Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

被引：19

作者：

Balzarini, Piera ^{[2
,3
]}

Benetti, Anna ^{[2
,3
]}

Invernici, Gloria ^{[1
]}

Cristini, Silvia ^{[1
]}

Zicari, Sonia ^{[4
,5
]}

Caruso, Arnaldo ^{[4
,5
]}

Gatta, Luisa B. ^{[2
,3
]}

Berenzi, Angiola ^{[2
,3
]}

Imberti, Luisa ^{[6
]}

Zanotti, Cinzia ^{[6
]}

Portolani, Nazario ^{[7
,8
]}

Giulini, Stefano M. ^{[7
,8
]}

Ferrari, Maura ^{[9
]}

Ciusani, Emilio ^{[10
]}

Navone, Stefania E. ^{[1
]}

Canazza, Alessandra ^{[1
]}

Parati, Eugenio A. ^{[1
]}

Alessandri, Giulio ^{[1
]}

机构：

[1] IRCCS Fdn Neurol Inst Carlo Besta, Dept Cerebrovasc Dis, Lab Cellular Neurobiol, I-20133 Milan, Italy

[2] Univ Brescia, Dept Pathol 2, Brescia, Italy

[3] Spedali Civil Brescia, Dept Pathol 2, I-25125 Brescia, Italy

[4] Univ Brescia, Dept Microbiol, Brescia, Italy

[5] Spedali Civil Brescia, Dept Microbiol, I-25125 Brescia, Italy

[6] Spedali Civil Brescia, Diagnost Dept, Biotechnol Lab, I-25125 Brescia, Italy

[7] Univ Brescia, Dept Med & Surg Sci, Brescia, Italy

[8] Spedali Civil Brescia, Dept Med & Surg Sci, I-25125 Brescia, Italy

[9] Expt Zooprofilattico Inst Lombardia & Emilia Roma, Brescia, Italy

[10] IRCCS Fdn Neurol Inst Carlo Besta, Dept Diagnost & Appl Technol, I-20133 Milan, Italy

来源：

LABORATORY INVESTIGATION | 2012年 / 92卷 / 09期

关键词：

adhesion molecules; angiogenesis; HCC; NCAM; stromal cells; TGF-beta; 1; vascular abnormalities; TUMOR ANGIOGENESIS; ENDOTHELIAL-CELL; BLOOD-VESSELS; PERICYTES; EXPRESSION; NCAM; ANGIOPOIETIN-1; FIBROBLASTS; STROMA; ACTIVATION;

D O I：

10.1038/labinvest.2012.94

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Hepatocellular carcinoma (HCC) is a very angiogenic and malignant cancer. Conventional chemotherapy is poorly effective because of the abnormal structural organization of HCC-infiltrating vessels. In previous work, we demonstrated that HCC angiogenesis is driven by transforming growth factor beta-1(TGF-beta 1)/CD105 axis, stimulating liver-derived microvascular endothelial cells (Ld-MECs) migration. As TGF-beta 1 also affects mural cells (MCs) recruitment and maturation, we asked whether it may contribute to HCC-induced vascular abnormalities. HCC and adjacent non-neoplastic liver (nNL) biopsies obtained from 12 patients were analyzed by immunohistochemistry for angiogenic markers CD105, TGF-beta 1, CD44 and vascular endothelial growth factor-a (VEGFa) and for MC markers NG2, alpha-smooth muscle actin (alpha SMA) and neural cell adhesion molecule (NCAM). The same markers were also investigated by immunocytochemistry on cultured HCC-derived stromal cells (HCC-StCs) and nNL-derived StCs (nNL-StCs) isolated from the same liver biopsies. Angiogenic factors released by StCs were analyzed by ELISA and the interaction between StCs and Ld-MECs by adhesion assay. Compared with nNL, HCC biopsies showed increased angiogenic markers and alpha SMA that was localized in vessels. By contrast, NG2 and NCAM were substantially localized in tumor cells but absent in vessels and stroma. Cultured HCC-StCs showed less expression of NG2, alpha SMA and NCAM. They also demonstrated a lower capacity to release angiogenic factors and adhered on Ld-MECs. HCC-StCs and nNL-StCs treated with TGF-beta 1 or with of HepG2 (a human hepatoma cell line) derived conditioned medium (CM), down-modulated NCAM expression, whereas anti-NCAM antibodies significantly reduced the adhesion of StCs to Ld-MECs. By further blocking TGF-beta 1 with anti-TGF-beta 1 antibodies or with Ly-364947 (a specific inhibitor TGF-beta 1-receptor) adhesion to Ld-MECs and NCAM expression respectively was partially restored. TGF-beta 1 contributes to HCC-induced vascular alterations by affecting the interaction between HCC-StCs and Ld-MECs through a down-modulation of NCAM expression. Laboratory Investigation (2012) 92, 1297-1309; doi:10.1038/labinvest.2012.94; published online 25 June 2012

引用

页码：1297 / 1309

页数：13

共 59 条

[51] Clinical evaluation of urinary transforming growth factor-beta 1 and serum alpha-fetoprotein as tumour markers of hepatocellular carcinoma [J].