The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

Kleeff, Jörg; Ishiwata, Toshiyuki; Maruyama, Haruhisa; Frieß, Helmut; Truong, Phuong Kim; Büchler, Markus W.; Falb, Dean; Korc, Murray

doi:10.1038/sj.onc.1202909

Cited by 241 publications

(179 citation statements)

References 52 publications

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“…The repression of Ihh mRNA by TGF-␤1 in Colo-357 indicates that TGF-␤1 has a potential role in the regulation of Ihh expression in pancreatic cancer. Inasmuch as most pancreatic cancers are resistant to TGF-␤ signaling due to Smad4 mutations, 7 Smad6/7 overexpression, 42,43 or reduced expression of TGF-␤ receptor I, 44 these alterations may result in loss of this repressive effect and then excessive activation of Ihh transcription in pancreatic cancer.…”

Section: Figurementioning

confidence: 99%

Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer

Kayed

Kleeff

Keleg

et al. 2004

Intl Journal of Cancer

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Section: Figurementioning

confidence: 99%

Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer

Kayed

Kleeff

Keleg

et al. 2004

Intl Journal of Cancer

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“…Aliquots of each sample ( 10 l) were then assayed using the MLX microtiter plate luminometer ( Dynex Technologies, Chantilly, VA ) 18, and the Promega assay reagent according to the manufacturers' instructions, as previously reported. 27 Adenoviral infection of L6 cells was carried out with minor modifications. Thus, L6 cells were seeded in 12 -well plates at a density of 25,000 cells /well.…”

Section: Luciferase Assaymentioning

confidence: 99%

Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors

et al. 2002

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Pancreatic ductal adenocarcinomas ( PDACs ) overexpress various cell -surface tyrosine kinase receptors, including the type I highaffinity fibroblast growth factor receptor ( FGFR -1 ). The purpose of this study was to determine whether FGFR -targeted gene therapy is feasible in this disorder. Accordingly, the effects of a conjugate consisting of fibroblast growth factor ( FGF ) -2 linked to a Fab 0 fragment against the adenovirus knob region were evaluated in human pancreatic cancer cell lines treated with an adenoviral vector containing the herpes simplex virus thymidine kinase ( AdTK ) gene. An adenoviral vector containing the firefly luciferase reporter gene ( AdLuc ) served to assess infection efficiency, and was initially tested in L6 rat myoblasts. In parental L6 cells that express exceedingly low levels of high -affinity FGFRs, transduction with AdLuc was enhanced 7 -to 10 -fold with the FGF2 -Fab 0 conjugate, whereas in L6 cells transfected to express FGFR -1, it was enhanced 39 -to 52 -fold. The pancreatic cancer cell lines expressed variable levels of the four high -affinity FGF receptors, and exhibited 2 -to 34 -fold increases in gene transduction in the presence of the FGF2 -Fab 0 conjugate. In the absence of FGF2 -Fab 0 there was no correlation between surface binding of FGF2 and AdLuc transduction efficiency, whereas in the presence of FGF2 -Fab 0 , enhanced AdLuc transduction efficiency correlated with greater surface binding of FGF2. In the absence of AdTK, all the cell lines were insensitive to ganciclovir, whereas after AdTK transduction, only ASPC -1 and PANC -1 cells were resistant to ganciclovir even in the presence of FGF2 -Fab 0 . Ganciclovir -mediated inhibition was dependent on the conjugate in CAPAN -1 and COLO -357 cells, but was independent of the conjugate in T3M4 and MIA -PaCa -2 cells. Real -time quantitative PCR of laser -captured cancer cells revealed high levels of various FGFR mRNA species in six of seven PDAC tumor samples. These findings indicate that transduction efficiency with FGF2 -Fab 0 in pancreatic cancer cells is independent of native adenoviral transduction efficiency and is greatest in cells that exhibit concomitant expression of various highaffinity FGFRs. In view of the overexpression of high -affinity FGFRs in the cancer cells in PDAC, our findings also suggest that the combined use of AdTK, ganciclovir, and FGF2 -Fab 0 may ultimately be a promising therapeutic approach in a subgroup of patients with PDAC.

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“…The role of TGF-b signaling as a tumor suppressor pathway in pancreatic carcinoma is best illustrated by the presence of chromosomal deletions and mutations in DPC4 in 55% of pancreatic tumors (Hahn et al, 1996), a tumor suppressor that has been implicated in mediating the growth inhibitory (Peng et al, 2002) and antiangiogenic (Schwarte-Waldhoff et al, 2000) effects of TGF-b. Fifty percent show an overexpression of the inhibitory Smad7 (Kleeff et al, 1999); moreover, in vivo disruption of TGF-b signaling by Smad7 leads to premalignant ductal lesions in the pancreas (Kuang et al, 2006). Inactivating mutations in both TGFBR1 (Goggins et al, 1998) and TGFBR2 have been observed in pancreatic carcinoma, but are less common than downregulation of ALK5 combined with elevated expression of TbRII (Friess et al, 1993a;Baldwin et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

Schniewind¹,

Groth²,

Müerköster³

et al. 2007

Oncogene

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In the present study, we have analysed the effects of transforming growth factor-beta (TGF-b) signaling on the growth behavior of pancreatic carcinoma cells in vitro and on their tumorigenicity in vivo. Ectopic expression of dominant-negative mutants of the TGF-b type II receptor or type I receptor/activin receptor-like kinase 5 (ALK5) in TGF-b-sensitive pancreatic ductal adenocarcinoma PANC-1 cells prevented the TGF-b-induced activation of transfected Smad-responsive reporter genes and growth arrest. The growth-inhibitory effect was mimicked by stable expression of kinase-active ALK5 (ALK5-T204D), and was dependent on ALK5's ability to activate Smad signaling, as a ALK5-derived mutant with an intact kinase domain but deficient in its ability to activate Smads (RImL45) failed to suppress proliferation in the absence of added TGF-b. Moreover, this mutant often displayed opposite effects to those of ALK5-TD and blocked various ligand-induced responses in vitro, indicating that it acts in a dominant-negative fashion to inhibit endogenous wild-type receptors. ALK5-TD-, but not RImL45-TDtransduced cells underwent epithelial-to-mesenchymal transition, exhibited a higher ratio of thrombospondin-1 to vascular endothelial growth factor-A expression and upregulated various metastasis-associated genes. Upon orthotopic transplantation of PANC-1 clones into immunodeficient mice, ALK5-TD, but not RImL45-TD, greatly reduced tumor size and induced the formation of liver metastases in otherwise non-metastatic PANC-1 cells. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-b in pancreatic tumor cells.

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The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer

Cited by 241 publications

References 52 publications

Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer

Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer

Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function

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