Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model.
Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model.
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DOI：
10.1002/hep4.1131
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发表时间：
2018-03
影响因子：
5.1
通讯作者：
Sirica AE
中科院分区：
文献类型：
--
作者：
Manzanares MÁ;Campbell DJW;Maldonado GT;Sirica AE
骨膜蛋白和间皮素都被认为是肝内胆管癌患者生存率差的预测因子，尽管这两种生物标志物的临床预后价值仍不确定。本研究的目的是研究这些生物标志物在大鼠胆管癌进展的原位肿瘤和三维培养模型中评估时作为肿瘤进展因子的潜力。使用我们的原位模型，我们证明了肿瘤与血清骨膜蛋白和间皮素之间的强正相关性，以及肝肿瘤质量的增加和相关的腹膜转移，这也反映了胆管癌细胞侵袭性和恶性等级的差异。骨膜蛋白免疫染色在较大的、侵袭性更强的肝肿瘤和腹膜转移瘤的促结缔组织增生间质中最为突出。相比之下，间皮素在胆管癌细胞中表达更高;生长较慢的高度分化的肝肿瘤表现出这种生物标志物的管腔癌细胞表面免疫染色，而快速生长的分化程度较低的肝和转移性肿瘤块主要表现出细胞质间皮素免疫反应性。鉴定了两种分子量形式的间皮素，一种为1040 kDa，另一种为1050 kDa的更重糖基化形式。在三维培养中，40 kDa间皮素的表达高于50 kDa形式的表达，预示着原位肝肿瘤和不同恶性潜能的胆管癌细胞的恶性进展增加。此外，癌相关肌成纤维细胞与胆管癌细胞的共培养促进了40 kDa间皮素的过表达，这与体外恶性进展增强相关。结论：在我们的大鼠促结缔组织增生性胆管癌模型中，骨膜蛋白和间皮素是肿瘤进展的有用预测因子。这支持了它们与人类肝内胆管癌的相关性。（Hepatology Communications 2018;2：155-172）
Periostin and mesothelin have each been suggested to be predictors of poor survival for patients with intrahepatic cholangiocarcinoma, although the clinical prognostic value of both of these biomarkers remains uncertain. The aim of the current study was to investigate these biomarkers for their potential to act as tumor progression factors when assessed in orthotopic tumor and three‐dimensional culture models of rat cholangiocarcinoma progression. Using our orthotopic model, we demonstrated a strong positive correlation between tumor and serum periostin and mesothelin and increasing liver tumor mass and associated peritoneal metastases that also reflected differences in cholangiocarcinoma cell aggressiveness and malignant grade. Periostin immunostaining was most prominent in the desmoplastic stroma of larger sized more aggressive liver tumors and peritoneal metastases. In comparison, mesothelin was more highly expressed in the cholangiocarcinoma cells; the slower growing more highly differentiated liver tumors exhibited a luminal cancer cell surface immunostaining for this biomarker, and the rapidly growing less differentiated liver and metastatic tumor masses largely showed cytoplasmic mesothelin immunoreactivity. Two molecular weight forms of mesothelin were identified, one at ∼40 kDa and the other, a more heavily glycosylated form, at ∼50 kDa. Increased expression of the 40‐kDa mesothelin over that of the 50 kDa form predicted increased malignant progression in both the orthotopic liver tumors and in cholangiocarcinoma cells of different malignant potential in three‐dimensional culture. Moreover, coculturing of cancer‐associated myofibroblasts with cholangiocarcinoma cells promoted overexpression of the 40‐kDa mesothelin, which correlated with enhanced malignant progression in vitro. Conclusion: Periostin and mesothelin are useful predictors of tumor progression in our rat desmoplastic cholangiocarcinoma models. This supports their relevance to human intrahepatic cholangiocarcinoma. (Hepatology Communications 2018;2:155–172)
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影响因子：
3.7
作者：
Fukamachi K;Iigo M;Hagiwara Y;Shibata K;Futakuchi M;Alexander DB;Hino O;Suzui M;Tsuda H
通讯作者：
Tsuda H
影响因子：
3.7
作者：
Choi, Sae-Byeol;Kim, Kyung-Sik;Chung, Jae-Bock
通讯作者：
Chung, Jae-Bock
影响因子：
3.6
作者：
Dumur, Catherine I.;Campbell, Deanna J. W.;Sirica, Alphonse E.
通讯作者：
Sirica, Alphonse E.
DOI：
10.1111/j.1872-034x.2012.01026.x
发表时间：
2012-11
期刊：
Hepatology research : the official journal of the Japan Society of Hepatology
影响因子：
--
作者：
Campbell DJ;Dumur CI;Lamour NF;Dewitt JL;Sirica AE
通讯作者：
Sirica AE
影响因子：
15.9
作者：
Koyama, Yukinori;Wang, Ping;Kisseleva, Tatiana
通讯作者：
Kisseleva, Tatiana