S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis

Abstract

Background Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. Results We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. Conclusions S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.

Unraveling the link between cardiorespiratory fitness and cancer: a state-of-the-art review

“…These cells play a vital role in modulating the tumor microenvironment by secreting growth factors and cytokines that can either suppress or support tumor growth [112][113][114][115]. Furthermore, robust endothelial function enhances barrier integrity, which may reduce the likelihood of cancer metastasis by limiting the extravasation of tumor cells [116][117][118]. However, in cases where endothelial health is compromised, a pro-inflammatory phenotype may prevail, potentially facilitating tumor progression and metastasis by disrupting normal cellular barriers and promoting an environment conducive to cancer cell migration and invasion [118][119][120][121][122][123].…”

“…Furthermore, robust endothelial function enhances barrier integrity, which may reduce the likelihood of cancer metastasis by limiting the extravasation of tumor cells [116][117][118]. However, in cases where endothelial health is compromised, a pro-inflammatory phenotype may prevail, potentially facilitating tumor progression and metastasis by disrupting normal cellular barriers and promoting an environment conducive to cancer cell migration and invasion [118][119][120][121][122][123]. Thus, through regular exercise-induced improvement of endothelial function, there is also a potential for modulation of cancer-related processes, highlighting a significant yet often overlooked pathway through which PA may influence cancer development and progression.…”