STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression

Abstract

Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.

PLEK2 mediates metastasis and vascular invasion via the ubiquitin‐dependent degradation of SHIP2 in non‐small cell lung cancer

“…For distant metastasis, primary tumor cells must invade the stromal environment, intravasate, disseminate through blood vessels, colonize the distant site, and finally form metastatic nodules . Both tumor cells and endothelial cells are critical for tumor progression and metastasis …”

“…3 Both tumor cells and endothelial cells are critical for tumor progression and metastasis. 4 Numerous studies have shown that transforming growth factor beta (TGF-β)-mediated epithelial-to-mesenchymal transition (EMT) plays a crucial role in tumor invasion and metastasis. [5][6][7] Moreover, destruction of the vascular endothelial barrier is an important process through which cancer cells invade blood vessels.…”

<p>Resveratrol Reverses Cigarette Smoke-Induced Urocystic Epithelial–Mesenchymal Transition via Suppression of STAT3 Phosphorylation in SV-HUC-1-Immortalized Human Urothelial Cells</p>

“…It is widely involved in the process of cell proliferation, differentiation, apoptosis, and immune inflammation regulation, and is an important pathway of many cytokine signal transductions. 7,8 STAT3 plays an important role in pathological processes, such as inflammatory signaling and immunosuppression. STAT3 is certainly the most eminent among cancers and plays a vital role in regulating EMT during cancer progression.…”

“…STAT3 can enhance the expression of matrix metalloproteinases (MMPs) that are responsible for the degradation of the basement membrane and extracellular matrix (ECM) in cancer invasion and metastasis. 8 Epithelial-mesenchymal transition (EMT) is a fundamental process by which cells change from epithelial-like state to a more mesenchymal-like phenotype. Thus, epithelial cells lose cell junction and gain the ability to invade and metastasize.…”

The role of the Oncostatin M/ OSM receptor β axis in activating dermal microvascular endothelial cells in Systemic Sclerosis

“…Persistent activation of STAT3 was observed in many diseases characterized by chronic in ammation and brosis including SSc [26]. In endothelial cells STAT3 activation was mostly linked to increased expression of adhesion molecules including E-selectin, P-selectin and VCAM [43,44]. In our experiments OSM induced ICAM1 and junction plakoglobin JUP, however it did not affect expression of E-and P-selectin or VCAM.…”