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Transforming growth factor-beta and cancer: a love-hate relationship?
1Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06520, USA. Michael_Reiss@quickmail.yale.edu
Abstract:
This commentary proposes the working hypothesis that transforming growth factor-beta (TGF-beta) can play two different and opposite roles with respect to the process of malignant progression. During the earliest stages of carcinogenesis, TGF-beta can act as potent tumor suppressor and may mediate the actions of chemopreventive agents such as retinoids and tamoxifen. However, at some point during the development and progression of malignant neoplasms, bioactive TGF-betas make their appearance in the tumor microenvironment and the tumor cells appear to escape from TGF-beta-dependent growth arrest. Evidence is accumulating rapidly that this TGF-beta resistance is the consequence of inactivating mutations in any one of the genes that encode signaling intermediates, which include the type I and type II TGF-beta receptors, as well as several Smad proteins. The potential implications of the phenotypic switch from TGF-beta sensitive to TGF-beta resistance that occurs during carcinogenesis for cancer prevention and treatment are discussed.
Insights
Transforming growth factor-beta (TGF-beta) acts as a tumor suppressor early in cancer but promotes progression later. Cancer cells develop resistance to TGF-beta
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor-beta (TGF-beta) is a cytokine with complex roles in cancer.
- Early in carcinogenesis, TGF-beta can inhibit tumor growth and mediate chemopreventive effects.
- Tumor cells can become resistant to TGF-beta during malignant progression.
Purpose of the Study:
- To propose a working hypothesis on the dual role of TGF-beta in malignant progression.
- To discuss the implications of TGF-beta's switch from tumor suppressor to tumor promoter.
- To explore the mechanisms and consequences of TGF-beta resistance in cancer.
Main Methods:
- This is a theoretical commentary based on existing evidence.
- It synthesizes findings from various studies on TGF-beta signaling and cancer.
- The authors propose a hypothesis and discuss its implications.
Main Results:
- TGF-beta acts as a tumor suppressor in early carcinogenesis.
- Later in cancer development, TGF-beta promotes malignant progression.
- Acquired resistance to TGF-beta, often due to mutations in signaling pathways (e.g., TGF-beta receptors, Smads), is a key event.
Conclusions:
- The dual role of TGF-beta in cancer is dependent on the stage of malignant progression.
- Understanding the switch to TGF-beta resistance is crucial for developing effective cancer prevention and treatment strategies.
- Targeting TGF-beta signaling or overcoming resistance mechanisms may offer therapeutic benefits.