Paclitaxel causes de novo induction of invasive breast cancer cells by repolarizing tumor-associated macrophages
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Metastasis is the leading cause of breast cancer (BC) death, and tumor cells must migrate and invade to metastasize. BC cells that express the pro-metastatic actin regulatory protein MenaINV have an enhanced ability to migrate and intravasate within the primary tumor and extravasate at secondary sites. Though chemotherapy improves patient survival, treatment with paclitaxel leads to upregulation of MenaINV and an increase in metastasis in mice. MenaINV expression can be induced in BC cells through cooperative NF-κB/ Notch1 signaling with macrophages, which are often increased in tumors in response to chemotherapy. MenaINV-expressing cells are also resistant to paclitaxel, begging the question of whether paclitaxel increases MenaINV by de novo induction or by selectively killing non-MenaINV-expressing cells. We hypothesized that paclitaxel causes de novo MenaINV induction by increasing macrophage-tumor cell NF-κB/ Notch1 signaling. Understanding this pro-metastatic effect of chemotherapy is crucial to refining treatment strategies.
Findings
Paclitaxel-treated tumors expressed significantly more MenaINV than vehicle-treated tumors. This effect was dependent upon both macrophages and NF-κB/ Notch signaling. This indicates that chemotherapy increases MenaINV expression by induction. Mechanistically, paclitaxel causes macrophages to take on a pro-inflammatory phenotype and increase NF-κB/ Notch1 signaling with tumor cells.
Conclusion
Paclitaxel causes de novo MenaINV induction. Mechanistically, paclitaxel repolarizes tumor-associated macrophages towards a pro-inflammatory phenotype. These pro-inflammatory macrophages then participate in enhanced NF-κB/ Notch1 signaling with tumor cells, which leads to MenaINV induction in the tumor cells. These results lay the groundwork for novel microenvironment-based therapies to alleviate the pro-metastatic effects of chemotherapy in BC.
