Immunohistochemical expression of angiogenic cytokines and their receptors in reactive benign lymph nodes and non-Hodgkin lymphoma.
Angiogenic cytokines regulate B-cell lymphopoiesis and are related to prognosis in B-cell lymphoproliferative disorders. Transforming growth factor-beta (TGF-beta) inhibits mature B-cell proliferation and immunoglobulin production. Increased levels of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are associated with poor prognosis in non-Hodgkin lymphoma (NHL). To understand the expression of angiogenic cytokines at different stages of B-cell differentiation in lymph nodes, we examined the immunohistochemical expression of TGF-beta, VEGF, bFGF, and their receptors in five patients with reactive benign lymphadenopathy and 12 patients with B-cell NHL (mantle cell lymphoma, 4; small cleaved cell follicular lymphoma, 5; lymphoplasmacytic lymphoma, 3). In benign lymph nodes, TGF-beta1, TGF-beta2, and TGFbetaRII were positive in prefollicular mantle cells, follicular center cells, and postfollicular plasma cells. Basic FGF, FGF-R1, and FGF-R4 were positive in large follicular center cells and postfollicular plasma cells. Vascular endothelial growth factor was positive in large follicular center cells and postfollicular plasma cells. In NHL, TGF-beta and its receptors were weakly positive in small cleaved cell follicular lymphoma; VEGF was strongly positive in lymphoplasmacytic lymphoma and weakly positive in mantle cell lymphoma. Basic FGF and its receptors were negative in NHL; however, FGF-R4 was positive in some cases of small cleaved cell follicular lymphoma. Our findings suggest that TGF-beta, bFGF, and their receptors have opposite roles in B-cell differentiation and maturation in benign lymph nodes. Transforming growth factor-beta and its receptors have an important role in germinal center development; loss of their activity could be associated with abnormal clonal proliferation of NHL.
Ho CL
，Sheu LF
，Li CY
《Annals of Diagnostic Pathology》
Immunohistochemical expression of growth factors in subacute thyroiditis and their effects on thyroid folliculogenesis and angiogenesis in collagen gel matrix culture.
The inflammatory-mechanistic basis of subacute thyroiditis remains unclear. To elucidate the roles of vascular endothelial cell growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB (PDGF), transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) in the inflammatory process, their immunoexpression was examined in biopsy specimens of ten cases. At the granulomatous stage, all cases expressed VEGF, bFGF, PDGF, and TGF-beta1 in monocytes/macrophages infiltrating into follicle lumina, and in both epithelioid histiocytes and multinucleated giant cells of the granulomas. In fibroblasts and endothelial cells around the granulomas, all cases displayed VEGF, bFGF, and PDGF, but TGF-beta1 was detected only in fibroblasts in two cases. No cases expressed EGF in any of the above cell types. At the regenerative stage, all cases expressed VEGF, bFGF, and EGF in regenerating thyrocytes, whereas three and no cases displayed PDGF and TGF-beta1, respectively. Ten, seven and six cases expressed PDGF in fibroblasts, endothelial cells, and monocytes, respectively. In these cell types, all cases expressed VEGF and bFGF, whereas no cases displayed TGF-beta1 and EGF. To estimate the roles of these growth factors in thyroid tissue regeneration, their effects on thyroid folliculogenesis and angiogenesis were examined using collagen gel culture of thyrocytes and endothelial cells, respectively. Cell proliferation was also studied by bromodeoxyuridine (BrdU) uptake. EGF decreased follicle formation and TGF-beta1 drastically inhibited it, but the others had no effect. VEGF showed the greatest effect on vessel formation, although all of the others promoted it. EGF and VEGF or bFGF caused the highest BrdU uptake in thyrocytes and endothelial cells, respectively. The data suggest firstly, that at the granulomatous stage of subacute thyroiditis, growth factor-rich monocytes/macrophages infiltrating into follicle lumina trigger the granulomatous reaction, and VEGF, bFGF, PDGF, and TGF-beta1 produced by the stromal cell types tested mediate the reaction; secondly, that at the regenerative stage, EGF serves follicle regeneration through its mitogenic effect on thyrocytes, although some cofactors with EGF are involved in folliculogenesis and the decreased expression of TGF-beta1, a fibrogenic factor, contributes to thyroid tissue repair; and thirdly, that VEGF and bFGF are more responsible for the angiogenesis at both stages than the other factors studied.
Toda S
，Nishimura T
，Yamada S
，Koike N
，Yonemitsu N
，Watanabe K
，Matsumura S
，Gärtner R
，Sugihara H
... -
《JOURNAL OF PATHOLOGY》
Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF beta expression.
Vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF-1 and -2), and transforming growth factor beta (TGFbeta) are potent angiogenic cytokines. Malignant mesothelioma of the pleura presents with a high intra-tumoural microvascular density (IMD) which also has prognostic relevance. This study was designed to verify the immunohistochemical expression of the angiogenic cytokines in mesothelioma as well as in non-neoplastic human mesothelial cells and to study the individual as well as the combined expression of these cytokines in mesothelioma in relation to both IMD and prognosis. In addition, four mesothelioma cell lines were studied by ELISA for the secretion of VEGF and FGF-2 in their supernatants and were shown to contain high levels of both of these cytokines. Immunohistochemically, VEGF, FGF-1 and -2, and TGFbeta immunoreactivity was present in 81, 67, 92 and 96 per cent of mesotheliomas, and in 20, 50, 40, and 10 per cent of samples of the non-neoplastic mesothelium, respectively. Co-ordinate expression of the cytokines was observed whereby mesotheliomas expressed more than one cytokine. The combined immunohistochemical expression levels for all four cytokines correlated significantly with both IMD (p=0.01) and prognosis (p=0. 0013). When studied individually, high FGF-2 expression correlated best with more tumour aggressiveness and worse prognosis for mesothelioma (p=0.0011). There was no significant correlation between prognosis and immunoexpression of VEGF (p=0.07), FGF-1 (p=0.3), or TGFbeta (p=0.1), or between IMD and any of the cytokines studied individually. These data support the assertion that selective angiogenic cytokines might contribute to the progressive changes of mesothelioma by tumour angiogenesis.
Kumar-Singh S
，Weyler J
，Martin MJ
，Vermeulen PB
，Van Marck E
... -
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