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Spheroid Assay to Measure TGF-β-induced Invasion
Published on: November 16, 2011
Somatic acquisition and signaling of TGFBR1*6A in cancer
Boris Pasche1, Thomas J Knobloch, Yansong Bian
1Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, The Feinberg School of Medicine, Northwestern, University, Chicago, Ill 60611, USA. b-pasche@northwestern.edu
JAMA
|October 6, 2005
Summary
The common TGFBR1*6A polymorphism is acquired by colorectal cancer metastases, potentially promoting tumor growth by altering TGF-beta signaling. This suggests TGFBR1*6A as a therapeutic target in cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The type I transforming growth factor beta receptor (TGFBR1) polymorphism, TGFBR1*6A, is linked to cancer susceptibility.
- The precise mechanisms by which TGFBR1*6A contributes to cancer development remain largely unelucidated.
Purpose of the Study:
- To investigate the somatic acquisition of TGFBR1*6A in primary tumors and metastases.
- To determine if the distinguishing 3-amino acid deletion in TGFBR1*6A is part of the mature receptor or signal sequence.
- To explore the functional impact of TGFBR1*6A signaling in cancer cells.
Main Methods:
- Analysis of tumor and germline tissues from 531 cancer patients (head and neck, colorectal, breast).
- In vitro translation assays and stable transfection of cancer cell lines (MCF-7, DLD-1, SW48) with TGFBR1*6A variants.
- Assessment of TGF-beta-dependent cell proliferation and TGFBR1*6A somatic acquisition.
Main Results:
- TGFBR1*6A was somatically acquired in 29.5% of colorectal cancer metastases and in a smaller percentage of primary tumors.
- Somatic acquisition of TGFBR1*6A was not linked to genetic instability markers.
- The mature TGFBR1 and TGFBR1*6A receptors were identical, with signal sequences cleaved at the same site.
- TGFBR1*6A appeared to convert TGF-beta's inhibitory signals into growth-stimulatory signals in cancer cells.
Conclusions:
- TGFBR1*6A is somatically acquired in a significant proportion of colorectal cancer metastases, conferring a potential growth advantage.
- The functional effects of TGFBR1*6A in cancer appear mediated by its signal sequence, not the mature receptor.
- TGFBR1*6A represents a novel aspect of TGF-beta signaling in cancer and a potential therapeutic target.
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