Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor beta signaling.
Diffuse-type gastric carcinoma: progression, angiogenesis, and transforming growth factor beta signaling.
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DOI：
10.1093/jnci/djp058
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发表时间：
2009-04-15
期刊：
影响因子：
--
通讯作者：
Miyazono K
中科院分区：
文献类型：
--
作者：
Komuro A;Yashiro M;Iwata C;Morishita Y;Johansson E;Matsumoto Y;Watanabe A;Aburatani H;Miyoshi H;Kiyono K;Shirai YT;Suzuki HI;Hirakawa K;Kano MR;Miyazono K
弥漫型胃癌是一种预后不良的癌症，具有高水平的转化生长因子β（TGF-β）表达和厚基质纤维化。然而，TGF-β信号转导与弥漫型胃癌的关系尚未得到详细研究。我们使用慢病毒感染系统在弥漫型胃癌细胞系OCUM-2 MLN和OCUM-12中表达显性阴性TGF-β II型受体（dnTβRII）或绿色荧光蛋白（GFP）作为对照。将这些感染的细胞和相应的亲本对照细胞皮下或原位注射到裸鼠中。通过用携带血管生成抑制剂血小板反应蛋白-1基因的慢病毒感染细胞或通过向小鼠腹腔内注射小分子血管生成抑制剂索拉非尼或抗血管内皮生长因子（VEGF）中和抗体（每组6或8只小鼠）来抑制血管生成。应用免疫组化方法检测102例胃癌组织中磷酸化Smad 2和血小板反应蛋白1的表达。所有统计学检验均为双侧检验。DNTβRII在OCUM-2 MLN细胞中的表达不影响其体外增殖，但在体内可促进皮下或原位移植肿瘤的生长（例如，对于第10天皮下肿瘤相对于第0天的平均体积：dnTβRII肿瘤= 3.49和GFP肿瘤= 2.46，差异= 1.02，95%置信区间[CI] = 0.21至1.84; P = 0.003）。表达dnTβRII的肿瘤比表达GFP的肿瘤具有更高水平的血管生成，因为血小板反应蛋白-1的产生减少。用OCUM-12细胞获得了类似的结果。血小板反应蛋白-1在dnTβRII肿瘤中的表达或用索拉非尼或抗VEGF抗体治疗可降低肿瘤生长，而血小板反应蛋白-1表达的敲低导致OCUM-2 MLN肿瘤比GFP肿瘤生长更快（例如，相对于第0天的平均肿瘤体积，第14天的平均肿瘤体积：血小板反应蛋白-1-敲低肿瘤= 4.91和GFP肿瘤= 3.79，差异= 1.12，95%CI = 0.80至1.44; P < .001）。胃癌组织中磷酸化Smad 2与血小板反应蛋白-1的表达呈正相关。在弥漫型胃癌模型中，TGF-β信号传导的破坏似乎加速了肿瘤生长，这显然是通过血小板反应蛋白-1表达减少诱导的肿瘤血管生成增加来实现的。
Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor β (TGF-β) expression and thick stromal fibrosis. However, the association of TGF-β signaling with diffuse-type gastric carcinoma has not been investigated in detail. We used a lentiviral infection system to express a dominant-negative TGF-β type II receptor (dnTβRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided. Expression of dnTβRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTβRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnTβRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTβRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1–knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues. Disruption of TGF-β signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.
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影响因子：
11.5
作者：
Ebbinghaus, Scot;Hussain, Maha;Figlin, Robert
通讯作者：
Figlin, Robert
影响因子：
13.6
作者：
Nakagawa, T;Lan, HY;Sautin, YY
通讯作者：
Sautin, YY
影响因子：
11.5
作者：
Okano, H;Shinohara, H;Tanigawa, N
通讯作者：
Tanigawa, N
DOI：
10.1111/apm.1965.64.1.31
发表时间：
1965-01-01
期刊：
ACTA PATHOLOGICA ET MICROBIOLOGICA SCANDINAVICA
影响因子：
--
作者：
LAUREN, P
通讯作者：
LAUREN, P
影响因子：
11.2
作者：
Liu, Li;Cao, Yichen;Carter, Christopher
通讯作者：
Carter, Christopher