RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation

Abstract

Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer.

The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Progression

“…Clinical studies revealed that breast cancer tumors show cytoplasmic CCR7 expression [120,121]. The same cytoplasmic-confined phenomena were also reported later in 4T1 cells [122]. These data confirm the internalization and activation of the CCR7 receptor upon ligand binding.…”

Targeting of crosstalk between tumor and tumor microenvironment by β‐D mannuronic acid (M2000) in murine breast cancer model

“…In this study, we investigated the potential antitumor and antimetastatic effects of BDM on 4T1 breast cancer cell line both in vitro and in vivo. The tumor invasion and metastasis require the ability of tumor cells to degrade and adhere to ECM . Our in vitro results showed that BDM significantly reduces the MMP‐2, MMP‐9 activities (involved in degradation of the ECM) and adhesion of 4T1 cells to collagen I, fibronectin, and laminin (major components of the ECM) in a concentration‐dependent manner.…”

Ginsenoside Rg3 Alleviates ox-LDL Induced Endothelial Dysfunction and Prevents Atherosclerosis in ApoE−/− Mice by Regulating PPARγ/FAK Signaling Pathway

“…Meanwhile, Rg3 significantly decreased macrophage aggregation, increased contractile vascular smooth muscle cells (the marker protein is a-SMA) in mice aorta, these results suggest that Rg3 potentially protects against AS caused by abnormal lipid metabolism. FAK was discovered as a substrate of the oncogene product of the sarcoma virus that exists in many cancer cells (Mousson et al, 2018), it is a key molecule that promotes the adhesion of cancer cells to adjacent organs by accelerating the expression of adhesion molecules, resulting in tumor metastasis (Leung et al, 2015). Increasing numbers of studies have shown that FAK may exist in non-cancer cells, participating in other pathological processes related to adhesion.…”