Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness, epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma

Bhuria, Vikas; Xing, Jinchun; Scholta, Tim; Bui, Khac Cuong; Nguyen, Mai Ly Thi; Malek, Nisar P.; Bożko, Przemysław; Plentz, Ruben R.

doi:10.1016/j.yexcr.2019.111671

Cited by 60 publications

(38 citation statements)

References 70 publications

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“…We also identified the ciliary protein ARL13b. This protein is involved in hedgehog signaling [27,28], which in turn appears to be involved in cystogenesis [29] and even malignancy [30].…”

Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

Zadjali

Kumar

Yao

et al. 2020

IJMS

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The tuberous sclerosis complex (Tsc) proteins regulate the conserved mTORC1 growth regulation pathway. We identified that loss of the Tsc2 gene in mouse inner medullary collecting duct (mIMCD) cells induced a greater than two-fold increase in extracellular vesicle (EV) production compared to the same cells having an intact Tsc axis. We optimized EV isolation using a well-established size exclusion chromatography method to produce high purity EVs. Electron microscopy confirmed the purity and spherical shape of EVs. Both tunable resistive pulse sensing (TRPS) and dynamic light scattering (DLS) demonstrated that the isolated EVs possessed a heterogenous size distribution. Approximately 90% of the EVs were in the 100–250 nm size range, while approximately 10% had a size greater than 250 nm. Western blot analysis using proteins isolated from the EVs revealed the cellular proteins Alix and TSG101, the transmembrane proteins CD63, CD81, and CD9, and the primary cilia Hedgehog signaling-related protein Arl13b. Proteomic analysis of EVs identified a significant difference between the Tsc2-intact and Tsc2-deleted cell that correlated well with the increased production. The EVs may be involved in tissue homeostasis and cause disease by overproduction and altered protein content. The EVs released by renal cyst epithelia in TSC complex may serve as a tool to discover the mechanism of TSC cystogenesis and in developing potential therapeutic strategies.

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“…We also identified the ciliary protein ARL13b. This protein is involved in hedgehog signaling [27,28], which in turn appears to be involved in cystogenesis [29] and even malignancy [30].…”

Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

Zadjali

Kumar

Yao

et al. 2020

IJMS

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“…LDE225 treatment can repress phosphorylation of focal adhesion kinase (FAK) and paxillin [22,23], two molecules critically implicated in integrin-dependent motility and invasiveness in numerous cancers, including MB [24]. SHH signaling promotes epithelial to mesenchymal transition (EMT) and lymph node invasion in bladder cancer [25,26] and hypoxia-induced up-regulation of cancer stem cell genes and EMT in cholangiocarcinoma [27]. Wang et al [28] furthermore proposed that EMT in esophageal adenocarcinoma is mediated through increased GLI1 expression and is associated with PI3-K AKT signaling.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

Neve

Migliavacca

Capdeville

et al. 2019

Cancers

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In the Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB), tumor initiation and progression are in part driven by smoothened (SMO) and fibroblast growth factor (FGF)-receptor (FGFR) signaling, respectively. We investigated the impact of the SMO-FGFR crosstalk on tumor growth and invasiveness in MB. We found that FGFR signaling represses GLI1 expression downstream of activated SMO in the SHH MB line DAOY and induces MKI67, HES1, and BMI1 in DAOY and in the group 3 MB line HD-MBO3. FGFR repression of GLI1 does not affect proliferation or viability, whereas inhibition of FGFR is necessary to release SMO-driven invasiveness. Conversely, SMO activation represses FGFR-driven sustained activation of nuclear ERK. Parallel activation of FGFR and SMO in ex vivo tumor cell-cerebellum slice co-cultures reduced invasion of tumor cells without affecting proliferation. In contrast, treatment of the cells with the SMO antagonist Sonidegib (LDE225) blocked invasion and proliferation in cerebellar slices. Thus, sustained, low-level SMO activation is necessary for proliferation and tissue invasion, whereas acute, pronounced activation of SMO can repress FGFR-driven invasiveness. This suggests that the tumor cell response is dependent on the relative local abundance of the two factors and indicates a paradigm of microenvironmental control of invasion in SHH MB through mutual control of SHH and FGFR signaling.

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“…CD133, also known as prominin-1, is a pentaspan transmembrane glycoprotein that appears to be an epithelial marker in tissues in addition to being a CSC marker (24). Although the precise function of CD133 remains unclear, considerable evidence exists for the increased capabilities for tumor initiation in CD133 + cell cultures and tumor xenografts (24)(25)(26)(27)(28). The presence of CD133 along with other suspected CSC markers has also been associated with poorer overall survival in patients with CCA (29).…”

Section: Defining Cancer Stem Cellsmentioning

confidence: 99%

Targeting cancer stem cells in cholangiocarcinoma (Review)

McGrath

et al. 2020

Int J Oncol

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The incidence of cholangiocarcinoma has been increasing steadily over the past 50 years, but the survival rates remained low due to the disease being highly resistant to non-surgical treatment interventions. Cancer stem cell markers are expressed in cholangiocarcinoma, suggesting that they serve a significant role in the physiology of the disease. Cancer stem cells are frequently implicated in tumor relapse and acquired resistance to a number of therapeutic strategies, including chemotherapy, radiation and immune checkpoint inhibitors. Novel targeted therapies to eradicate cancer stem cells may assist in overcoming treatment resistance in cholangiocarcinoma and reduce the rates of relapse and recurrence. Several signaling pathways have been previously documented to regulate the development and survival of cancer stem cells, including Notch, janus kinase/STAT, Hippo/yes-associated protein 1 (YAP1), Wnt and Hedgehog signaling. Although pharmacological agents have been developed to target these pathways, only modest effects were reported in clinical trials. The Hippo/YAP1 signaling pathway has come to the forefront in the field of cancer stem cell research due to its reported involvement in epithelium-mesenchymal transition, cell adhesion, organogenesis and tumorigenesis. In the present article, recent findings in terms of cancer stem cell research in cholangiocarcinoma were reviewed, where the potential therapeutic targeting of cancer stem cells in this disease was discussed.

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Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness, epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma

Cited by 60 publications

References 70 publications

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

Targeting cancer stem cells in cholangiocarcinoma (Review)

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