Association of Vasculogenic Mimicry Formation and CD133 Expression with Poor Prognosis in Ovarian Cancer

Liang, Jun; Yang, Bo; Cao, Qinying; Wu, Xiaohua

doi:10.1159/000445747

Cited by 32 publications

(36 citation statements)

References 29 publications

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“…Consistent with our findings, ALDH1 overexpression in response to BRAF and MEK1/2 inhibition was recently reported in melanoma [68]. Given that high expression of ALDH1 and CD133 in ovarian tumors is strongly associated with poor prognosis and chemoresistance [69][70][71][72][73], we conclude that prolonged treatment of cisplatin-resistant HGSOC with trametinib might promote CSC enrichment.…”

Section: Trametinib Treatment Drastically Reduces the Growth Rates Ofsupporting

confidence: 91%

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

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Rationale: High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.Methods: MEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.Results: MEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133 + fraction and increased expression of stemness-associated genes.Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions. Conclusions: MEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumorgrowth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

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Section: Trametinib Treatment Drastically Reduces the Growth Rates Ofsupporting

confidence: 91%

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

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“…The sample sizes of the included studies ranged from 11 to 440. Among these studies, 15 studies involved patients with ALDH1 [19, 22, 26, 30-41], 8 studies involved patients with CD133 [18, 23, 25, 30, 31, 37, 42, 43], 25 studies involved patients with CD44 [17, 21, 24, 44-64, 66], 7 studies involved patients with CD117 [13, 20, 26, 27, 67-69], 3 studies involved patients with ALDH1 and CD133 [30, 31, 37], and 1 study involved patients with ALDH1 and CD117 [26]. According to the NOS quality assessment, 52 of the studies were categorized as high quality.…”

Section: Resultsmentioning

confidence: 99%

Clinicopathological and Prognostic Significance of Cancer Stem Cell Markers in Ovarian Cancer Patients: Evidence from 52 Studies

Tao

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Relevant markers of cancer stem cells (CSCs) may serve as commonly used biomarkers of ovarian cancer (OC). However, their actual clinicopathological and prognostic significance remains inconclusive. Thus, we conducted a meta-analysis to quantitatively evaluate the association between the expression of CSC-relevant markers (ALDH1, CD117, CD133, and CD44) and OC. Methods: We used an odds ratio (OR) and a hazard ratio (HR) with a 95% confidence interval (CI) to estimate the effects by analyzing 52 studies from a literature search. Heterogeneity and sensitivity were evaluated, as well. Publication bias was assessed using funnel plots and Egger tests. Results: ALDH1 expression was statistically associated with FIGO stage (OR=1.872, 95%CI=1.14-3.076, P=0.013) and lymph invasion (OR=2.78, 95%CI=1.08-7.152, P=0.034). CD117 expression was significantly associated with FIGO stage (OR=2.01, 95%CI=1.35-2.98, P=0.001). CD133 expression was correlated with FIGO stage (OR=3.410, 95%CI=2.196-5.294, P< 0.001) and differentiation grade (OR=2.672, 95%CI=1.354-5.272, P=0.005). CD44s was related to chemotherapy resistance (OR=3.218, 95%CI=1.148-9.016, P=0.026). Furthermore, overexpression of ALDH1 (HR=1.494, 95%CI=1.207-1.849, P< 0.001), CD117 (HR=1.395, 95%CI=1.025-1.898, P=0.034) or CD44s (HR=1.725, 95%CI=1.135-2.623, P=0.011) was associated with poor OS. Further, overexpression of both ALDH1 (HR=1.524, 95%CI=1.158-2.007, P=0.003) and CD44s (HR=2.12, 95%CI=1.692-2.657, P< 0.001) was correlated with worse DFS. Conclusion: CSC markers are useful predictive or prognostic biomarkers for OC in clinical assessments. Combined detection of CSC marker expression may be a powerful tool for prognostic predictions in clinical practice for patients with OC.

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“…Many research studies have investigated the clinical implications of VM and TIN 12,19–24. Although some of their biologic roles have been revealed, the relations among VM and TIN in the context of EC have not yet been established.…”

Section: Discussionmentioning

confidence: 99%

Vasculogenic mimicry is associated with increased tumor-infiltrating neutrophil and poor outcome in esophageal squamous cell carcinoma

Zhang

Deng

et al. 2017

OTT

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PurposeVasculogenic mimicry (VM) is known to be a mechanism to nourish the tumor, but little is known about its prognostic significance in esophageal squamous cell carcinoma (ESCC). We characterized the predictive relevance of VM expression and tumor-infiltrating neutrophil (TIN) density in patients with resectable ESCC.MethodsWe retrospectively collected clinicopathologic characteristics of 117 esophageal cancer (EC) patients undergoing complete resection and without preoperative therapy. Immunohistochemistry was used to detect the expression of E-cadherin and CD66b. CD34/periodic acid-schiff (PAS) double staining was used to detect the expression of VM.ResultsVM expression was observed in 56 (47.9%) patients. VM was negatively correlated with E-cadherin (correlation coefficient =−0.364, P<0.001) and was positively correlated with infiltration of CD66b neutrophil (correlation coefficient =0.421, P<0.001). VM and CD66b+ neutrophil infiltration are important markers for poor overall survival and disease-free survival. Multivariate analysis showed that VM, CD66b+ neutrophil infiltration, pathologic tumor node metastasis (TNM) (pTNM) stage, and tumor differentiation are significant independent prognostic predictors in ECs (P=0.001, 0.025, 0.001, 0.011, respectively). VM expression is identified in ~47.9% of ESCC, and it is associated with poor outcome and increased TIN.ConclusionTIN is an important factor for VM formation. Therefore, studies of invasive ability of EC in patients with VM could supply significant information for therapeutic strategy.

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Association of Vasculogenic Mimicry Formation and CD133 Expression with Poor Prognosis in Ovarian Cancer

Cited by 32 publications

References 29 publications

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Clinicopathological and Prognostic Significance of Cancer Stem Cell Markers in Ovarian Cancer Patients: Evidence from 52 Studies

Vasculogenic mimicry is associated with increased tumor-infiltrating neutrophil and poor outcome in esophageal squamous cell carcinoma

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