Oft M, Heider K H, Beug H
IMP Research Institute for Molecular Pathology Dr Bohrgasse 7 A 1030 Vienna Austria Onyx Pharmaceuticals 3031 Research Drive, Building A, Richmond, California, 94806, USA.
Curr Biol. 1998 Nov 19;8(23):1243-52. doi: 10.1016/s0960-9822(07)00533-7.
Invasive growth of epithelial tumor cells, a major cause of death from cancer in humans, involves loss of epithelial polarity and dedifferentiation. Transforming growth factor beta (TGFbeta) is regarded as a major tumor suppressor during early tumor development because it inhibits cell-cycle progression and tumor growth. Many dedifferentiated, late-stage tumors are resistant to growth inhibition by TGFbeta, however, and even secrete TGFbeta. In line with this, TGFbeta is involved in angiogenesis, wound healing and epithelial-mesenchymal transition (EMT) during development. Ha-Ras-transformed mammary epithelial cells (EpRas) undergo TGFbeta-induced EMT maintained via a TGFbeta autocrine loop. Thus, we have analyzed whether signal transduction by the TGFbeta receptor (TGFbetaR) is required for local tumor cell invasion and metastasis.
A dominant-negative type II TGFbetaR (TGFbetaRII-dn) was expressed using retroviral vectors in EpRas cells and highly metastatic mesenchymal mouse colon carcinoma cells (CT26). In both cell types, TGFbetaRII-dn blocked TGFbetaR signaling and heavily delayed tumor formation. In EpRas cells, TGFbetaRII-dn prevented EMT. In the dedifferentiated mesenchymal CT26 cells, TGFbetaRII-dn caused mesenchymal-to-epithelial transition and inhibited their in vitro invasiveness in several assays. In addition, TGFbetaRII-dn completely abolished metastasis formation by CT26 cells. Furthermore, several human carcinoma lines lost in vitro invasiveness when treated with neutralizing TGFbeta antibodies or soluble receptor variants. Finally, human colon carcinoma cells (hnPCC) expressing a mutated, non-functional TGFbetaRII were non-invasive in vitro, a defect restored by re-expressing wild-type TGFbetaRII.
Cell-autonomous TGFbeta signaling is required for both induction and maintenance of in vitro invasiveness and metastasis during late-stage tumorigenesis. TGFbetaRII therefore represents a potential target for therapeutical intervention in human tumorigenesis.
上皮肿瘤细胞的侵袭性生长是人类癌症死亡的主要原因，涉及上皮极性丧失和去分化。转化生长因子β（TGFβ）在肿瘤早期发展过程中被视为主要的肿瘤抑制因子，因为它能抑制细胞周期进程和肿瘤生长。然而，许多去分化的晚期肿瘤对TGFβ介导的生长抑制具有抗性，甚至会分泌TGFβ。与此相符的是，TGFβ在发育过程中参与血管生成、伤口愈合和上皮-间质转化（EMT）。Ha-Ras转化的乳腺上皮细胞（EpRas）通过TGFβ自分泌环维持TGFβ诱导的EMT。因此，我们分析了TGFβ受体（TGFβR）的信号转导是否是局部肿瘤细胞侵袭和转移所必需的。
使用逆转录病毒载体在EpRas细胞和高转移性间充质小鼠结肠癌细胞（CT26）中表达显性负性II型TGFβR（TGFβRII-dn）。在这两种细胞类型中，TGFβRII-dn均阻断TGFβR信号传导并严重延迟肿瘤形成。在EpRas细胞中，TGFβRII-dn可防止EMT。在去分化的间充质CT26细胞中，TGFβRII-dn导致间质向上皮转化，并在多种实验中抑制其体外侵袭性。此外，TGFβRII-dn完全消除了CT26细胞的转移形成。此外，几种人癌细胞系在用中和性TGFβ抗体或可溶性受体变体处理后丧失了体外侵袭性。最后，表达突变的、无功能的TGFβRII的人结肠癌细胞（hnPCC）在体外无侵袭性，通过重新表达野生型TGFβRII可修复该缺陷。
在晚期肿瘤发生过程中，细胞自主的TGFβ信号传导对于体外侵袭性和转移的诱导及维持均是必需的。因此，TGFβRII代表了人类肿瘤发生治疗干预的潜在靶点。
