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TGFbeta-regulated transcriptional mechanisms in cancer
Volker Ellenrieder1, Anita Buck, Thomas M Gress
1Department of Internal Medicine I, University of Ulm, Ulm, Germany. volker.ellenrieder@medizin.uni-ulm.de
Abstract:
Transforming growth factor-beta (TGFbeta) has been implicated in oncogenesis for many years. The multifunctional activities of TGFbeta endow it with both tumor suppressor and tumor promoting activities, depending on the stage of carcinogenesis and the responsivity of the tumor cell. In early tumor stages, TGFbeta inhibits epithelial cell growth through induction of apoptosis and cell cycle arrest. During tumor development, however, many tumor cells lose their growth-inhibitory responses to TGFbeta owing to genetic alterations or signaling perturbations such as oncogenic Ras signaling. Loss of TGFbeta-growth inhibition is commonly associated with increased tumor cell invasion and metastasis of tumor cells that undergo an epithelial-mesenchymal transition. Interestingly, the tumor-promoting effects of TGFbeta on the tumor cells are observed particularly in cells in which TGFbeta-signaling remains functional despite loss of growth control by TGFbeta. New insights into transcriptional mechanisms activated by TGFbeta are providing a better understanding of the cellular changes involved in the switch of TGFbeta from a tumor suppressor to a tumor promotor.
Insights
Transforming growth factor-beta (TGFbeta) acts as a tumor suppressor early in cancer but can promote tumor growth and metastasis later. Understanding TGFbeta
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Transforming growth factor-beta (TGFbeta) exhibits dual roles in oncogenesis, acting as both a tumor suppressor and promoter.
- TGFbeta's function varies with cancer stage and tumor cell responsiveness.
- Early-stage cancers show TGFbeta-induced growth inhibition via apoptosis and cell cycle arrest.
Purpose of the Study:
- To elucidate the mechanisms behind TGFbeta's switch from tumor suppression to promotion.
- To understand how tumor cells evade TGFbeta-mediated growth inhibition.
- To explore the role of TGFbeta signaling in tumor invasion and metastasis.
Main Methods:
- Analysis of transcriptional mechanisms activated by TGFbeta.
- Investigation of genetic alterations and signaling perturbations (e.g., oncogenic Ras) affecting TGFbeta responsiveness.
- Study of epithelial-mesenchymal transition in relation to TGFbeta signaling.
Main Results:
- Many tumor cells lose growth inhibition by TGFbeta due to genetic alterations or signaling issues.
- Loss of TGFbeta growth inhibition correlates with increased tumor cell invasion and metastasis.
- TGFbeta promotes tumor cells that retain functional signaling despite lost growth control.
Conclusions:
- TGFbeta's dual role is critical in cancer progression.
- Understanding TGFbeta's transcriptional regulation is key to explaining its context-dependent functions.
- Targeting TGFbeta signaling pathways may offer therapeutic strategies for advanced cancers.