Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90

Yoshida, Minoru; Yamashita, Taro; Okada, Hikari; Oishi, Naoki; Nio, Kouki; Hayashi, Takuo; Nomura, Yoshimoto; Hayashi, Tomoyuki; Asahina, Yasuhiko; Ohwada, Mika; Sunagozaka, Hajime; Takatori, Hajime; Colombo, Federico; Porretti, Laura; Honda, Masao

doi:10.1038/s41598-017-11848-z

Cited by 26 publications

(25 citation statements)

References 29 publications

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“…Moreover, MDA-MB-231 cells induced to express high EPCAM were found to have reduced invasion phenotype [27]. Ha et al [28] and Yoshida et al [29] reported similar inhibition of migration and invasion in hepatocellular carcinoma cells after sorafenib treatment. In association with reduced migration and in- Breast cancer stem cells, responsible for cancer initiation, progression, chemoresistance and recurrence were identified as CD44 + /CD24 -/lo along with other markers such ALDH and CD49F [23,24,30].…”

Section: Discussionmentioning

confidence: 94%

Sorafenib Inhibits Proliferation, Migration and Invasion of Breast Cancer Cells

et al. 2020

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Introduction: Metastatic breast cancer has poor prognosis due to limited therapeutic options. Protein kinase dysregulations have a major role in breast cancer progression and metastasis. In this study, we investigated the anti-cancer activity of sorafenib, a multikinase inhibitor, which targets receptor tyrosine kinases in breast cancer. Although treatment with sorafenib has increased the patient survival and inhibited metastatic migration in hepatocellular carcinoma, its role in breast cancer migration, metastasis, and intracellular signaling modulation is unknown. Methods: Breast cancer cell lines MCF7 and MDA-MB-231 were treated with sorafenib and its effect on proliferation, migration, invasion and gene expression was analyzed. Results: We found that sorafenib has an anti-proliferative and cytotoxic effect on breast cancer cells. Importantly, sorafenib inhibited the migration and invasion of breast cancer cells in vitro. Mechanistically, sorafenib increased mitochondrial superoxide production, suppressed breast cancer stem cell self-renewal, inhibited epithelial mesenchymal transition and ERK signaling. Con-clusion: Thus, sorafenib has anti-cancer activity against breast cancer cells and could improve the survival of breast cancer patients by inhibiting their invasive and metastatic properties.wells in DMEM with 2% FBS and spheroids were allowed to migrate. Invasion of the cells from the spheroid into the collagen matrix was monitored and documented microscopically. Colony Formation AssayOne hundred cells were plated in each well of a 6-well plate and treated with test materials for 48 h. Fresh media was added

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Section: Discussionmentioning

confidence: 94%

Sorafenib Inhibits Proliferation, Migration and Invasion of Breast Cancer Cells

et al. 2020

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“…Sorafenib inhibits the tyrosine phosphorylation of VEGFR-1, 2 and 3; PDGFR-β; Flt-3; and c-Kit [87]. Sorafenib is the priority drug used for advanced hepatocellular carcinoma (HCC) [65], as it inhibits the lung metastasis of HCC mediated by CD90 + cancer stem cells (CSCs) [66]. The combination of sorafenib and carfilzomib synergistically suppresses the metastasis of HCC via inducing tumor cell apoptosis [67].…”

Section: Tyrosine Kinase Inhibitor Therapymentioning

confidence: 99%

The Tumor Vessel Targeting Strategy: A Double-Edged Sword in Tumor Metastasis

Yong

et al. 2019

Cells

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Tumor vessels provide essential paths for tumor cells to escape from the primary tumor and form metastatic foci in distant organs. The vessel targeting strategy has been widely used as an important clinical cancer chemotherapeutic strategy for patients with metastatic tumors. Our review introduces the contribution of angiogenesis to tumor metastasis and summarizes the application of Food and Drug Administration (FDA)-approved vessel targeting drugs for metastatic tumors. We recommend the application and mechanisms of vascular targeting drugs for inhibiting tumor metastasis and discuss the risk and corresponding countermeasures after vessel targeting treatment.

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“…Li et al reported that 23.5% of patients with HCC (136 of 578 patients) had EHM prior to IHR (38.9%) after hepatectomy; the overall 5‐year survival rate in patients with EHM was 10.0%, which was significantly lower than that noted in patients who developed IHR alone (34.1%) 6 . Encouragingly, recent studies have demonstrated that sorafenib suppressed postoperative EHM and prolonged overall survival (OS) in patients with advanced HCC with EHM, thereby offering a potential option for postoperative adjuvant therapy to prevent EHM 4,9 . However, considering the confined efficacy in selected patients and intolerable side effects of sorafenib, 10‐12 the precise prediction of postoperative EHM is urgently needed to stratify patients for early prophylactic and therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

Postoperative circulating tumor cells: An early predictor of extrahepatic metastases in patients with hepatocellular carcinoma undergoing curative surgical resection

Sun

Wang

Zi-tong

et al. 2020

Cancer Cytopathology

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BACKGROUND: Postoperative extrahepatic metastases (EHM) contribute to a grim outcome in patients with hepatocellular carcinoma (HCC) who are undergoing curative surgical resection. The current study investigated the clinical value of circulating tumor cells (CTCs) in predicting EHM after curative surgery. METHODS: A total of 197 patients with HCC who were undergoing curative surgical resection were assigned to a retrospective training cohort (144 patients) or a prospective validation cohort (53 patients). The CELLSEARCH system was used for the detection of CTCs prior to surgical resection and 1 month thereafter. The cutoff value of CTCs was estimated using receiver operating characteristic analysis. Bonferroni correction was applied for multiple testing in a Cox proportional hazards regression model. RESULTS: In the training cohort, EHM was found to be associated with a higher postoperative CTC burden compared with no EHM (mean: 4.33 vs 0.52; P < .001). Receiver operating characteristic analysis demonstrated a postoperative CTC count ≥3 as the optimal cutoff value for the prediction of EHM. Patients with a postoperative CTC count ≥3 experienced a higher EHM risk (56.3% vs 5.5%) and a shorter median overall survival (31.25 months vs not reached) (all P < .001). The prognostic significance of a postoperative CTC count ≥3 also applied to patient subgroups with a low EHM risk, such as those with an α-fetoprotein level ≤400 ng/mL, absence of vascular invasion, well differentiation, and early tumor stage, and its predictive value was retained in patients with a continuous normal α-fetoprotein level during postoperative follow-up (all P < .05). The results were confirmed in the validation cohort. CONCLUSIONS: A postoperative CTC count ≥3 appears to be a surrogate marker for the prediction of EHM after curative surgical resection of HCC. More careful surveillance should be recommended to patients with a high CTC load to ensure the greater possibility of early interventions for postoperative EHM.

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Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90

Cited by 26 publications

References 29 publications

Sorafenib Inhibits Proliferation, Migration and Invasion of Breast Cancer Cells

Sorafenib Inhibits Proliferation, Migration and Invasion of Breast Cancer Cells

The Tumor Vessel Targeting Strategy: A Double-Edged Sword in Tumor Metastasis

Postoperative circulating tumor cells: An early predictor of extrahepatic metastases in patients with hepatocellular carcinoma undergoing curative surgical resection

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