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TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis
1IMP Research Institute for Molecular Pathology Dr Bohrgasse 7 A 1030 Vienna Austria Onyx Pharmaceuticals 3031 Research Drive, Building A, Richmond, California, 94806, USA. martin@onyx-pharm.com.
Background:
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.
Results:
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.
Conclusions:
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.
Insights
Transforming growth factor beta receptor (TGFbetaR) signaling is essential for tumor cell invasion and metastasis. Blocking TGFbetaR inhibits cancer cell invasiveness and metastasis, suggesting TGFbetaR as a therapeutic target for late-stage cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Invasive tumor growth, a primary cause of cancer mortality, involves loss of epithelial polarity and dedifferentiation.
- Transforming growth factor beta (TGFbeta) typically suppresses early tumor development but is often co-opted by late-stage tumors.
- TGFbeta plays roles in angiogenesis, wound healing, and epithelial-mesenchymal transition (EMT), a process crucial for invasion.
Purpose of the Study:
- To investigate the role of signal transduction by the TGFbeta receptor (TGFbetaR) in local tumor cell invasion and metastasis.
- To determine if TGFbetaR signaling is required for the invasive and metastatic potential of dedifferentiated tumor cells.
Main Methods:
- Engineered dominant-negative TGFbetaRII (TGFbetaRII-dn) in epithelial and metastatic cancer cell lines.
- Assessed tumor formation, EMT, in vitro invasiveness, and metastasis.
- Utilized neutralizing TGFbeta antibodies and soluble receptor variants in human carcinoma lines.
- Examined human colon carcinoma cells with mutated or wild-type TGFbetaRII.
Main Results:
- Expression of TGFbetaRII-dn significantly delayed tumor formation and prevented EMT in epithelial cells.
- In mesenchymal cells, TGFbetaRII-dn induced a mesenchymal-to-epithelial transition and inhibited in vitro invasiveness.
- TGFbetaRII-dn abolished metastasis in vivo and reduced invasiveness in human carcinoma cells.
- Non-functional TGFbetaRII in human colon cancer cells correlated with non-invasiveness, which was restored by wild-type TGFbetaRII re-expression.
Conclusions:
- Cell-autonomous TGFbeta signaling is indispensable for the induction and maintenance of invasiveness and metastasis in late-stage cancers.
- TGFbetaRII is a critical mediator of tumor cell invasion and metastasis.
- TGFbetaRII emerges as a promising therapeutic target for intervening in human tumorigenesis.