Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth:: Involvement of transforming growth factor β1
Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth:: Involvement of transforming growth factor β1
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DOI：
10.1038/13524
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发表时间：
1999-10-01
期刊：
影响因子：
82.9
通讯作者：
Jain, RK
中科院分区：
文献类型：
--
作者：
Gohongi, T;Fukumura, D;Jain, RK
由原发性肿瘤产生的血管生成抑制剂可以产生全身性抗血管生成环境，并使转移性肿瘤细胞保持休眠状态（1，2）。我们在这里表明，胆囊微环境调节转化生长因子（TGF）-β 1，一种多功能的细胞因子，作为一种内源性的抗血管生成和抗肿瘤因子在颅窗准备的生产。我们发现，各种各样的人胆囊肿瘤表达TGF-β 1的组织学类型无关。我们在没有肿瘤的小鼠或具有皮下或胆囊肿瘤的小鼠的颅窗中植入浸渍有碱性成纤维细胞生长因子（3）或Mz-ChA-2肿瘤的凝胶，以研究次级部位的血管生成和肿瘤生长。在胆囊肿瘤小鼠中，血管中的血管生成、白细胞-内皮细胞相互作用和颅窗中的肿瘤生长基本上受到抑制。胆囊肿瘤小鼠血浆中的TGF-β 1浓度比无肿瘤或皮下肿瘤小鼠血浆中的浓度高300%。相反，其他抗血管生成因子和促血管生成因子的血浆水平没有差异。用抗TGF-β 1中和抗体治疗可逆转胆囊肿瘤诱导的血管生成抑制和白细胞滚动抑制。TGF-β 1还抑制Mz-ChA-2肿瘤细胞增殖。我们的研究结果表明，抗血管生成/增殖因子的生产是由肿瘤-宿主相互作用。
Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy(1,2). We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta 1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and antitumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta 1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor(3) or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta 1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta 1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta 1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.