Cancer metastasis and EGFR signaling is suppressed by amiodarone-induced versican V2

Lee, Hung Chieh; Su, Mai Yan; Lo, Hao‐Yung; Wu, Chin Chieh; Hu, Jia; Lo, Dao Ming; Chao, Tsu Yi; Tsai, Huai Jen; Dai, Ming

doi:10.18632/oncotarget.5621

Cited by 23 publications

(20 citation statements)

References 50 publications

(48 reference statements)

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“…VCAN was the most up-regulated gene in SC. Of interest, VCAN has also been shown to interact with and influence EGFR signaling (50,51). VCAN is a major component of the extracellular matrix, being produced by both tumor cells and the surrounding stroma (52).…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer

Singh

Graves‐Deal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated in 3D in type-I collagen. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained their parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), the EGFRneutralizing monoclonal antibody, cetuximab, strongly inhibited growth of CC, whereas SC was resistant to growth inhibition, and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. To further characterize these two lines, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most upregulated genes in CC was the tumor suppressor 15-PGDH/HPGD, and the most up-regulated gene in SC was versican (VCAN) in 3D and xenografts. Analysis of a CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic strategies and disease-relevant genes in CRC and possibly other solid tumors.colorectal cancer | versican | HPGD | 3D culture | cetuximab resistance T raditionally, epithelial cells have been cultured on plastic as a flat monolayer, precluding formation of their characteristic apico-basolateral structural organization. Pioneering work by Mina Bissell and Joan Brugge has shown that select breast epithelial cell lines can be grown in 3D in Matrigel as polarizing cysts with intact apico-basolateral polarity (1-3). These 3D cultures have been used to study oncogene-induced transformation and are shown to better predict in vivo behavior than 2D cultures (4, 5). Similar work in colonic epithelial cells has lagged behind; a notable exception is the work of Alan Hall and colleagues with Caco-2 cells that form uniform polarizing cysts in 3D Matrigel (6).We sought to identify human colorectal cancer (CRC) lines that exhibit apico-basolateral polarity in a better-defined 3D environment than Matrigel, which is a complex, incompletely defined extracellular matrix secreted by Engelbreth-Holm-Swarm mouse sarcoma cells (7). We previously observed that a human CRC line, HCA-7, cultured in type-1 collagen, gave rise to colonies consisting of unilamellar cysts with intact apico-basolateral polarity or less frequent colonies composed of irregular solid masses of cells (8). We derived CC and SC lines from cystic and spiky colonies, respectively. When injected sub...

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Section: Discussionmentioning

confidence: 99%

Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer

Singh

Graves‐Deal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Lumican seems to be a potent inhibitor of EMT, as Wu et al () show that this SLRP is transcriptionally inhibited by HMGA2 and its expression is lost in high‐grade serous papillary carcinoma. A preventive role for hyalactan, versican 2, has been proposed in tumor cell lines, as up‐regulation of this PG leads to suppression of EMT‐related transcription factors' expressions through EGFR/Erk/GSK3‐β (Lee et al, ). Indeed, versican has been correlated with the opposite to EMT, the process of mesenchymal–epithelial transition (MET) (Soltermann et al, ; Gao et al, ).…”

Section: Discussionmentioning

confidence: 99%

Role of the extracellular matrix in cancer‐associated epithelial to mesenchymal transition phenomenon

Tzanakakis

Kavasi

Voudouri

et al. 2017

Developmental Dynamics

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The epithelial to mesenchymal transition (EMT) program is a crucial component in the processes of morphogenesis and embryonic development. The transition of epithelial to mesenchymal phenotype is associated with numerous structural and functional changes, including loss of cell polarity and tight cell-cell junctions, the acquisition of invasive abilities, and the expression of mesenchymal proteins. The switch between the two phenotypes is involved in human pathology and is crucial for cancer progression. Extracellular matrices (ECMs) are multi-component networks that surround cells in tissues. These networks are obligatory for cell survival, growth, and differentiation as well as tissue organization. Indeed, the ECM suprastructure, in addition to its supportive role, can process and deliver a plethora of signals to cells, which ultimately regulate their behavior. Importantly, the ECM derived signals are critically involved in the process of EMT during tumorigenesis. This review discusses the multilayer interaction between the ECM and the EMT process, focusing on contributions of discrete mediators, a strategy that may identify novel potential target molecules. Developmental Dynamics 247:368-381, 2018. V C 2017 Wiley Periodicals, Inc.

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“…Amiodarone, a widely administered anti-arrhythmic drug [1], was shown by several pre-clinical studies to reverse multidrug resistance and sensitize several types of cancers to chemotherapy. Pre-clinical studies demonstrated its anti-cancer effects as a single therapeutic or in combination with other anti-cancer drugs on different cancers, including prostate, hepatocellular and breast carcinomas [6][7][8][9][24][25][26]. Based on this, we opted to investigate its anti-cancer effects on GBM, the most common and aggressive primary malignant brain tumor with a dismal prognosis outcome [13].…”

Section: Discussionmentioning

confidence: 99%

Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

Steinberg

Fluksman

Zemmour

et al. 2020

Preprint

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Background: Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. In this study, we examined Amiodarone's effects on glioblastoma multiforme (GBM), a highly aggressive and hypervascularized cancer. We hypothesized that Amiodarone would show an anti-angiogenic effect on GBM in addition to its previously suggested anti-cancer activity, and that an ultra-low dose would be both effective and possibly avert the drug’s side effects. Methods: The anti-cancer activity of Amiodarone was assessed by several in vitro assays using GBM cells. This included cytotoxicity, proliferation, transwell migration, Anoikis, colony-formation and three-dimensional (3D) spheroid growth assays. The anti-angiogenic effect of Amiodarone was tested on endothelial cells, using toxicity, proliferation, migration and tube formation in vitro assays. The anti-cancer and anti-angiogenic activity of Amiodarone was examined in vivo on three different murine models. C57BL/6J mice were utilized for the corneal neovascularization model and the Matrigel plug assay. Foxn1 nu mice were inoculated with GBM cells and used for the GBM tumor xenograft model.Results: In this study, we showed that Amiodarone has a significant anti-cancer and anti-angiogenic activity in vitro. Moreover, ultra-low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect in vivo. Conclusions: Our results strongly suggest that Amiodarone possess dual cancer fighting properties.

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Cancer metastasis and EGFR signaling is suppressed by amiodarone-induced versican V2

Cited by 23 publications

References 50 publications

Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer

Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer

Role of the extracellular matrix in cancer‐associated epithelial to mesenchymal transition phenomenon

Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

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