Targeting Endogenous Transforming Growth Factor β Receptor Signaling in SMAD4-Deficient Human Pancreatic Carcinoma Cells Inhibits Their Invasive Phenotype
Abstract
Transforming growth factor-β (TGF-β) suppresses tumor formation by blocking cell cycle progression and maintaining tissue homeostasis. In pancreatic carcinomas, this tumor suppressive activity is often lost by inactivation of the TGF-β-signaling mediator, Smad4. We found that human pancreatic carcinoma cell lines that have undergone deletion of MADH4 constitutively expressed high endogenous levels of phosphorylated receptor-associated Smad proteins (pR-Smad2 and pR-Smad3), whereas Smad4-positive lines did not. These elevated pR-Smad levels could not be attributed to a decreased dephosphorylation rate nor to increased expression of TGF-β type I (TβR-I) or type II (TβR-II) receptors. Although minimal amounts of free bioactive TGF-β1 and TGF-β2 were detected in conditioned medium, treatment with a pan-specific (but not a TGF-β3 specific) TGF-β-neutralizing antibody and with anti-αVβ6 integrin antibody decreased steady-state pSmad2 levels and activation of a TGF-β-inducible reporter gene in neighboring cells, respectively. Thus, activation of TGF-β at the cell surface was responsible for the increased autocrine endogenous and paracrine signaling. Blocking TβR-I activity using a selective kinase inhibitor (SD-093) strongly decreased the in vitro motility and invasiveness of the pancreatic carcinoma cells without affecting their growth characteristics, morphology, or the subcellular distribution of E-cadherin and F-actin. Moreover, exogenous TGF-β strongly stimulated in vitro invasiveness of BxPC-3 cells, an effect that could also be blocked by SD-093. Thus, the motile and invasive properties of Smad4-deficient pancreatic cancer cells are at least partly driven by activation of endogenous TGF-β signaling. Therefore, targeting the TβR-I kinase represents a potentially powerful novel therapeutic approach for the treatment of this disease.
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Early examples showed reduction of breast cancer metastasis in response to anti-TGF-β antibodies or soluble TβRII-based ligand trap.
“Early examples showed reduction of breast cancer metastasis in response to anti-TGF-β antibodies or soluble TβRII-based ligand trap306,326,327.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [326]
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- Authors
- Subramanian, G., Schwarz, R. E., Higgins, L., McEnroe, G., Chakravarty, S., Dugar, S., & Reiss, M.
- Affiliations
- 1Internal Medicine (Medical Oncology) and Departments of
- Rutgers Cancer Institute (US)
- 3Scios, Inc., Fremont, California
- Venue
- Cancer Research
- Published
- 2004-08-01
- Volume
- 64
- Issue
- 15
- Pages
- 5200-5211
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2171478975
- Cited by
- 138
- References
- 91
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 4 · 2015: 4 · 2014: 11 · 2013: 7 · 2012: 4
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5u01ca094431-04)
- National Cancer Institute (CA-41556, R01CA041556, CA-94431)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- TGF-beta signaling, pancreatic cancer, TGF-beta type I receptor, autocrine and paracrine signaling, integrin αvβ6, tumor invasion, cell motility, TGF-beta neutralizing antibody, BxPC-3 cells, therapeutic target
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Antigens, Neoplasm, Cell Movement, DNA-Binding Proteins, Enzyme Inhibitors, Humans, Neoplasm Invasiveness, Pancreatic Neoplasms, Phenotype, Phosphorylation, Tumor Cells, Cultured, Wound Healing, Signal Transduction, Trans-Activators, Cadherins, Integrins, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Gene Deletion, Receptors, Transforming Growth Factor beta, Activin Receptors, Type I, Smad2 Protein, Smad3 Protein, Smad4 Protein, Transforming Growth Factor beta1, Transforming Growth Factor beta2, Transforming Growth Factor beta3
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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