TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis

Abstract

Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial–mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism

“…However, it is not clear what drives cancer cells to choose the lymphatic system for migration. Mikael C. Karlsson et al demonstrated that EMT promotes the migration of breast cancer through the lymphatic system to lymph nodes and that HLECs secrete chemokines to attract EMT cells [39,40]. Similar to those results, we found that LNMICC overexpression could induce EMT in cervical cancer cells and activate the expression of VEGF-C to promote lymphangiogenesis via FABP5-mediated reprogramming of FA metabolism.…”

ICAM3 mediates inflammatory signaling to promote cancer cell stemness

“…Among these 72 candidate genes, genes that control cancer cell stemness (including NF-κB1 [34], IL-1β [35], and CCR7 [36, 37]) and that scored significantly in the screen were selected, thereby demonstrating the effectiveness of the screen. However, genes that control pluripotency (including IL-6, and STAT3 [38]) did not score significantly in the screen possibly reflecting insufficient knockdown, redundancy, or that their role in CSC identity did not involve OCT4 expression.…”

The relationship between vasculogenic mimicry and epithelial‐mesenchymal transitions

“…The mechanism is via both Smad-dependent and -independent pathways including p38 MAPK. P38 MAPK can also be activate by Ras and Wnt which act with TGF-b synergistically, while the Smad pathway is unique to TGF-b signalling [19]. Hepatocyte growth factor plays a crucial role in initiating EMT via both PI3K/Akt pathway and RAF-MEK-ERK pathway [20,21].…”