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Differential expression of transforming growth factor beta receptors in human pancreatic adenocarcinoma
K Venkatasubbarao1, M M Ahmed, M Mohiuddin
1Department of Surgery, University of Texas Health Science Center, San Antonio 78284, USA.
Background:
Many cancer cells show resistance to transforming growth factor beta (TGF-beta)-mediated growth inhibition. This resistance to TGF-beta is associated with an increased tumorigenic phenotype.
Objective:
In this study, we determined whether a loss in expression of TGF-beta receptors or DPC4, an important down stream target of TGF-beta signaling, might account for this lack of TGF-beta sensitivity in pancreatic adenocarcinoma.
Materials And Methods:
To accomplish this, six established pancreatic cancer cell lines, twenty-six surgically resected tumor specimens of pancreatic adenocarcinoma and ten non-tumor pancreas tissues were analyzed for the mRNA expression of the three TGF-beta receptors (RI, RII, and RIII) and DPC4.
Results:
We report here that five of six pancreatic cancer cell lines were not sensitive to TGF-beta. All the ten non-tumor specimens of pancreas showed expression of RI, and DPC4; while nine of ten showed expression of RIII and eight of ten showed expression of RII. Five of six pancreatic cancer cell lines and 23 of 26 tumor specimens showed expression of RI. Two cell lines and about half (46%) of the tumor specimens did not express RII. Only two cell lines showed appreciable levels of RIII expression; while ten of 26 (38%) tumor specimens did not show expression of RIII. DPC4 expression was observed in three of the six (50%) cell lines and 19 of 24 (79%) tumor specimens.
Conclusion:
This study indicates that apart from the functional loss of DPC4 due to mutations or homozygous deletion, a lack of the TGF-beta receptors, particularly RII and RIII, may contribute to a loss of TGF-beta signaling in a population of pancreatic cancers.
Insights
Pancreatic cancers often resist TGF-beta growth inhibition. Loss of TGF-beta receptors (RI, RII, RIII) or DPC4 signaling contributes to this resistance, impacting pancreatic adenocarcinoma development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Many cancer cells exhibit resistance to transforming growth factor beta (TGF-beta)-mediated growth inhibition.
- This resistance is linked to an enhanced tumorigenic phenotype in cancer cells.
Purpose of the Study:
- To investigate if reduced expression of TGF-beta receptors or DPC4 explains TGF-beta insensitivity in pancreatic adenocarcinoma.
- To analyze the expression patterns of TGF-beta receptors (RI, RII, RIII) and DPC4 in pancreatic cancer.
Main Methods:
- Analysis of mRNA expression of TGF-beta receptors (RI, RII, RIII) and DPC4.
- Study included six pancreatic cancer cell lines, 26 tumor specimens, and 10 non-tumor pancreas tissues.
Main Results:
- Five of six pancreatic cancer cell lines were insensitive to TGF-beta.
- Reduced expression of TGF-beta receptors RII and RIII was observed in cell lines and tumor specimens.
- DPC4 expression was also altered in a significant portion of cell lines and tumors.
Conclusions:
- Loss of TGF-beta receptors (RII, RIII) and/or DPC4 contributes to TGF-beta signaling loss in pancreatic cancers.
- These molecular alterations may play a role in the development and progression of pancreatic adenocarcinoma.