RESUMO
The role of angiogenesis and lymphangiogenesis in thyroid cancer pathogenesis has not been elucidated. Patterns for tumour behaviour and metastasic spread vary according to tumour type and whether differences in the angiogenic or lymphangiogenic phenotype influence the route for tumour metastases or determine a more aggressive behaviour has not been fully explored. The angiogenic and lymphangiogenic phenotypes of a large cohort of thyroid proliferative lesions (n=191) were studied. Using immunohistochemistry for CD34, lymphatic vessel endothelial receptor-1 (LYVE-1) (specific markers for vascular and lymphatic endothelium respectively), vascular endothelial growth factor (VEGF-A), VEGF-C and fibroblast growth factor-2 (FGF-2), this study analyses microvascular density (MVD), lymphatic vascular density (LVD), and expression of angiogenic and lymphangiogenic factors in normal thyroid (NT; n=19), multinodular goitre (n=25), toxic multinodular goitre (n=8), Graves' hyperplasia (n=22), follicular adenoma (n=54), papillary carcinoma (PC; n=27), incidental papillary microcarcinoma (PMC; n=8), follicular carcinoma (FC; n=20) and medullary carcinoma (MC; n=8). MVD was decreased in proliferative lesions, benign and malignant, compared with NT (P<0.0001). In contrast, VEGF-A expression was increased in thyroid carcinomas (PC, FC and MC) when compared with PMC, benign lesions and NT (P<0.0001). LVD was higher in PC and PMC (P=0.001), and VEGF-C expression was increased in PC (P<0.0001). Despite higher LVD and increased expression of VEGF-A and VEGF-C in thyroid cancers, these markers were not related to poor prognosis in terms of tumour size, multifocality and/or presence of lymphatic or distant metastases. In conclusion, angiogenesis is reduced in thyroid proliferative lesions compared with NT tissue. However, VEGF-A expression is upregulated in thyroid cancers. Lymphangiogenesis and VEGF-C expression are increased in thyroid tumours prone to lymphatic metastases. This may be an important mechanism underlying the differences in metastatic behaviour between papillary and follicular thyroid cancer.
Assuntos
Linfangiogênese , Neovascularização Patológica , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fator 2 de Crescimento de Fibroblastos/análise , Humanos , Imuno-Histoquímica , Vasos Linfáticos/patologia , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/irrigação sanguínea , Neoplasias da Glândula Tireoide/cirurgia , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
Tumours are dependent on angiogenesis for growth and inhibition of angiogenesis has become a target for antineoplastic therapy. In the pituitary, unlike other tissues, vascularization is lower in adenomas compared to the normal gland. Despite this finding, a relationship between increased vascularity and several aspects of prolactinoma behaviour such as size, invasiveness, surgical outcome and malignancy, has been demonstrated. The process of angiogenesis is the result of a balance of stimulating and inhibiting factors. It is likely that an interaction between gene expression (such as pituitary tumour transforming gene (PTTG) and a novel gene located within the Edpm5 quantitative trait locus), hormonal stimuli including oestrogens, dopamine, 16 kDa fragments of prolactin and proangiogenic and antiangiogenic growth factors (for example, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2), determine the final angiogenic phenotype of prolactinomas, and thus subsequent tumour behaviour. The elucidation of all the factors involved in the regulation of angiogenesis and their interactions might open new possibilities in the treatment of prolactinomas, especially in those cases with resistance or intolerance to dopamine agonists.
Assuntos
Neovascularização Patológica , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/fisiopatologia , Prolactinoma/irrigação sanguínea , Prolactinoma/fisiopatologia , Dopamina/genética , Dopamina/fisiologia , Agonistas de Dopamina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Estrogênios/genética , Estrogênios/fisiologia , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/fisiologia , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/genética , Neoplasias Hipofisárias/genética , Prolactina/genética , Prolactina/fisiologia , Prolactinoma/genética , Securina , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
Angiogenesis, the process of development of a new vasculature, plays a crucial role in tumour growth. In the pituitary, unlike other tissues, vascularization is lower in adenomas compared to the normal gland. Despite this finding, a relationship between increased vascularity and some aspects of tumour behaviour such as size, invasiveness, surgical outcome and malignancy, has been demonstrated. The process of angiogenesis is the result of a balance of stimulating and inhibiting factors. It is likely that an interaction between gene expression (such as pituitary tumour transforming gene), hormonal stimuli including oestrogens, corticosteroids, dopamine, 16-kDa fragments of prolactin and growth hormone, somatostatin analogues, and pro- and anti-angiogenic growth factors (e.g. vascular endothelial growth factor and fibroblast growth factor), determine the final angiogenic phenotype of pituitary tumours, and thus subsequent tumour behaviour.