Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells

Duda, Dan G.; Sunamura, Makoto; Lefter, Liviu P.; Furukawa, Toru; Yokoyama, Toshiharu; Yatsuoka, Toshimasa; Abe, Tadayoshi; Inoue, Hiroko; Motoi, Fuyuhiko; Egawa, Shinichi; Matsuno, Seiki; Horii, Akira

doi:10.1038/sj.onc.1206751

Cited by 94 publications

(80 citation statements)

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“…These results are in line with data showing that restoration of Smad4 to human pancreatic carcinoma cells suppressed tumor formation in vivo (Schwarte-Waldhoff et al, 2000;Duda et al, 2003). Interestingly, RImL45-TD inhibited phosphorylation of Smad2 and repression of the Myc promoter in response to exogenous ligand and in some assays relieved the autoinhibitory effect of endogenously produced TGF-b (see above), together suggesting that this mutant acts in a dominant-negative fashion for Smad-mediated responses triggered by either exogenous or endogenous TGF-b.…”

Section: Tgf-b Receptor Type I In Tgf-b-induced Tumor Suppressionsupporting

confidence: 90%

“…This strongly suggests that Smad-mediated suppression of neoangiogenesis contributed to the antitumor effect and is in line with animal experiments showing that functional Smad4 expression blocks in vivo growth of pancreatic tumor cells by inhibiting neoangiogenesis, mechanistically occurring in part through upregulation of TSP-1 expression (Schwarte-Waldhoff et al, 2000) and/or downregulation of VEGF (Duda et al, 2003). TGF-b is known to have both angiogenic and antiangiogenic properties consistent with its ability to induce VEGF-A and TSP-1.…”

Section: Tgf-b Receptor Type I In Tgf-b-induced Tumor Suppressionsupporting

confidence: 79%

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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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Section: Tgf-b Receptor Type I In Tgf-b-induced Tumor Suppressionsupporting

confidence: 90%

Section: Tgf-b Receptor Type I In Tgf-b-induced Tumor Suppressionsupporting

confidence: 79%

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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“…35 However, no significant association was observed between the abrogation of DUSP6 and the abrogation of SMAD4 in spite of our previous results showing the frequent concordant losses of 12q and 18q in Figure 2 Frequency of inactivation of DUSP6, CDKN2A, TP53, and SMAD4 in pancreata with ductal dysplasia/pancreatic intraepithelial neoplasia (PanIN) and invasive ductal carcinoma (IDC) (a) and those with intraductal papillary-mucinous adenoma/borderline (IPMA/B), intraductal papillary-mucinous carcinoma (IPMC), invasive colloid mucinous carcinoma associated with intraductal papillary-mucinous neoplasm (IPMN-COL), and invasive ductal carcinoma associated with intraductal papillarymucinous neoplasm (IPMN-DUC) (b). Asterisks denote significant differences between the groups statistically evaluated by w 2 test.…”

Section: Dusp6 In Pancreatic Precursor Lesionsmentioning

confidence: 99%

Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas

et al. 2005

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DUSP6/MKP-3 is identified as a candidate tumor suppressor gene for pancreatic cancer. The aim of this study was to elucidate the roles of DUSP6 in the pancreatic carcinogenesis through the pancreatic intraepithelial neoplasia and/or intraductal papillary-mucinous neoplasms, both of which are considered to be precursor lesions of invasive carcinoma of the pancreas, by comparing with involvements of other major tumor suppressive pathways. Expressions of DUSP6, CDKN2A, TP53, and SMAD4 were investigated by immunohistochemistry in a total of 206 lesions of dysplastic ductal precursors and carcinomas retrieved from 52 pancreata with invasive ductal carcinomas and 51 of those with intraductal papillary-mucinous neoplasms. The intensity of staining was evaluated in lesions at different atypical grades and statistically compared among them. Mutations of KRAS2 were analyzed by methods of the allele-specific oligonucleotide hybridization and nucleotide sequencing. In pancreata with invasive ductal carcinomas, expressions of DUSP6 were abrogated exclusively in the invasive carcinoma cells in contrast to its fairly preserved expressions in pancreatic intraepithelial neoplasia. In pancreata with intraductal papillary-mucinous neoplasms, abrogated expressions of DUSP6 were observed in a relatively small fraction of intraductal adenoma/borderlines and intraductal carcinomas. Most of the intraductal adenoma/borderline lesions with abrogation of DUSP6 harbored mutations of KRAS2. None of the molecules was associated with each other in any grade of lesions. Morphological variations of papillae of the intraductal papillary-mucinous neoplasms were evaluated and analyzed for their associations with abrogations of the molecules, which resulted in finding of no significant associations. Our results suggest that the abrogation of DUSP6 is associated exclusively with progression from pancreatic intraepithelial neoplasia to the invasive ductal carcinoma while it is potentially associated with initiation of intraductal papillary-mucinous neoplasms with mutated KRAS2, which is independent of other major tumor suppressive pathways in both types of neoplasms.

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“…Moreover, as p53 acts as a tetramer, the presence of a mutant inactive form leads to a dominant negative effect limiting p53 gene restoration efficiency [12]. Restoring a wild type SMAD4 did not always block tumor cells [13] rendering the use of this tumor suppressor controversial [14]. Many oncogenes can be deregulated and/or mutated in pancreatic cancers.…”

Section: Correcting Altered Genesmentioning

confidence: 99%

“…Restoring a wild type SMAD4 did not always block tumor cells [13] rendering the use of this tumor suppressor controversial [14]. Many oncogenes can be deregulated and/or mutated in pancreatic cancers.…”

Section: Introductionmentioning

confidence: 99%

Gene Therapy of Pancreatic Cancer

Dabernat¹,

Lafitte²,

Bedel³

et al. 2013

J Genet Syndr Gene Ther

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a 5-year survival rate of less than 5%. The poor prognosis of the disease is associated with late diagnosis and a high degree of drug resistance has not been overcome during the past decades. Gemcitabine-based regimens are the first line therapy for advanced pancreatic cancer but are not curative. Recent new combination chemotherapies achieved significant benefits but toxicity makes their use controversial. Novel approaches are currently being developed; in particular cancer gene therapies are undergoing preclinical and clinical validation and are the topic of the present review. We will present different ways to design gene therapy against pancreatic cancers that have been validated in preclinical studies. We also reviewed the clinical trials already published or still ongoing.Citation: Dabernat S, Lafitte M, Bedel A, de Verneuil H, Moreau-Gaudry F (2013) Gene Therapy of Pancreatic Cancer. J Genet Syndr Gene Ther 4: 138. doi:10.4172/2157-7412.1000138 Page 2 of 6Volume 4 • Issue 4 • 1000138 Suicide Gene Therapy of Cancer J Genet Syndr Gene Ther ISSN: 2157-7412 JGSGT, an open access journal gene restoration efficiency [12]. Restoring a wild type SMAD4 did not always block tumor cells [13] rendering the use of this tumor suppressor controversial [14]. Many oncogenes can be deregulated and/or mutated in pancreatic cancers. Among them, mutations in the KRAS oncogene occur in almost all pancreatic adenorcinomas [9]. Thus, it is tempting to use direct anti-KRAS strategies to inhibit tumor growth (Figure 1b), since disappointing results have been obtained with inhibition of farnesyl transferases [1]. RNAi directed against mutated KRAS showed anti-tumor activity [15], limited the aggressive phenotype of the tumor cells [16] and potentiated gemcitabine antitumor activity [17]. Preclinical studies showed encouraging results with viral delivery systems such as oncolytic adenovirus [18]. However, this strategy has not been further tested in phase I clinical trials.In fact, pancreatic adenocarcinomas present very complex genetic alterations profiles. The Pancreatic Cancer Genome project has analyzed 23,219 transcripts and identified an average of 63 somatic mutations per PDAC affecting 12 core signaling pathways and the overexpression of 500 different genes in 24 tumors [19]. These highly versatile and unpredictable molecular patterns can explain the failure of single gene/pathway targeted adjuvant therapies. It is now critical to test therapies targeting several pathways or therapies that induce specific tumor cell death. Delivering a Suicide GeneWith the suicide gene approach, a gene that encodes a protein triggering tumor cell death is delivered to the tumor cells ( Figure 1c). The expression of the therapeutic gene can directly kill the cells (diphtheria toxin, [20]), or can render the cells sensitive to certain otherwise non toxic prodrugs (Gene Directed Enzyme Prodrug Therapy, GDEPT,[21]), or based on gemcitabine association ...

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Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells

Cited by 94 publications

References 39 publications

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

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

Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas

Gene Therapy of Pancreatic Cancer

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