Relationships between cell division, expression of growth factors and microcirculation in the thyroids of Tg-A2aR transgenic mice and patients with Graves' disease.
Tissue heterogeneity and nodule formation are hallmarks of thyroid growth. This is accounted for by the clonality theory that acknowledges different individual cellular abilities to respond to trophic stimuli. In order to test the hypothesis that functional and mitotic properties of thyrocytes could be influenced by paracrine interactions with neighbour endothelial cells, studies were conducted in both mouse and human goitre models. In the first part of the study, homogenous goitres in C57 black mice were compared with heterogeneous goitres in transgenic hyperthyroid mice expressing the A2 adenosine receptor (Tg-A2aR). The second part of the study concentrated on comparing human thyroid tIssue of control individuals and of patients with Graves' disease. The rate of cell division was evaluated by immunohistochemical detection of cells positive for proliferating cell nuclear antigen (PCNA). Their spatial distribution was then correlated with immunohistochemical cellular expression of growth- and vasoactive-related factors (fibroblast growth factor-2, transforming growth factor-beta, endothelin-1, vascular endothelial growth factor, nitric oxide synthase III), and with microcirculation expansion. Observations were made on digitalised images of histological serial sections. The nearest-neighbour method was used to distinguish between random or clustered distribution. PCNA-positive cells were both randomly and uniformly distributed in homogenous goitres from C57 black mice, and were clustered in tIssue areas identified as papillary and hyperplastic zones in heterogeneous goitres from Tg-A2aR mice. However, they were absent in the so-called compact cellular zones featuring resting cells. Moreover, whereas papillary and hyperplastic zones were highly vascularised, compact zones were nearly free of microvessels. Spatial distribution of dividing cells was positively correlated with the expression of growth-related factors. A similar pattern was observed in the thyroids of patients with Graves' disease. In accordance with the recent demonstration of the presence of angiofollicular units in the thyroid, these data strongly support the hypothesis that functional and mitotic properties of each single thyrocyte, likely to be responsible for growth heterogeneity of hyperplastic glands, may be adjusted at tIssue level by specific interactions with neighbour endothelial cells that, in turn, could alter the mitotic rate of thyrocytes through paracrine signals.
Histology Unit, Université Catholique de Louvain, Medical School, UCL-5229, 52 Av. Mounier, B-1200, Brussels, Belgium.
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AC
Gérard
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JF
Denef
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MC
Many
P
P
Gathy
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de Burbure
M-F
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van den Hove
F
F
Coppée
C
C
Ledent
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Colin
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000032:analysis; D019332:Endothelin-1 / Q000032:analysis; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D006111:Graves Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D008222:Lymphokines / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D015415:Biomarkers; D016228:Endothelial Growth Factors; D019332:Endothelin-1; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D018809:Proliferating Cell Nuclear Antigen; D018047:Receptors, Purinergic P1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse