Tumour cell preparing for directional migration: f-actin (green) re-distributes to the leading edge in response to interstitial flow. Arrow denotes flow direction.

Image courtesy of Dr. Melody A. Swartz, Ecole Polytechnique Fédérale de Lausanne, Switzerland.

Malignant cancer cells exploit the lymphatic system as a major route to spread throughout the body, but how these cells are guided toward lymphatic vessels is still unclear. A recent study published in Cancer Cell proposes that, aside from sensing cues from the lymphatics, tumour cells themselves secrete chemoattractants that form a luring gradient under the influence of interstitial flow.

Immune cells require the chemokine receptor CCR7 to access the lymphatics and expression of this receptor has previously been associated with lymph node metastasis of tumour cells. Shields et al. tested tumour cells lines for the presence of CCR7 and found that, in contrast to normal cells — which only express very low levels of CCR7 — cancer cells expressed the receptor at high levels. By exposing cells to a gradient of the CCR7 ligand CCL21, they also showed the CCR7 receptor triggers a strong chemotactic response. But what is the source of the CCR7 ligand that allows cancer cells to migrate to the lymphatic system? Surprisingly, the authors found that CCL21 is secreted not only by lymphatic endothelial cells (LECs), but also by the cancer cells themselves.

Directed cell migration can occur only if the extracellular guidance cue is present in a gradient. Shields et al. addressed the question of how such a gradient is obtained by developing a 3D in vitro culture system that mimics the tumour microenvironment. They observed that cancer cell lines migrated toward a chemoattractant source that was produced by LECs. However, the introduction of an interstitial flow through the culture was able to induce a CCR7-mediated chemotactic response in the direction of flow in the absence of LECs. These results showed that tumour-secreted chemoattractants can induce directed cell migration in the presence of a flow — a mechanism termed 'autologous chemotaxis'. The authors hypothesized that this flow alters the distribution of secreted chemoattractants to create a signal gradient, and were able to confirm this using computer modelling.

To visualize autologous chemotaxis at the cellular level, Shields et al. analysed the distribution of the signalling molecule PHAKT (AKT pleckstrin homology domain) using real-time fluorescence microscopy. Upon its recruitment from the cytoplasm to the plasma membrane, PHAKT becomes part of a receptor complex that signals the induction of actin polymerization. Cells exposed to LECs and/or interstitial flow showed polar localization of PHAKT at the plasma membrane. This, together with actin filament visualization in fixed cells, suggests that these conditions can initiate cellular events essential for polarized cell migration.

Shields et al. provide the first evidence that tumour cells respond to autocrine CCR7 ligands during chemotaxis. They also show that interstitial flow is sufficient to stimulate cell migration in the direction of flow — such as towards draining lymphatics — and thereby identify a mechanism by which tumour cells home toward the lymphatic system. Levels of secreted chemoattractant directly correlate to the degree of cancer invasiveness, making CCR7 ligand secretion a potential target for preventing metastatic spread.

Author: Kim Baumann