| 1. |
- Giannelli, Gianluigi, et al.
(author)
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The rationale for targeting TGF-beta in chronic liver diseases
- 2016
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In: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 46:4, s. 349-361
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Research review (peer-reviewed)abstract
- BackgroundTransforming growth factor (TGF)- is a pluripotent cytokine that displays several tissue-specific biological activities. In the liver, TGF- is considered a fundamental molecule, controlling organ size and growth by limiting hepatocyte proliferation. It is involved in fibrogenesis and, therefore, in worsening liver damage, as well as in triggering the development of hepatocellular carcinoma (HCC). TGF- is known to act as an oncosuppressor and also as a tumour promoter in HCC, but its role is still unclear. DesignIn this review, we discuss the potential role of TGF- in regulating the tumoural progression of HCC, and therefore the rationale for targeting this molecule in patients with HCC. ResultsA considerable amount of experimental preclinical evidence suggests that TGF- is a promising druggable target in patients with HCC. To support this hypothesis, a phase II clinical trial is currently ongoing using a TGF- pathway inhibitor, and results will soon be available. ConclusionsThe identification of new TGF- related biomarkers will help to select those patients most likely to benefit from therapy aimed at inhibiting the TGF- pathway. New formulations that may provide a more controlled and sustained delivery of the drug will improve the therapeutic success of such treatments.
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| 2. |
- Hawinkels, Lukas J. A. C., et al.
(author)
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Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors
- 2016
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 22:1, s. 96-106
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Journal article (peer-reviewed)abstract
- Purpose: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap. Experimental Design: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis. Results: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. Animmunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone. Conclusions: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc.
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| 3. |
- Colak, Selcuk, et al.
(author)
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Targeting TGF-beta Signaling in Cancer
- 2017
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In: Trends in Cancer. - : CELL PRESS. - 2405-8025 .- 2405-8033. ; 3:1, s. 56-71
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Research review (peer-reviewed)abstract
- The transforming growth factor (TGF)-beta signaling pathway is deregulated in many diseases, including cancer. In healthy cells and early-stage cancer cells, this pathway has tumor-suppressor functions, including cell-cycle arrest and apoptosis. However, its activation in late-stage cancer can promote tumorigenesis, including metastasis and chemoresistance. The dual function and pleiotropic nature of TGF-beta signaling make it a challenging target and imply the need for careful therapeutic dosing of TGF-beta drugs and patient selection. We review here the rationale for targeting TGF-beta signaling in cancer and summarize the clinical status of pharmacological inhibitors. We discuss the direct effects of TGF-beta signaling blockade on tumor and stromal cells, as well as biomarkers that can predict the efficacy of TGF-beta inhibitors in cancer patients.
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| 4. |
- de Boeck, Miriam, et al.
(author)
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Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model
- 2016
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Journal article (peer-reviewed)abstract
- The transforming growth factor-beta (TGF-beta) family is known to play critical roles in cancer progression. While the dual role of TGF-beta is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo.
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| 5. |
- de Miranda, Noel F. C. C., et al.
(author)
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Transforming Growth Factor beta Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2
- 2015
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 148:7, s. 1427-1437.e8
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor beta receptor II (TGFBR2). TGF beta signaling therefore is believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGF beta. We investigated how TGF beta signaling might continue in MSI-H CRC cells. METHODS: We sequenced the 10-adenines microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGF beta signaling was detected by SMAD2 phosphorylation and through use of a TGF beta-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells, which do not respond to TGF beta, and their activities were measured. RESULTS: SMAD2 was phosphorylated in most MSI-H CRC tissues (strong detection in 44% and weak detection in 34% of MSI-H tumors). Phosphorylation of SMAD2 in MSI-H cells required TGFBR2-even the form encoding a frameshift mutation. Transcription and translation of TGFBR2 with a 1-nucleotide deletion at its microsatellite sequence still produced a full-length TGFBR2 protein. However, protein expression required preservation of the TGFBR2 microsatellite sequence; cells in which this sequence was replaced with a synonymous nonmicrosatellite sequence did not produce functional TGFBR2 protein. CONCLUSION: TGF beta signaling remains active in some MSI-H CRC cells despite the presence of frameshift mutations in the TGFBR2 gene because the mutated gene still expresses a functional protein. Strategies to reactivate TGF beta signaling in colorectal tumors might not be warranted, and the functional effects of mutations at other regions of microsatellite instability should be evaluated.
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| 6. |
- De Vinuesa, Amaya García, et al.
(author)
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Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function
- 2016
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In: Biochemical Society Transactions. - 0300-5127. ; 44:4, s. 1142-1149
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Journal article (peer-reviewed)abstract
- Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs). ALK1 has been shown to play a pivotal role in regulating angiogenesis by binding to bone morphogenetic protein (BMP)9 and 10. Two main pharmacological inhibitors, an ALK1-Fc fusion protein (Dalantercept/ACE-041) and a fully human antibody against the extracellular domain of ALK1 (PF-03446962) are currently under clinical development. Herein, we briefly recapitulate the role of ALK1 in blood vessel formation and the current status of the preclinical and clinical studies on inhibition of ALK1 signalling as an anti-angiogenic strategy. Future directions in terms of new combination regimens will also be presented.
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| 7. |
- Dekker, T. J. A., et al.
(author)
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Disorganised stroma determined on pre-treatment breast cancer biopsies is associated with poor response to neoadjuvant chemotherapy : Results from the NEOZOTAC trial
- 2015
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In: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 9:6, s. 1120-1128
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Journal article (peer-reviewed)abstract
- Introduction: The tumor-associated stoma is of importance for tumor progression and is generally accepted to have a significant influence on patient prognosis. However, little is known regarding specific features of tumor-associated stromal tissues and response to (neoadjuvant) chemotherapy. This study investigated the predictive value of extracellular matrix organization on response to chemotherapy in patients treated in the NEOZOTAC trial. Methods: Stromal organisation was analyzed via a simple method using image analysis software on hematoxylin and eosin (H&E)-stained slides from primary tumor biopsies collected as part of the NEOZOTAC trial. Heidenhain's AZAN trichrome-stained slides were also analyzed for comparison of collagen evaluation. Sections were stained for phospho-Smad2 (pS2) in order to determine the relationship of TGF-beta signaling with stromal organization. Results: A statistically significant relationship was observed between stroma consisting of organised collagen and pathological response to neoadjuvant chemotherapy (Odds Ratio 0.276, 95%CI 0.124-0.614, P = 0.002). This parameter was also related to ER-status (P = 0.003), clinical tumor -status (P = 0.041), nodal status (P = 0.029) and pS2 status (P = 0.025). Correlation between stromal organisation determined on H&E-stained and AZAN-stained tissue sections was high (Pearson's correlation coefficient = 0.806). Conclusion: Intratumoral stromal organisation determined using pre-treatment breast cancer biopsies was related to pathological response to chemotherapy. This parameter might play a role in the management of breast cancer for identifying those patients that are likely to benefit from neoadjuvant chemotherapy.
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| 8. |
- Li, Yihao, et al.
(author)
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c-Myb Enhances Breast Cancer Invasion and Metastasis through the Wnt/beta-Catenin/Axin2 Pathway
- 2016
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:11, s. 3364-3375
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Journal article (peer-reviewed)abstract
- The molecular underpinnings of aggressive breast cancers remain mainly obscure. Here we demonstrate that activation of the transcription factor c-Myb is required for the prometastatic character of basal breast cancers. An analysis of breast cancer patients led us to identify c-Myb as an activator of Wnt/beta-catenin signaling. c-Myb interacted with the intracellular Wnt effector beta-catenin and coactivated the Wnt/beta-catenin target genes Cyclin D1 and Axin2. Moreover, c-Myb controlled metastasis in an Axin2-dependent manner. Expression microarray analyses revealed a positive association between Axin2 and c-Myb, a target of the proinflammatory cytokine IL1 beta that was found to be required for IL1 beta-induced breast cancer cell invasion. Overall, our results identified c-Myb as a promoter of breast cancer invasion and metastasis through its ability to activate Wnt/beta-catenin/Axin2 signaling. (C) 2016 AACR.
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| 9. |
- Li, Yihao, et al.
(author)
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Genetic depletion and pharmacological targeting of alpha v integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models
- 2015
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 17
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Journal article (peer-reviewed)abstract
- Introduction: Increased expression of alpha v integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which alpha v integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of alpha v integrins in breast cancer also have yet to be investigated. Methods: We knocked down alpha v integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the alpha v antagonist GLPG0187. The effects of alpha v integrin depletion on mesenchymal markers, transforming growth factor-beta (TGF-beta)/Smad signaling and TGF-beta-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of alpha v integrin on breast cancer cell migration was investigated by transwell assay in vitro, and its effect on breast cancer progression was assessed by both zebrafish and mouse xenografts in vivo. In the mouse model, GLPG0187 was administered separately, or in combination with the standard-of-care anti-resorptive agent zoledronate and the chemotherapeutic drug paclitaxel, to study the effects of combinational treatments on breast cancer metastasis. Results: Genetic interference and pharmacological targeting of alpha v integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of alpha v integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-beta/Smad response. TGF-beta induced alpha v integrin mRNA expression and alpha v integrin was required for TGF-beta-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-beta signaling. In the mouse xenografts GLPG0187 inhibited the progression of bone metastasis. Maximum efficacy of inhibition of bone metastasis was achieved when GLPG0187 was combined with the standard-of-care metastatic breast cancer treatments. Conclusion: These findings show that alpha v integrin is required for efficient TGF-beta/Smad signaling and TGF-beta-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting alpha v integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress alpha v integrin.
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| 10. |
- Liu, Sijia, et al.
(author)
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Regulation of the TGF-beta pathway by deubiquitinases in cancer
- 2016
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In: International Journal of Biochemistry and Cell Biology. - : Elsevier BV. - 1357-2725 .- 1878-5875. ; 76, s. 135-145
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Research review (peer-reviewed)abstract
- The transforming growth factor-beta (TGF-beta) pathway regulates diverse cellular processes. It signals via serine/threonine kinase receptors and intracellular Smad and non-Smad effector proteins. In cancer cells, aberrant TGF-beta signalling can lead to loss of growth inhibition and an increase in invasion, epithelial-to-mesenchymal transition (EMT) and metastasis. Therapeutic targeting of the pro-oncogenic TGF-beta responses is currently being explored as a potential therapy against certain invasive and metastatic cancer types. The ubiquitin post-translational regulation system is emerging as a key regulatory mechanism for the control of TGF-beta pathway components. In this review, we focus on the role of deubiquitinases (DUBS), which counteract the activity of E3 ubiquitin ligases. We will discuss the mechanisms by which specific DUBs control Smad and non-Smad TGF-beta signalling routes, and how perturbation of the expression and function of DUBs contributes to misregulation of TGF-beta signalling in cancer.
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