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Abstract
Substantial evidence supports important independent roles for lymphangiogenic growth factor signaling and prostaglandins in the metastatic spread of cancer. The significance of the lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, is well established in animal models of metastasis, and a strong correlation exits between an increase in expression of VEGF-C and VEGF-D, and metastatic spread in various solid human cancers. Similarly, key enzymes that control the production of prostaglandins, cyclooxygenases (COX-1 and COX-2, prototypic targets of Non-steroidal anti-inflammatory drugs (NSAIDs)), are frequently over-expressed or de-regulated in the progression of cancer. Recent data have suggested an intersection of lymphangiogenic growth factor signaling and the prostaglandin pathways in the control of metastatic spread via the lymphatic vasculature. Furthermore, this correlates with current clinical data showing that some NSAIDs enhance the survival of cancer patients through reducing metastasis. Here, we discuss the potential biochemical and cellular basis for such anti-cancer effects of NSAIDs through the prostaglandin and VEGF signaling pathways.
Highlights
The lethality of many solid tumors is primarily associated with the ability to spread to distant organs in a process known as metastasis [1]
The importance of PG-mediated dilation during metastasis was demonstrated in an animal model of lymphogenous spread, in which it was shown that the lymphangiogenic factors vascular endothelial growth factor (VEGF)-C and VEGF-D were able to induce dilation of collecting lymphatic vessels draining the primary tumor mass, leading to increased metastatic load in the sentinel lymph node [6]
Emerging evidence from histopathological, genetic and clinical analyses has revealed that the VEGF-C/VEGF-D and PG signaling pathways intersect, adding to the number of pathways that make up the total signaling necessary to establish lymphogenous spread
Summary
The lethality of many solid tumors is primarily associated with the ability to spread to distant organs in a process known as metastasis [1]. The complex multistep process of metastasis involves local invasion of cancer cells followed by intravasation of cancer cells into blood and/or lymphatic vessels; trafficking of cancer cells through these vessels; extravasation to the lymph node or distant organs; formation of micrometastases consisting of small cancer nodules, and the formation of macrometastases. The complexity of these processes indicates that they are likely to depend on a multitude of signalling networks [4]. We will describe the nature of the lymphatic system in the context of metastasis and explore the role of VEGF-C/VEGF-D and prostaglandin signaling pathways in lymphogenous spread, with a view to the clinical benefit of NSAIDs to target lymphatic vessels during metastatic disease
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