Antitumor activity of ALK1 in pancreatic carcinoma cells

Ungefroren, Hendrik; Schniewind, Bodo; Groth, S.; Chen, Wenbin; Müerköster, Susanne Sebens; Kalthoff, Holger; Fändrich, F.

doi:10.1002/ijc.22393

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…Our data are in agreement with the increased migratory activity and invasive behavior in vitro following stimulation of PANC-1 cells with TGF-b1 (Ellenrieder et al, 2001a, b). Notably, following xenotransplantation of PANC-1 cells into mouse pancreas ALK5-TD strongly induced hepatic metastasis, while neither the Smadbinding-defective mutant (this study) nor a kinase-active mutant of the related ALK1, which signals through Smad1/5, was capable to do so (Ungefroren et al, 2007). This suggests a crucial role for Smad2/3 in TGF-bdriven metastasis of pancreatic carcinoma cells to the liver and resembles the situation in MDA-MB-231 breast cancer cells where Smads are required for metastasis to bone (Kang et al, 2005;Deckers et al, 2006).…”

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

confidence: 53%

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 Suppressionmentioning

confidence: 53%

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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“…Finally, because ALK1 is reported to be expressed by, and possibly functionally important for, lymphatic ECs, cells of the pituitary gland, hepatic stellate cells, chondrocytes, and pancreatic ductal cells, special care should be taken to record adverse events from the treatment of ALK1 inhibitors related to processes regulated by these particular tissues. 21,55,70,83,84 …”

Section: Possible Side Effects From Alk1 Inhibitionmentioning

confidence: 99%

ALK1 as an emerging target for antiangiogenic therapy of cancer

Cunha

Pietras

2011

Blood

165

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IntroductionThe introduction of antiangiogenic therapies into oncologic practice has been highly anticipated because of the success of extensive preclinical testing. However, the initial clinical experience with this new class of anticancer drugs has been sobering, with a measurable therapeutic benefit of a few months observed and very little effect on overall patient survival. To fully realize the potential of therapies inhibiting neoangiogenesis, it is likely that drugs impinging on multiple regulatory pathways must be combined, and thus we must learn more about the biology of various signaling factors affecting endothelial cell (EC) growth and function. Activin receptor-like kinase 1 (ALK1) is an EC-restricted receptor of the large TGF-␤ family. 1 Herein, we will review our current understanding of ALK1 signaling and the potential of ALK1 to serve as a drug target for antiangiogenic therapy for cancer. Signaling by ALK1 in ECsThe large family of TGF-␤ extracellular ligands consists of Ͼ 30 cytokines that exert influence on several cellular compartments, notably epithelial cells, fibroblasts, immune cells, and endothelial and perivascular cells. TGF-␤, the prototypical member of the family, elicits a diverse set of cellular responses, such as growth arrest, immune suppression, differentiation, apoptosis, and specification of developmental cell fate during embryogenesis and pathogenesis, in species ranging from flies and worms to mammals. 2,3 On secretion and subsequent activation, the mature TGF-␤ ligand initiates signaling by inducing specific serine/threonine kinase type I and type II receptor heterotetrameric complexes. 4 Ligand binding results in signal propagation inside the cell by phosphorylation of specific effector proteins, so-called Smads, which translocate to the nucleus and activate transcription of target genes. 2,5 In ECs, TGF-␤ has been shown to signal via both the ubiquitously expressed type I receptor ALK5 and through the predominantly EC restricted receptor ALK1 (Figure 1). Depending on which type I receptor is recruited, different Smad signaling cascades are activated; ALK1 activation induces phosphorylation of Smad1/5/8, whereas ALK5 leads to Smad 2/3 activation. [6][7][8][9] Consequent to engagement of either Smad pathway, the receptoractivated Smads further form a heteromeric complex with a common and related partner molecule, Smad4, which translocates the complexes into the nucleus, where cell type-specific transcriptional modulators collaborate to activate or repress transcription of specific target genes in the angiogenic response. 10,11 In addition to the canonical signaling through Smad activation, TGF-␤ stimulation may lead to Smad-independent regulation of cellular outcomes, such as apoptosis and cell-cycle progression, through the direct modulation of prototypical signaling mediators, including MAP kinases and p21. 12 Furthermore, a third type of TGF-␤ receptor, the type III receptors, is represented by betaglycan and endoglin. Endoglin, primarily a vascular marker, is an auxilia...

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“…TβRI, a serine/threonine kinase, subsequently phosphorylates SMAD2 and SMAD3, which form heterotrimers with SMAD4 and translocate to the nucleus, where they interact with DNA-binding transcription factors and either activate or repress transcription. TGFβ signaling in EMT is complicated by the fact that the type I receptors ALK1, ALK2, and ALK5 have distinct and sometimes opposing functions: Whereas, for example, the principal ALK5 receptor mediates EMT, ALK1 can counteract this effect [17]. Moreover, the TGFβ signal can be relayed in a non-canonical, i.e.…”

Section: Emt Signaling Pathwaysmentioning

confidence: 99%

Epithelial-Mesenchymal Transition in Pancreatic Carcinoma

Maier

Wirth

Beug

2010

Cancers

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Pancreatic carcinoma is the fourth-leading cause of cancer death and is characterized by early invasion and metastasis. The developmental program of epithelial-mesenchymal transition (EMT) is of potential importance for this rapid tumor progression. During EMT, tumor cells lose their epithelial characteristics and gain properties of mesenchymal cells, such as enhanced motility and invasive features. This review will discuss recent findings pertinent to EMT in pancreatic carcinoma. Evidence for and molecular characteristics of EMT in pancreatic carcinoma will be outlined, as well as the connection of EMT to related topics, e.g., cancer stem cells and drug resistance.

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Antitumor activity of ALK1 in pancreatic carcinoma cells

Cited by 10 publications

References 38 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

ALK1 as an emerging target for antiangiogenic therapy of cancer

Epithelial-Mesenchymal Transition in Pancreatic Carcinoma

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