responses and participate in many normal and pathological conditions. In this study, we demonstrated that PDGF isoforms (PDGF-A, B, C, and D) and PDGFRs (PDGFR-α and β) are involved in the pathogenesis of human brain RN. We speculated on their roles, with a focus on their potential involvement in angiogenesis and inflammation in RN.

Methods: Seven surgical specimens of RN, obtained from 2006 to 2013 at our department, were subjected to histopathological analyses and stained with hematoxylin and eosin. We qualitatively analyzed the protein expression of each isoform of PDGF by immunohistochemistry. We also examined their expression with double immunofluorescence.

Results: All PDGFs were expressed in macrophages, microglia, and endothelial cells in the boundary of the core of RN, namely, the perinecrotic area (PN), as well as in undamaged brain tissue (UB). PDGF-C, D and PDGFR-α were also expressed in reactive astrocytes in PN. PDGFs and PDGFR-α were scarcely detected in UB, but PDGFR-β was specifically expressed in endothelial cells not only in PN but also in UB.

Conclusions: PDGFs/PDGFRs play critical roles in angiogenesis and possibly in inflammation, and they contribute to the pathogenesis of RN, irrespective of the original tumor pathology and applied radiation modality. Treatments for the inhibition of PDGF-C, PDGF-D, and PDGFR-α may provide new approaches for the treatment of RN induced by common radiation therapies.

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Results of hematoxylin and eosin staining (H&E) and immunohistochemistry from case 1. H&E staining (A) revealed a necrotic core (NC) and perinecrotic area (PN), including micro bleeding (A, arrowhead) and abnormal angiogenesis (A, arrow). Immunostaining results for PDGF-C are presented as a representative example (B). PDGF-C (C and D), D (E and F) and PDGFR-α (G) were produced by monocytic cells (C, E, G, arrow) and reactive astrocytic cells (D, F, G, arrowhead) in PN. On the other hand, PDGFR-β (H and I) was expressed mainly in endothelial cells (H and I*). There was partially nonspecific staining in NC (B) or around blood vessels (I). Original magnification, A, B and H × 40, C, D, E, F, G and I × 200.
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Figure 1: Results of hematoxylin and eosin staining (H&E) and immunohistochemistry from case 1. H&E staining (A) revealed a necrotic core (NC) and perinecrotic area (PN), including micro bleeding (A, arrowhead) and abnormal angiogenesis (A, arrow). Immunostaining results for PDGF-C are presented as a representative example (B). PDGF-C (C and D), D (E and F) and PDGFR-α (G) were produced by monocytic cells (C, E, G, arrow) and reactive astrocytic cells (D, F, G, arrowhead) in PN. On the other hand, PDGFR-β (H and I) was expressed mainly in endothelial cells (H and I*). There was partially nonspecific staining in NC (B) or around blood vessels (I). Original magnification, A, B and H × 40, C, D, E, F, G and I × 200.

Mentions: Figure 1 shows the results of H&E staining and immunohistochemistry from case 1. H&E staining revealed a necrotic core (NC) (Figure 1A. NC) and PN (Figure 1A. PN), in which micro bleeding (Figure 1A. arrowhead) and abnormal angiogenesis (Figure 1A. arrow) were confirmed. PDGF-A, B, C, and D-positive cells were detected in PN. The results of immunostaining for PDGF-C are shown as a typical example of these distribution analyses (Figure 1B, C, D). Morphologically, PDGF-A and B were produced by some monocytic cells [see Additional file 2] in PN. On the other hand, PDGF-C and D (Figure 1E, F) were produced by many monocytic cells (arrows in Figure 1C, E), reactive astrocytic cells (arrowheads in Figure 1D, F), and endothelial cells (Figure 1D*). PDGF-A, B, C, and D were scarcely detectable in UB (Figure 2).


The roles of platelet-derived growth factors and their receptors in brain radiation necrosis.

Miyata T, Toho T, Nonoguchi N, Furuse M, Kuwabara H, Yoritsune E, Kawabata S, Kuroiwa T, Miyatake S - Radiat Oncol (2014)

Results of hematoxylin and eosin staining (H&E) and immunohistochemistry from case 1. H&E staining (A) revealed a necrotic core (NC) and perinecrotic area (PN), including micro bleeding (A, arrowhead) and abnormal angiogenesis (A, arrow). Immunostaining results for PDGF-C are presented as a representative example (B). PDGF-C (C and D), D (E and F) and PDGFR-α (G) were produced by monocytic cells (C, E, G, arrow) and reactive astrocytic cells (D, F, G, arrowhead) in PN. On the other hand, PDGFR-β (H and I) was expressed mainly in endothelial cells (H and I*). There was partially nonspecific staining in NC (B) or around blood vessels (I). Original magnification, A, B and H × 40, C, D, E, F, G and I × 200.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3927833&req=5

Figure 1: Results of hematoxylin and eosin staining (H&E) and immunohistochemistry from case 1. H&E staining (A) revealed a necrotic core (NC) and perinecrotic area (PN), including micro bleeding (A, arrowhead) and abnormal angiogenesis (A, arrow). Immunostaining results for PDGF-C are presented as a representative example (B). PDGF-C (C and D), D (E and F) and PDGFR-α (G) were produced by monocytic cells (C, E, G, arrow) and reactive astrocytic cells (D, F, G, arrowhead) in PN. On the other hand, PDGFR-β (H and I) was expressed mainly in endothelial cells (H and I*). There was partially nonspecific staining in NC (B) or around blood vessels (I). Original magnification, A, B and H × 40, C, D, E, F, G and I × 200.
Mentions: Figure 1 shows the results of H&E staining and immunohistochemistry from case 1. H&E staining revealed a necrotic core (NC) (Figure 1A. NC) and PN (Figure 1A. PN), in which micro bleeding (Figure 1A. arrowhead) and abnormal angiogenesis (Figure 1A. arrow) were confirmed. PDGF-A, B, C, and D-positive cells were detected in PN. The results of immunostaining for PDGF-C are shown as a typical example of these distribution analyses (Figure 1B, C, D). Morphologically, PDGF-A and B were produced by some monocytic cells [see Additional file 2] in PN. On the other hand, PDGF-C and D (Figure 1E, F) were produced by many monocytic cells (arrows in Figure 1C, E), reactive astrocytic cells (arrowheads in Figure 1D, F), and endothelial cells (Figure 1D*). PDGF-A, B, C, and D were scarcely detectable in UB (Figure 2).

Bottom Line: All PDGFs were expressed in macrophages, microglia, and endothelial cells in the boundary of the core of RN, namely, the perinecrotic area (PN), as well as in undamaged brain tissue (UB).PDGF-C, D and PDGFR-α were also expressed in reactive astrocytes in PN.PDGFs and PDGFR-α were scarcely detected in UB, but PDGFR-β was specifically expressed in endothelial cells not only in PN but also in UB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka 569-8686, Japan. neu070@poh.osaka-med.ac.jp.

ABSTRACT

Background: Brain radiation necrosis (RN) occurring after radiotherapy is a serious complication. We and others have performed several treatments for RN, using anticoagulants, corticosteroids, surgical resection and bevacizumab. However, the mechanisms underlying RN have not yet been completely elucidated. For more than a decade, platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been extensively studied in many biological processes. These proteins influence a wide range of biological responses and participate in many normal and pathological conditions. In this study, we demonstrated that PDGF isoforms (PDGF-A, B, C, and D) and PDGFRs (PDGFR-α and β) are involved in the pathogenesis of human brain RN. We speculated on their roles, with a focus on their potential involvement in angiogenesis and inflammation in RN.

Methods: Seven surgical specimens of RN, obtained from 2006 to 2013 at our department, were subjected to histopathological analyses and stained with hematoxylin and eosin. We qualitatively analyzed the protein expression of each isoform of PDGF by immunohistochemistry. We also examined their expression with double immunofluorescence.

Results: All PDGFs were expressed in macrophages, microglia, and endothelial cells in the boundary of the core of RN, namely, the perinecrotic area (PN), as well as in undamaged brain tissue (UB). PDGF-C, D and PDGFR-α were also expressed in reactive astrocytes in PN. PDGFs and PDGFR-α were scarcely detected in UB, but PDGFR-β was specifically expressed in endothelial cells not only in PN but also in UB.

Conclusions: PDGFs/PDGFRs play critical roles in angiogenesis and possibly in inflammation, and they contribute to the pathogenesis of RN, irrespective of the original tumor pathology and applied radiation modality. Treatments for the inhibition of PDGF-C, PDGF-D, and PDGFR-α may provide new approaches for the treatment of RN induced by common radiation therapies.

Show MeSH
Related in: MedlinePlus