Role of Angiogenesis Inhibitors in Colorectal Cancer: Sensitive and Insensitive Tumors

Bagnasco, Luca; Piras, Daniela; Parodi, Silvio; Bauer, Inga; Zoppoli, Gabriele; Patrone, Franco; Ballestrero, Alberto

doi:10.2174/156800912800190929

Cited by 20 publications

(19 citation statements)

References 120 publications

(135 reference statements)

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“…Angiogenesis has been found to play an important role in the growth and migratory potential of colon cancer (Bagnasco et al 2012). In the present study, we further examined whether BDNF regulates expression of the angiogenic factor VEGF in HCT-116 cells.…”

Section: Bdnf-directed Colon Cancer Cell Migration Involves Vegf Exprmentioning

confidence: 94%

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Huang¹,

Lin²,

Lin³

et al. 2015

Endocrine-Related Cancer

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Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominantnegative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.

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Section: Bdnf-directed Colon Cancer Cell Migration Involves Vegf Exprmentioning

confidence: 94%

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Huang¹,

Lin²,

Lin³

et al. 2015

Endocrine-Related Cancer

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“…Currently, the approved agents for treatment of CRC include monoclonal antibodies or small molecule tyrosine kinase inhibitors against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways, as well as the standard chemotherapeutic agents 5-FU, irinotecan, and oxaliplatin (Ortega et al, 2010; Bagnasco et al, 2012; Strumberg et al, 2012). Current research in this disease is primarily focused on various iterations of these therapies, while novel agent development is stalled.…”

Section: Introductionmentioning

confidence: 99%

Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models

Pitts¹,

Kulikowski²,

Tan³

et al. 2013

Front. Pharmacol.

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The p21-activated kinase (PAK) family of serine/threonine kinases, which are overexpressed in several cancer types, are critical mediators of cell survival, motility, mitosis, transcription, and translation. In the study presented here, we utilized a panel of colorectal cancer (CRC) cell lines to identify potential biomarkers of sensitivity or resistance that may be used to individualize therapy to the PAK inhibitor PF-03758309. We observed a wide range of proliferative responses in the CRC cell lines exposed to PF-03758309, this response was recapitulated in other phenotypic assays such as anchorage-independent growth, three-dimensional (3D) tumor spheroid formation, and migration. Interestingly, we observed that cells most sensitive to PF-03758309 exhibited up-regulation of genes associated with a mesenchymal phenotype (CALD1, VIM, ZEB1) and cells more resistant had an up-regulation of genes associated with an epithelial phenotype (CLDN2, CDH1, CLDN3, CDH17) allowing us to derive an epithelial-to-mesenchymal transition (EMT) gene signature for this agent. We assessed the functional role of EMT-associated genes in mediating responsiveness to PF-3758309, by targeting known genes and transcriptional regulators of EMT. We observed that suppression of genes associated with the mesenchymal phenotype conferred resistance to PF-3758309, in vitro and in vivo. These results indicate that PAK inhibition is associated with a unique response phenotype in CRC and that further studies should be conducted to facilitate both patient selection and rational combination strategies with these agents.

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“…22,40 In clinical practice, angiogenesis inhibition by way of vascular endothelial growth factor (VEGF) blockade is demonstrated to produce a great number of benefits. 41,42 Nevertheless, resistance to VEGF inhibitors is emerging as a significant problem of clinical oncology. 18 Fortunately, some studies have found that blockade of DLL4 results in non-productive angiogenesis with an inhibitory effect on tumour growth, including tumour resisted to VEGF inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Role of delta-like ligand-4 in chemoresistance against docetaxel in MCF-7 cells

et al. 2016

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As Notch receptors have been shown to induce chemoresistance, we hypothesized that delta-like ligand-4 (DLL4), a central Notch signalling ligand, might also participate in chemoresistance in breast cancer. To investigate this issue, overexpression of DLL4 was induced by transfection with expression vectors for DLL4 in the human breast cancer cell line Michigan cancer foundation-7 (MCF-7). It was found that DLL4 could be adaptively upregulated by docetaxel (DOC) treatment in a dose-dependent manner, but Notch1 was unaffected. Overexpression of DLL4 could significantly attenuate the cytotoxic effects of DOC by increasing Bcl-2 expression, while decreasing Bax expression, apoptosis rate and DNA damage. The protective effects of DLL4 made cells acquire chemoresistance against DOC and resulted in cancer cell survival. DLL4 is normally regarded as a regulator of vascular development. Our results expanded the understanding of DLL4. Since DLL4 may play an important role in the process of acquiring chemoresistance, it may be a promising target in overcoming chemoresistance in breast cancer.

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Role of Angiogenesis Inhibitors in Colorectal Cancer: Sensitive and Insensitive Tumors

Cited by 20 publications

References 120 publications

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Association of the epithelial-to-mesenchymal transition phenotype with responsiveness to the p21-activated kinase inhibitor, PF-3758309, in colon cancer models

Role of delta-like ligand-4 in chemoresistance against docetaxel in MCF-7 cells

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