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Figure 8 | Molecular Cancer

Figure 8

From: A critical role for lymphatic endothelial heparan sulfate in lymph node metastasis

Figure 8

Summary of mechanistic considerations: Role of lymphatic endothelial heparan sulfate in chemokine-mediated lymph node metastasis. A. In peripheral lymphatic vessels (e.g., lymphatic vascular bed of a primary tumor), HS-binding chemokines produced by the lymphatic endothelium such as CCL21 may "cluster" on lymphatic-bound as well as secreted HS proteoglycans. In the setting of intra-lymphatic flow (thin arrows), spatial gradients of the chemokine scaffolded on HS chains in the extracellular matrix and lymphatic endothelium may facilitate tumor-cell migration into lymphatic vessels. This may occur in coordination with other adhesion systems such as integrins or selectins. Clustering of chemokines (as dimers in this example) on HS in the peri-lymphatic extracellular matrix may also be critical for receptor activation (e.g., CCR7) on migrating tumor cells. Targeting HS biosynthesis may thus alter chemokine-receptor interactions (large black arrow, mechanism "1") as well as chemokine gradients (large grey arrow, mechanism "2"). B. In the lymph node, similar principles may apply; however, the direction of trans-lymphatic flow and chemokine gradient are reversed, facilitating extra-vasation (colonization) of trafficking tumor cells expressing cognate chemokine receptors. Interfering with the biosynthesis of lymphatic heparan sulfate (e.g., genetically targeting the sulfation of HS through lymphatic endothelial Ndst1 mutation) may thus abrogate lymph node metastasis by altering such co-receptor and gradient-mediating functions served by the glycan.

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