Serum KIAA1199 Is a Surrogate Marker for Epithelial-Mesenchymal Transition that Predicts the Postoperative Metastasis and Prognosis of Cholangiocarcinoma

2019 ◽  
Author(s):  
Xiangyu Zhai ◽  
Wei Wang ◽  
Yunlong Ma ◽  
Yijia Zeng ◽  
Dandan Dou ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
Mesenchymal Transition

scholarly journals AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 801
Author(s):  
Joyce Y. Buikhuisen ◽  
Patricia M. Gomez Barila ◽  
Arezo Torang ◽  
Daniëlle Dekker ◽  
Joan H. de Jong ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
High Expression ◽  
Mesenchymal Transition ◽  
High Propensity ◽  
Colorectal Cancer Cells ◽  
Epithelial Compartment ◽  
Selection Of

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.

Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations

2021 ◽  
pp. 1-16
Author(s):  
Masaki Nakano ◽  
Yachiyo Mitsuishi ◽  
Lei Liu ◽  
Naoki Watanabe ◽  
Emi Hibino ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Extracellular Release ◽  
Activity Dependent ◽  
Aβ Production

Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

scholarly journals Epithelial-type systemic breast carcinoma cells with a restricted mesenchymal transition are a major source of metastasis

2019 ◽  
Vol 5 (6) ◽  
pp. eaav4275 ◽  
Author(s):  
Xiao Liu ◽  
Junjian Li ◽  
Bruno Loureiro Cadilha ◽  
Anamarija Markota ◽  
Cornelia Voigt ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Lung Metastases ◽  
Ex Vivo ◽  
Surrogate Marker ◽  
Metastatic Breast ◽  
Distant Metastases ◽  
Carcinoma Cells ◽  
Clinical Samples ◽  
Mesenchymal Transition ◽  
Syngeneic Mouse Model

Carcinoma cells undergo epithelial-mesenchymal transition (EMT); however, contributions of EMT heterogeneity to disease progression remain a matter of debate. Here, we addressed the EMT status of ex vivo cultured circulating and disseminated tumor cells (CTCs/DTCs) in a syngeneic mouse model of metastatic breast cancer (MBC). Epithelial-type CTCs with a restricted mesenchymal transition had the strongest lung metastases formation ability, whereas mesenchymal-type CTCs showed limited metastatic ability. EpCAM expression served as a surrogate marker to evaluate the EMT heterogeneity of clinical samples from MBC, including metastases, CTCs, and DTCs. The proportion of epithelial-type CTCs, and especially DTCs, correlated with distant metastases and poorer outcome of patients with MBC. This study fosters our understanding of EMT in metastasis and underpins heterogeneous EMT phenotypes as important parameters for tumor prognosis and treatment. We further suggest that EpCAM-dependent CTC isolation systems will underestimate CTC numbers but will quantify clinically relevant metastatic cells.

Prognostic significance of circulating tumor cells in patients with gastric cancer: Epithelial mesenchymal transition and perioperative kinetics.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 59-59 ◽  
Author(s):  
Yui Ishiguro
Keyword(s):  
Gastric Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Advanced Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Gradient Centrifugation ◽  
Prognostic Significance ◽  
Surrogate Marker ◽  
Recurrence Rates ◽  
Mesenchymal Transition

59 Background: Circulating tumor cells (CTCs) have been shown to be heterogeneous. This study aimed to identify the prognostic significance of CTCs in patients with gastric cancer, focusing on epithelial mesenchymal transition and perioperative kinetics. Methods: Peripheral blood (7.5 ml) was taken from patients (n = 54) before curative resection, and at 7 days, 1 and 6 months postoperatively. CTCs were enriched using density gradient centrifugation and magnetic-activated cell sorting (negative selection). Cell suspensions were characterized by multi-immunofluorescence staining against cytokeratin (CK) and N-cadherin, and by DAPI staining. CTCs were defined as nucleated cells expressing CK or N-cadherin. Threshold analysis identified 1 CTC/7.5 ml as an optimal cut-off value. The median observation period was 735 days. Results: CTCs were detected in seven patients (24%) with early cancer and 14 patients (56%) with advanced cancer (p < 0.05). Cells were identified as either N-cadherin+/CK−/CD45− or N-cadherin+/CK+/CD45−, but no N-cadherin−/CK+/CD45− cells were observed. The median follow-up period was 24.5 months. After 2 years, postoperative recurrence was detected in nine patients, all of whom had advanced gastric cancer and N-cadherin+/CK−/CD45− CTCs preoperatively. In terms of perioperative kinetics (just before, 7 days and 1 month after surgery), we divided patients with advanced cancer into three risk groups: A, preoperative CTCs ≥1 and increased postoperatively; B, preoperative CTCs ≥1 and decreased postoperatively; C; no preoperative CTCs. The recurrence rates in the above groups were 80% (4/5), 44% (4/9), and 0% (0/11), respectively. Conclusions: Numerous CTCs expressed N-cadherin but not CK. Perioperative measurement of CTCs may be a useful surrogate marker for recurrence risk.

scholarly journals N-glycosylation of CD24 mediates cell motility but inhibits cell proliferation in colorectal cancer

2021 ◽  
Author(s):  
Zaki Hakami ◽  
Teresa P Raposo ◽  
Abdullah Alsulaiman ◽  
William Dalleywater ◽  
Hassan Otifi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Viability ◽  
Cell Motility ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Surrogate Marker ◽  
Site Directed Mutagenesis ◽  
Mesenchymal Transition ◽  
Downstream Targets ◽  
Glycosylation Sites

CD24 confers features of stemness and enhances cell motility in colorectal cancer (CRC). It is heavily glycosylated and contains numerous O-glycosylation sites but just two N-glycosylation sites (N36, N52). Since N-glycosylation is thought to be important in mediating the function of glycoproteins, we hypothesized that CD24 might be dependent on N-glycosylation for its activities. To test this hypothesis, site-directed mutagenesis was used to remove N-glycosylation sites by converting the target asparagine residues to glutamine. Each site was removed individually (CD24N36Q and CD24N52Q) and in combination (CD24N[36,52]Q), and the mutant CD24 clones were ectopically expressed in HCT116 and SW480 cells (CRC cell lines with low endogenous CD24 expression). The effect of the mutant CD24 on cell viability, cell motility and induction of downstream targets was compared to wild-type CD24 (CD24WT) and empty vector controls (EVC). Ectopic expression of the individually mutated clones CD24N36Q and CD24N52Q resulted in increased cell motility compared to EVC but was significantly less than that induced by CD24WT. Ectopic expression of the double mutant clone CD24N[36,52]Q resulted in near-complete abrogation in the induction of cell motility. Unexpectedly, the expression of mutant clones (both single and double mutants) led to increased cell viability. Analysis of downstream targets and F-actin staining demonstrated reduced induction of known CD24 targets by the mutant vectors and a reduced cadherin-switch (a surrogate marker for Epithelial-Mesenchymal Transition (EMT). We conclude that each N-glycosylation sites contribute partially to the motility inducing activities of CD24 and that these are additive. Loss of the N-glycosylation results in an unexpected gain of proliferative function. Further studies are necessary to elucidate the exact mechanisms behind these activities.

Sign in / Sign up

Export Citation Format

Share Document