Lymphovascular and neural regulation of metastasis: shared tumour signalling pathways and novel therapeutic approaches

Abstract

The progression of cancer is supported by a wide variety of non-neoplastic cell types which make up the tumour stroma, including immune cells, endothelial cells, cancer-associated fibroblasts and nerve fibres. These host cells contribute molecular signals that enhance primary tumour growth and provide physical avenues for metastatic dissemination. This article provides an overview of the role of blood vessels, lymphatic vessels and nerve fibres in the tumour microenvironment and highlights the interconnected molecular signalling pathways that control their development and activation in cancer. Further, this article highlights the known pharmacological agents which target these pathways and discusses the potential therapeutic uses of drugs that target angiogenesis, lymphangiogenesis and stress-response pathways in the different stages of cancer care.

Keywords: NSAID; SNS; angiogenesis; beta-blocker; lymphangiogenesis; nerve fibres; sympathetic nervous system; vasculature.

Figure 1. Interactions between tumour cells and their microenvironment may be targeted by novel anti-cancer strategies

The stroma associated with a growing tumour consists of immune cell infiltrates, tumour-associated fibroblasts, sympathetic nerve fibres and endothelial cells and pericytes from blood and lymphatic vessels. Information flow in the form of soluble molecular signals and direct cell-cell contact occurs between the malignant tumour cells and the stromal cells. The boxes show examples of drug classes that may be used to manipulate these interactions in vivo.

Figure 2. Potential peri-operative application of drugs that target vasculature and neural signalling

Summary of the potential applications of different major drugs classes that target blood vessels, lymphatic vessels and neural signalling for cancer patients prior to surgery, in the peri-operative phase, and after surgery.