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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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Frequency of expression. We assessed the frequency of expression of PDGFs semi-quantitatively by the following method. Five fields of each PDGF isoform, in which abnormal angiogenesis were detected, were randomly selected with a microscope. The PDGF-positive mononuclear cells were counted. We observed all 7 cases and performed the counting using two observers to reduce bias. One observer, who was blind to the patients’ clinical and pathological information, evaluated the results of the immunohistochemical staining. The ratios of PDGF-positive cells to total cells in each field were calculated and were statistically analyzed using Steel-Dwass tests with JMP Pro 10 (SAS Institute Inc., Cary, NC, USA). Statistical analysis revealed that PDGF-C and D showed higher frequency of expression in the PN specimens than did PDGF-A and B. The difference was statistically significant (*p < 0.0001, Steel-Dwass test).
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Figure 3: Frequency of expression. We assessed the frequency of expression of PDGFs semi-quantitatively by the following method. Five fields of each PDGF isoform, in which abnormal angiogenesis were detected, were randomly selected with a microscope. The PDGF-positive mononuclear cells were counted. We observed all 7 cases and performed the counting using two observers to reduce bias. One observer, who was blind to the patients’ clinical and pathological information, evaluated the results of the immunohistochemical staining. The ratios of PDGF-positive cells to total cells in each field were calculated and were statistically analyzed using Steel-Dwass tests with JMP Pro 10 (SAS Institute Inc., Cary, NC, USA). Statistical analysis revealed that PDGF-C and D showed higher frequency of expression in the PN specimens than did PDGF-A and B. The difference was statistically significant (*p < 0.0001, Steel-Dwass test).

Mentions: Our statistical analysis revealed that PDGF-C and D showed higher frequencies of expression than PDGF-A and B in PN. The difference was statistically significant (p < 0.0001, Steel-Dwass test) (Figure 3). We also grouped the cases into a GBM group (cases 3, 4, 5, 6) and non-GBM group (cases 1, 2, 7) and analyzed the differences in protein expression between them. No statistically significant differences in the expression of any of the isoforms were observed between the two groups by the Steel-Dwass test [see Additional file 4]. Therefore, we considered that these primary diseases did not affect the expression of PDGFs.


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)

Frequency of expression. We assessed the frequency of expression of PDGFs semi-quantitatively by the following method. Five fields of each PDGF isoform, in which abnormal angiogenesis were detected, were randomly selected with a microscope. The PDGF-positive mononuclear cells were counted. We observed all 7 cases and performed the counting using two observers to reduce bias. One observer, who was blind to the patients’ clinical and pathological information, evaluated the results of the immunohistochemical staining. The ratios of PDGF-positive cells to total cells in each field were calculated and were statistically analyzed using Steel-Dwass tests with JMP Pro 10 (SAS Institute Inc., Cary, NC, USA). Statistical analysis revealed that PDGF-C and D showed higher frequency of expression in the PN specimens than did PDGF-A and B. The difference was statistically significant (*p < 0.0001, Steel-Dwass test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Frequency of expression. We assessed the frequency of expression of PDGFs semi-quantitatively by the following method. Five fields of each PDGF isoform, in which abnormal angiogenesis were detected, were randomly selected with a microscope. The PDGF-positive mononuclear cells were counted. We observed all 7 cases and performed the counting using two observers to reduce bias. One observer, who was blind to the patients’ clinical and pathological information, evaluated the results of the immunohistochemical staining. The ratios of PDGF-positive cells to total cells in each field were calculated and were statistically analyzed using Steel-Dwass tests with JMP Pro 10 (SAS Institute Inc., Cary, NC, USA). Statistical analysis revealed that PDGF-C and D showed higher frequency of expression in the PN specimens than did PDGF-A and B. The difference was statistically significant (*p < 0.0001, Steel-Dwass test).
Mentions: Our statistical analysis revealed that PDGF-C and D showed higher frequencies of expression than PDGF-A and B in PN. The difference was statistically significant (p < 0.0001, Steel-Dwass test) (Figure 3). We also grouped the cases into a GBM group (cases 3, 4, 5, 6) and non-GBM group (cases 1, 2, 7) and analyzed the differences in protein expression between them. No statistically significant differences in the expression of any of the isoforms were observed between the two groups by the Steel-Dwass test [see Additional file 4]. Therefore, we considered that these primary diseases did not affect the expression of PDGFs.

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