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TGF-Beta suppresses VEGFA-mediated angiogenesis in colon cancer metastasis
Liying Geng1, Anathbandhu Chaudhuri, Geoffrey Talmon
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Abstract:
The FET cell line, derived from an early stage colon carcinoma, is non-tumorigenic in athymic nude mice. Engineered FET cells that express TGF-α (FETα) display constitutively active EGFR/ErbB signaling. These cells readily formed xenograft tumors in athymic nude mice. Importantly, FETα cells retained their response to TGF-beta-mediated growth inhibition, and, like the parental FET cells, expression of a dominant negative TGF-beta type II receptor (DNRII) in FETα cells (FETα/DNRII) abrogated responsiveness to TGF-beta-induced growth inhibition and apoptosis under stress conditions in vitro and increased metastatic potential in an orthotopic model in vivo, which indicates metastasis suppressor activity of TGF-beta signaling in this model. Cancer angiogenesis is widely regarded as a key attribute for tumor formation and progression. Here we show that TGF-beta signaling inhibits expression of vascular endothelial growth factor A (VEGFA) and that loss of autocrine TGF-beta in FETα/DNRII cells resulted in increased expression of VEGFA. Regulation of VEGFA expression by TGF-beta is not at the transcriptional level but at the post-transcriptional level. Our results indicate that TGF-beta decreases VEGFA protein stability through ubiquitination and degradation in a PKA- and Smad3-dependent and Smad2-independent pathway. Immunohistochemical (IHC) analyses of orthotopic tumors showed significantly reduced TGF-beta signaling, increased CD31 and VEGFA staining in tumors of FETα/DNRII cells as compared to those of vector control cells. These results indicate that inhibition of TGF-beta signaling increases VEGFA expression and angiogenesis, which could potentially contribute to enhanced metastasis of those cells in vivo. IHC studies performed on human colon adenocarcinoma specimens showed that TGF-beta signaling is inversely correlated with VEGFA expression, indicating that TGF-beta-mediated suppression of VEGFA expression exists in colon cancer patients.
Insights
Transforming growth factor-beta (TGF-β) signaling suppresses colon cancer metastasis by inhibiting vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Loss of TGF-β signaling increases VEGFA, promoting tumor growth and spread.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- The FET cell line, derived from colon carcinoma, is non-tumorigenic but becomes tumorigenic when engineered to express TGF-α (FETα), activating EGFR/ErbB signaling.
- TGF-β signaling normally inhibits growth and induces apoptosis in FET cells, but blocking TGF-β receptor type II (DNRII) abrogates this response and increases metastatic potential.
Purpose of the Study:
- To investigate the role of TGF-β signaling in colon cancer metastasis, focusing on its regulation of angiogenesis and VEGFA expression.
- To elucidate the mechanism by which TGF-β controls VEGFA levels and its impact on tumor progression and metastasis.
Main Methods:
- Utilized engineered FETα cells with dominant-negative TGF-β type II receptor (FETα/DNRII) to study TGF-β signaling loss in vitro and in vivo orthotopic models.
- Analyzed VEGFA expression, angiogenesis markers (CD31), and TGF-β signaling activity via immunohistochemistry (IHC).
- Investigated TGF-β's regulation of VEGFA at the post-transcriptional level, including ubiquitination and protein degradation pathways.
Main Results:
- Loss of TGF-β signaling in FETα/DNRII cells led to increased VEGFA expression and angiogenesis, correlating with enhanced metastatic potential.
- TGF-β inhibits VEGFA protein stability post-transcriptionally via ubiquitination and degradation, dependent on PKA and Smad3 but independent of Smad2.
- IHC analysis of human colon adenocarcinoma specimens revealed an inverse correlation between TGF-β signaling and VEGFA expression.
Conclusions:
- TGF-β signaling acts as a metastasis suppressor in this colon cancer model by inhibiting VEGFA expression and subsequent angiogenesis.
- Disruption of TGF-β signaling promotes tumor angiogenesis and metastasis through increased VEGFA levels.
- The findings highlight TGF-β's role in controlling VEGFA stability and suggest therapeutic potential in targeting this pathway for colon cancer treatment.
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