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.
Highlights
Lymph metastasis is the earliest sign of metastatic spread and the most powerful prognostic factor in breast cancer.[1,2] Lymph vessel invasion may be a better prognostic marker in breast cancer compared with blood vessel invasion.[3]
Transforming growth factor-β (TGF-β)-induced epithelial–mesenchymal transition (EMT) promotes lymphatic dissemination of mammary tumor cells To study whether the induction of EMT would affect tumor cell dissemination through the lymphatic system, we set up a mouse model frequently used to study trafficking of dendritic cells (DCs) to draining lymph nodes after the subcutaneous injection of cells into the hind footpad of syngeneic, recipient BALB/c mice (Figure 1a)
The findings presented in this study describe TGF-β-induced EMT as a mechanism, which activates tumor cells for targeted dissemination through the lymphatic system
Summary
Lymph metastasis is the earliest sign of metastatic spread and the most powerful prognostic factor in breast cancer.[1,2] Lymph vessel invasion may be a better prognostic marker in breast cancer compared with blood vessel invasion.[3] Unlike blood vessels, lymphatic vessels are equipped with unique button-like junctions that support entry of both fluid and dendritic cells (DCs) into the lymphatic system.[4] there may be a structural-based prerequisite for migratory tumor cells to intravasate into lymphatic vessels rather than blood vessels within the tumor microenvironment It is not clear how tumor cells find their way to lymphatic vessels and whether this is a regulated or more of a stochastic process. Recent data indicate that breast cancer cells undergoing EMT acquire immune cell properties.[15,16]
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