Endothelial transdifferentiation in hepatocellular carcinoma: loss of Stabilin-2 expression in peri-tumourous liver correlates with increased survival

被引：71

作者：

Geraud, Cyrill ^{[1
,2
,3
]}

Mogler, Carolin ^{[6
]}

Runge, Anja ^{[4
,5
]}

Evdokimov, Konstantin ^{[1
,2
,3
]}

Lu, Shun ^{[1
,2
,3
]}

Schledzewski, Kai ^{[1
,2
,3
]}

Arnold, Bernd ^{[7
]}

Haemmerling, Guenter ^{[7
]}

Koch, Philipp S. ^{[1
,2
,3
]}

Breuhahn, Kai ^{[6
]}

Longerich, Thomas ^{[6
]}

Marx, Alexander ^{[2
,8
]}

Weiss, Christel ^{[9
]}

Damm, Friederike ^{[1
,2
,3
]}

Schmieder, Astrid ^{[1
,2
,3
]}

Schirmacher, Peter ^{[6
]}

Augustin, Hellmut G. ^{[4
,5
]}

Goerdt, Sergij ^{[1
,2
,3
]}

机构：

[1] Univ Med Ctr, Dept Dermatol Venereol & Allergol, Mannheim, Germany

[2] Heidelberg Univ, Med Fac Mannheim, Mannheim, Germany

[3] Ctr Excellence Dermatol, Mannheim, Germany

[4] Heidelberg Univ, Med Fac Mannheim, Joint Res Div Vasc Biol, Heidelberg, Germany

[5] German Canc Res Ctr, Heidelberg, Germany

[6] Heidelberg Univ, Inst Pathol, Univ Clin Heidelberg, Heidelberg, Germany

[7] German Canc Res Ctr, Dept Mol Immunol, Heidelberg, Germany

[8] Univ Med Ctr, Dept Pathol, Mannheim, Germany

[9] Heidelberg Univ, Med Fac Mannheim, Div Med Stat, Mannheim, Germany

来源：

LIVER INTERNATIONAL | 2013年 / 33卷 / 09期

关键词：

CD32; hepatocellular carcinoma; LSEC; Lyve-1; sinusoidal endothelial cell; Stabilin; tumour endothelium; ALTERNATIVELY ACTIVATED MACROPHAGES; DYSPLASTIC NODULES; CELL-ADHESION; SINUSOIDAL ENDOTHELIUM; VESSEL COOPTION; MODEL; ANGIOGENESIS; PROTEIN; GROWTH; HYALURONAN;

D O I：

10.1111/liv.12262

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

Background & Aims: Hepatocellular carcinoma (HCC) is a malignant tumour that is characterized by extensive vascular remodelling and responsiveness to treatment with the anti-angiogenic multikinase inhibitor sorafenib. The aim was to study endothelial remodelling in HCC. Methods: The murine inducible albumin-SV40-large T-antigen model and two tissue micro-arrays (TMA) with 295 tumourous and 83 peri-tumourous samples of 296 patients with HCC were analysed for expression of liver sinusoidal endothelial cell (LSEC)-specific marker proteins, stabilin-1 and stabilin-2, LYVE-1 and CD32b. Results: LSEC marker proteins were sequentially lost during HCC progression in the murine HCC model being absent from tumour nodules larger than 800 mu m in diameter. Similarly, the TMA analysis of human HCCs revealed loss of all four marker proteins in the majority of tumourous tissue samples. Preservation of LYVE-1 expression showed a significant correlation with low grading (G1). In corresponding peri-tumourous liver tissue, loss of all marker proteins was seen in a minor proportion of cases (34%) while the majority of cases retained expression of at least one of the marker proteins. Loss of stabilin-2 expression in peri-tumourous liver tissue of patients with HCC was significantly less likely to occur (38%) than loss of the other marker proteins (63-95%) and it was associated with significantly longer tumour-specific (P = 0.0523) and overall (P = 0.0338) survival. Loss of stabilin-2 may enhance survival in HCC by preventing endothelial-tumour cell adhesive interactions and microvascular invasion. Conclusions: In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.

引用

页码：1428 / 1440

页数：13

共 59 条

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