Metformin inhibits esophageal squamous cell carcinoma-induced angiogenesis by suppressing JAK/STAT3 signaling pathway

Yang, Yi; Jin, Guoguo; Liu, Hangfan; Liu, Kangdong; Zhao, Jimin; Chen, Xinhuan; Wang, Dongyu; Bai, Ru; Li, Xiang; Jang, Yanan; Lü, Jing; Xing, Ying; Dong, Ziming

doi:10.18632/oncotarget.20341

Cited by 30 publications

(21 citation statements)

References 41 publications

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“…Contrary to the present findings, the CM of hepatocellular carcinoma and esophageal squamous cell carcinoma cells enhanced the tube-formation abilities of ECs (8,35). In another study, the CM from colon and breast cancer cells supported EC tube formation (36).…”

Section: Discussioncontrasting

confidence: 99%

Tumor‑type‑dependent effects on the angiogenic abilities of endothelial cells in an in vitro rat cell model

Al‐Abboodi

Weber

et al. 2019

Oncol Rep

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Adequate vascularization is pivotal for tumor progression and metastasis. Tumor angiogenesis is based on a sequence of interactions between the tumor and surrounding cells and the extracellular matrix. It is widely known that a tumor can influence and control its surroundings to create favorable conditions for further growth. To investigate the influence of various tumor types on endothelial cells (ECs), an in vitro rat cell model was used and rat liver EC52 cells were co-cultured with conditioned medium derived from breast cancer MCR86, osteosarcoma ROS-1, colon cancer CC531 and rhabdomyosarcoma R1H cell lines. In a distinct tumor-type-dependent manner, the EC52 cells exhibited changes in their function and gene expression. In all functional cell culture assays (proliferation, migration, transmigration, invasion and tube formation) the breast cancer cells exerted a significant effect on the angiogenic abilities of the ECs. When comparing the various tumor cell types, only the breast and colon cancer cells led to a significant stimulation of the EC migration and invasion. Proliferation, migration, invasion and tube formation were not or only hardly influenced by the osteosarcoma or rhabdomyosarcoma cells. Similarly, the breast and colon cancer cells exhibited the strongest influence on the upregulation of EC angiogenic genes, including the ones encoding vascular endothelial growth factor A, platelet and endothelial cell adhesion molecule 1, fibroblast growth factor 2, Von Willebrand factor, C-X-C motif chemokine ligand 12 and tyrosine kinase with immunoglobulin-like and EGF-like domains 1. Therefore, it is hypothesized that tumor cells enhance the angiogenic properties of ECs, including proliferation, migration, invasion and tube formation in a tumor-type-dependent manner. This is likely based on the upregulation of pro-angiogenic genes in ECs induced by varying cytokine secretion signatures of tumor cells.

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Section: Discussioncontrasting

confidence: 99%

Tumor‑type‑dependent effects on the angiogenic abilities of endothelial cells in an in vitro rat cell model

Al‐Abboodi

Weber

et al. 2019

Oncol Rep

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“…Despite technological advances made in combining surgical resection with chemotherapy or radiotherapy, treatment options remain suboptimal due to early local invasion and systemic metastasis . ESCC is a major histological subtype of esophageal carcinoma diagnosed in East Asian countries, especially in China . Previous studies have demonstrated that multiple biological markers may not only facilitate diagnosis and treatment of ESSC but may also help predict early recurrence and clinical outcomes following surgery.…”

Section: Introductionmentioning

confidence: 99%

RasGRP3, a Ras guanyl releasing protein 3 that contributes to malignant proliferation and aggressiveness in human esophageal squamous cell carcinoma

Zhang

et al. 2018

Clin Exp Pharma Physio

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Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide; however, clinical and pathological parameters have limited ability in discriminating between clinically significant and indolent ESCC. Since RasGRP3 transcript levels have prognostic value in discriminating ESCC with different clinical aggressiveness, we decided to investigate its putative oncogenic role in ESCC. We found that RasGRP3 was highly expressed in ESCC cells. Suppression of endogenous RasGRP3 expression in esophageal cell lines reduced Ras-GTP formation as well as AKT phosphorylation. RasGRP3 suppression also inhibited cell invasion and migration and reduced proliferation, demonstrating the importance of RasGRP3 for the transformed phenotype of melanoma cells. Suppression of RasGRP3 expression in these cells inhibited downstream RasGRP3 responses and suppressed cell growth and migration, confirming the functional role of RasGRP3 in the altered behaviour of these cells. This suggests that RasGRP3 may function as a Ras activator in the phosphoinositide signalling pathway and may potentially serve as a new therapeutic target.

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“…Metformin inhibits IL-6-induced cell transition which may be related to the blocking of STAT3 phosphorylation [131]. Metformin also inhibits the nuclear translocation of NF-jB and phosphorylation of STAT3 [132] and the Janus kinase (JAK), STAT3, c-MYC signaling axis [133][134][135]. By downregulating STAT3, Metformin promotes autophagy [136] as discussed earlier [67].…”

Section: Metformin and Cell Transitionmentioning

confidence: 80%

Metformin alters signaling induced crosstalk and homeostasis in the carcinogenesis paradigm “Epistemology of the origin of cancer”

Brücher

Jamall

2019

4open

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The anti-hyperglycemic drug, Metformin, is effective in treating early stages of diabetes and has been associated with a 37% decrease in cancer incidence. While the precise mechanisms for the anti-cancer effects of Metformin remain to be elucidated, this review shows the multiplicity of its effects on interdicting signaling and crosstalk, anti-inflammatory effects and in restoring homeostasis, which, taken together, go beyond its well-known anti-hyperglycemic effect that serves as the basis for its use in type 2 diabetes. Metformin is much more than a one-trick pony. The recent discovery of several signaling pathways influenced by Metformin appears to have potential value in cancer therapy. Based on what we know at present, Metformin promotes beneficial effects attributed to its anti-inflammatory and anti-fibrotic effects largely demonstrated in vitro. Metformin activates or upregulates while it simultaneously inhibits or downregulates multiple signaling pathways of cell-cycle arrest and apoptosis accompanied by oxidative stress, which are in accordance with the 6-step sequence of carcinogenesis. Furthermore, in vivo studies in laboratory animals and in cancer patients are beginning to address the magnitude of the anti-cancer effects and delineate its anti-cancer effects. In this context, results from prior pancreatic and non-pancreatic cancer trials, which contained a significant proportion of the patient population treated with Metformin, will have to be reexamined in light of the observed anti-cancerous effects to gain additional insights. The detailed exploration of Metformin in the context of the “Disruption of signaling homeostasis induced crosstalk in the carcinogenesis paradigm Epistemology of the origin of cancer” can provide helpful insights into the anti-proliferative mechanisms and could play a relevant role in anti-cancer therapy in the future.

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Metformin inhibits esophageal squamous cell carcinoma-induced angiogenesis by suppressing JAK/STAT3 signaling pathway

Cited by 30 publications

References 41 publications

Tumor‑type‑dependent effects on the angiogenic abilities of endothelial cells in an in vitro rat cell model

Tumor‑type‑dependent effects on the angiogenic abilities of endothelial cells in an in vitro rat cell model

RasGRP3, a Ras guanyl releasing protein 3 that contributes to malignant proliferation and aggressiveness in human esophageal squamous cell carcinoma

Metformin alters signaling induced crosstalk and homeostasis in the carcinogenesis paradigm “Epistemology of the origin of cancer”

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