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Contextual effects of transforming growth factor beta on the tumorigenicity of human colon carcinoma cells
S C Ye1, J M Foster, W Li
1Department of Biochemistry and Molecular Biology, Medical College of Ohio at Toledo, 43614-2595, USA.
Abstract:
Transforming growth factor betas (TGF-betas) are a growth factor family with negative autocrine growth functions for most epithelial cells including colon carcinoma cell lines. Both type I (RI) and type II (RII) transmembrane TGF-beta receptors have been shown to be indispensable for TGF-beta-mediated cell growth regulation. Previous studies using different model systems have shown that both overexpression of TGF-beta1 and transfection of antisense TGF-beta1 to reduce TGF-beta1 expression could lead to increased tumorigenicity. These results are seemingly contradictory and suggest that effects of TGF-beta modulation on malignant properties of cancer cells may be contextual. This study addresses this issue using human colon carcinoma cells (CBS and FET) to determine the effects of modulation of the various components of the TGF-beta system on in vitro and in vivo growth properties in two independent isogenic models of colon carcinoma. Cells were stably transfected with a tetracycline-repressible RII expression vector (CBS4-RII), a tetracycline-repressible expression vector containing a truncated RII cDNA lacking the serine/threonine kinase domain (CBS4-deltaRII and FET6-deltaRII), or with a vector containing the TGF-beta1 cDNA (CBS4-beta1S and FET-beta1S). Expression of the truncated RII reduced TGF-beta sensitivity, whereas overexpression of RII increased TGF-beta sensitivity. TGF-beta overexpression did not affect TGF-beta response. In vivo tumorigenicity assays revealed that CBS4-RII cells had lower tumorigenicity than control cells, whereas CBS4-deltaRII and CBS4-beta1S had higher tumorigenicity than controls. The CBS4 cells are poorly tumorigenic in athymic mice, and the wild-type FET6 cells are nontumorigenic. FET6-deltaRII cells formed rapidly growing tumors, and FET-beta1S cells also formed tumors. These data illustrate the paradoxical tumor-promoting and -suppressing effects of TGF-beta signaling activity in two isogenic model systems from human colon carcinomas, thus demonstrating that the effects of modulation of TGF-beta expression or TGF-beta signaling capability affects malignancy in a contextual manner.
Insights
Transforming growth factor-beta (TGF-beta) signaling has paradoxical effects on colon carcinoma. Modulating TGF-beta receptors or ligands can either suppress or promote tumor growth depending on the specific genetic context.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Transforming growth factor-betas (TGF-betas) are known for their negative autocrine growth functions in epithelial cells, including colon carcinoma.
- Both type I (RI) and type II (RII) TGF-beta receptors are crucial for TGF-beta-mediated growth regulation.
- Previous studies on TGF-beta modulation in cancer have yielded contradictory results regarding tumorigenicity, suggesting context-dependent effects.
Purpose of the Study:
- To investigate the context-dependent effects of modulating the TGF-beta system on colon carcinoma cell growth.
- To determine how alterations in TGF-beta receptor II (RII) expression or TGF-beta1 ligand levels impact in vitro and in vivo tumorigenicity.
- To elucidate the paradoxical tumor-promoting and -suppressing roles of TGF-beta signaling in colon cancer.
Main Methods:
- Utilized two independent isogenic human colon carcinoma cell line models (CBS and FET).
- Generated stable cell lines with tetracycline-repressible expression vectors for RII, a truncated RII lacking kinase activity (deltaRII), or TGF-beta1.
- Assessed TGF-beta sensitivity, in vitro growth, and in vivo tumorigenicity in athymic mice.
Main Results:
- Overexpression of RII increased TGF-beta sensitivity and reduced tumorigenicity in CBS4 cells.
- Expression of truncated RII (deltaRII) or TGF-beta1 (beta1S) increased TGF-beta insensitivity and enhanced tumorigenicity in both CBS4 and FET6 models.
- FET6-deltaRII and FET-beta1S cells formed rapidly growing tumors, while wild-type FET6 cells were nontumorigenic.
Conclusions:
- TGF-beta signaling exhibits paradoxical tumor-suppressing and tumor-promoting effects in colon carcinoma.
- The impact of TGF-beta modulation on malignancy is highly contextual, depending on the specific genetic alterations and cellular environment.
- These findings highlight the complex role of TGF-beta in colon cancer progression and suggest therapeutic strategies must consider context-specific signaling.