A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor beta1.
A subset of metastatic human colon cancers expresses elevated levels of transforming growth factor beta1.
复制标题
DOI：
--
复制
发表时间：
1998-06
期刊：
影响因子：
--
通讯作者：
A. Picon;L. Gold;Jingping Wang;A. Cohen;Eileen Friedman
中科院分区：
文献类型：
--
作者：
A. Picon;L. Gold;Jingping Wang;A. Cohen;Eileen Friedman
虽然转化生长因子（TGF）-β 1是正常上皮细胞（包括结肠细胞）的有效生长抑制剂，但TGF-β 1也被认为是结肠癌转移的增强剂。通过反义方法降低转移性U9结肠癌细胞系中的TGF-β 1蛋白水平可降低U9细胞向肝和皮下的转移。裸鼠系统中的肿瘤形成，并且确实出现的肿瘤已经恢复了TGF-β 1表达（F. Huang等人，Cell Growth Differ.，6：1635-1642，1995）。此外，在一项临床免疫组织化学研究中，发现在切除原发肿瘤后，TGF-β 1蛋白水平升高的结肠癌作为远处转移复发的可能性是表达低TGF-β 1水平的结肠癌的18倍（E. Friedman等人，Cancer Epidemiol.生物标记。Prev.，4：549-554，1995）。由于这两项研究都涉及TGF-β 1在结肠癌转移中的作用，我们希望知道对TGF-β 1的选择性偏倚是否在转移细胞中维持，或者仅仅是可能转移的原发部位肿瘤的一种特性。使用两种不同的抗体在成对的原发部位癌症及其转移灶中通过免疫组织化学和在选定的病例中通过Western印迹分析测量TGF-β 1水平。在21例抗体G和31例抗体P的病例中，分别有16例（76%）和23例（74%）在浸润局部淋巴结的结肠癌细胞中发现TGF-β 1的表达高于原发部位结肠癌细胞，或（分别有2例和6例）原发部位癌的高TGF-β 1表达在浸润细胞中得以维持。使用这两种抗体的Western印迹分析也表明，与原发部位肿瘤或正常组织相比，在转移灶中发现更高水平的TGF-β 1蛋白。检查了配对原发部位结肠癌、局部淋巴结转移和癌细胞转移至远处部位的其他病例。在8例此类病例中的6例（75%）中，与原发部位癌症（5例）相比，两种侵袭性细胞群中的TGF-β 1水平均升高，或者原发部位癌症中的高水平在转移性细胞中维持（1例）。这些数据表明，在大约75%的病例中，TGF-β 1在整个转移过程中促进结肠癌转移中发挥作用。TGF-β 1可能通过旁分泌机制增加转移，如抑制局部免疫反应或增加血管生成，如在U9细胞系中所见。在那些具有非突变的TGF-β受体和非突变的smad蛋白如U9细胞的癌症中，TGF-β 1也可以以自分泌方式起作用，通过增加细胞运动性来增加侵袭（Hsu et al.，细胞生长差异，5：267-275，1994）。
Although transforming growth factor (TGF)-beta1 is a potent growth inhibitor of normal epithelial cells including colonocytes, TGF-beta1 has also been implicated as an enhancer of colon cancer metastasis. Decreasing TGF-beta1 protein levels in the metastatic U9 colon cancer cell line by antisense methodology decreased both U9 cell metastasis to the liver and s.c. tumor formation in a nude mouse system, and the tumors that did arise had regained TGF-beta1 expression (F. Huang et al, Cell Growth Differ., 6: 1635-1642, 1995). In addition, in a clinical immunohistochemistry study, colon cancers with elevated TGF-beta1 protein levels were found to be 18 times more likely to recur as distant metastases than colon cancers expressing low TGF-beta1 levels, after resection of the primary tumor (E. Friedman et al, Cancer Epidemiol. Biomark. Prev., 4:549-554, 1995). Because both studies implicated TGF-beta1 in colon cancer metastasis, we wished to know whether a selection bias for TGF-beta1 was maintained in metastatic cells or was only a property of the primary site tumors that were likely to metastasize. TGF-beta1 levels were measured using two different antibodies in paired primary site cancers and their metastases by immunohistochemistry and, in selected cases, by Western blot analysis. In 16 of 21 cases (76%) with antibody G and 23 of 31 cases (74%) with antibody P, higher expression of TGF-beta1 was found in colon cancer cells invading local lymph nodes compared with primary site colon cancer cells, or (2 and 6 cases, respectively) high TGF-beta1 expression in the primary site cancer was maintained in invasive cells. Analysis by Western blotting using both antibodies also demonstrated that higher levels of TGF-beta1 protein were found in metastases compared with the primary site tumor or normal tissue. Additional cases of paired primary site colon cancer, local lymph node metastases, and cancer cells metastasizing to distant sites were examined. In six of eight such cases (75%), TGF-beta1 levels were increased in both invasive cell populations compared with the primary site cancer (five cases), or high levels in the primary site cancer were maintained in the metastatic cells (one case). These data suggest that TGF-beta1 plays a role in promoting colon cancer metastasis throughout the metastatic process in roughly 75% of cases. TGF-beta1 may increase metastasis by paracrine mechanisms, such as suppression of local immune response or increased angiogenesis, as was seen with the U9 cell line. In those cancers with nonmutated TGF-beta receptors and nonmutated smad proteins like U9 cells, TGF-beta1 could also act in an autocrine manner to increase invasion by increasing cell motility (Hsu et al., Cell Growth Differ., 5: 267-275, 1994).