Blood and lymphatic microvessel damage in irradiated human skin: The role of TGF-β, endoglin and macrophages.
OBJECTIVE
Microvascular damage is an important component of late radiation-induced morbidity. In our pre-clinical models, we demonstrated that repair of vessel injury is dependent on proper endoglin-mediated transforming growth factor-beta (TGF-β) signalling and that it can be affected by infiltrating macrophages. We now wanted to extend these findings in irradiated patients, using skin as a model system, and assess whether bisphosphonates could modulate the response.


METHODS
Paired skin biopsies from irradiated and non-irradiated sites were obtained from 48 breast cancer patients. In 8 patients, biopsies were repeated after 4months of bisphosphonate treatment. Immunohistochemistry was used to assess vascular alterations and leucocyte infiltration. Western Blot and qPCR were used to assess expression of growth factors and their receptors.


RESULTS
Decreased blood vessel numbers at early time points were followed by increased endoglin expression and restoration of vessel number. Loss of small lymphatic vessels was associated with increased TGF-β levels, whereas dilation of lymphatic vessels correlated with increased macrophage infiltration. Bisphosphonate treatment reduced leucocyte infiltration, but also prevented restoration of blood vessel numbers after irradiation.


CONCLUSIONS
Radiation injury of the microvasculature is mediated through TGF-β, whereas repair is modulated by the co-receptor endoglin and promoted by macrophages.
Department of Radiation Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address: n.russell@nki.nl.
Nicola S
NS
Russell
Division of Cellular Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Ben
B
Floot
Department of Biometrics, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Erik
E
van Werkhoven
Division of Cellular Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Mitchel
M
Schriemer
Division of Cellular Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Regina
R
de Jong-Korlaar
Department of Plastic Surgery, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Leonie A E
LA
Woerdeman
Division of Cellular Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Fiona A
FA
Stewart
Division of Cellular Stress Response, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Marion
M
Scharpfenecker
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000502:physiology*; D001706:Biopsy; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy; D000071063:Endoglin; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000528:radiation effects; D008264:Macrophages / Q000528:radiation effects*; D055806:Microvessels / Q000528:radiation effects*; D008875:Middle Aged; D010766:Phosphorylation / Q000528:radiation effects; D011832:Radiation Injuries / Q000209:etiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply* / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000502:physiology* / Q000528:radiation effects
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta
Bisphosphonates; Endoglin; Lymphoedema; TGF-beta; Telangiectasia; Vascular damage