Lymphangiogenesis and metastatic spread of cancer cells

The dissemination of malignant cells to the regional lymph nodes is an early step in the progression of many solid tumours and is an important determinant of prognosis. Recently, some tumours are thought to be lymph-angiogenic, i.e., they have the ability to generate their own lymphatics and thereby provide direct conduit to metastasise to the regional lymph nodes. Although the molecular regulation of lymphangiogenesis is still unclear, the discovery of the vascular endothelial growth factors and receptors has made a real progress in this field. Understanding the molecular signalling pathways in lymphangiogenesis might help to develop new therapeutic strategies against cancer lymphatic spread.

Tumour cell dissemination is mediated by mechanisms including local tissue invasion, lymphatic and blood spread, or direct seeding of body cavities (135). Regional lymph nodes are often the first sites to develop metastases (32, 136), either draining via pre-existing afferent lymphatic vessels and/or via newly formed lymphatic capillaries. This is indeed the basis of the sentinel lymph node biopsy and indicates the particular importance in surgical management of cancers including breast, melanoma, and others. However, not all tumours metastasise to the regional lymph nodes first. Furthermore, the presence of a metastasis in a lymph node does not necessarily mean that the tumour cells have been arrived via the lymphatic vessels (137). Tumour cells may pass directly into the blood vascular system through veno-lymphatic communications. The mechanisms determining whether regional lymph nodes or other sites first develop metastases remain poorly understood. In fact, most disseminated tumour cells have a limited lifespan in bloodstream. While many surviving cancer cells remain dormant in the host tissues, only a few develop into clinically detectable micrometastases. However, identification of those occult tumours cells, and prevention of their re-growth would be of great clinical significance.

Tumorigenesis in humans is a multistep process, and these steps reflect the genetic alterations that drive the progressive transformation to cancer. Contrary to normal cells, cancer cells have defective regulatory circuits that control normal proliferation and homeostasis. While normal cells require mitogenic signals to proliferate, malignant cells are self-sufficient for the growth signals and insensitive to the growth-inhibitory signals. Therefore, tumour cells are independent in generating their own growth signals. It has been well established that a complex series of cellular interactions between several types of cells like fibroblasts, immune cells, and endothelial cells as well as malignant cells within the tumour tissues could lead to cancer cells growth and metaststasis (138). In addition to the ability to synthesise their own growth factors leading to an autocrine stimulation, cancer cells could indeed induce the stimulation of other cells like endothelial cells via a paracrine mechanism, thus generating neovascularization in the local tumour micro-environment.

Although the significance of pre-existing peritumoral lymphatics as conduits for tumour cell dissemination has been well recognised (139), lymphatic vessels have been thought to be absent from tumours themselves (140). Until recently, it has remained unclear whether tumours can stimulate lymphangiogenesis or tumour metastasis stimulates molecular activation of the lymphatic system. Previous studies have failed to detect intratumoral functional lymphatics and therefore it was thought that lymphangiogenesis might not play a role in tumour metastasis (141-143). There the initial concept of lymphatic spread of tumours was that tumour cells metastasise solely by the invasion of pre-existing lymphatics surrounding the tumour margin, i.e., tumours are not lymphangiogenic. However, the absence of intratumoral lymphatics may simply reflect the collapse of lymphatics within tumours due to the increased pressure and mechanical stress generated by the proliferating cancer cells (144). The detection of dilated and engorged lymphatics in the peritumoral stroma was not sufficient evidence to claim that they are newly formed, although they were linked to the growth factors produced by tumour cells (144). Therefore the existense of intratumoral lymphatic vessels was rather a disputable issue (7, 140, 142-147). However, most of these studies are indirect and performed using tracers or perfusion models, in which no lymphatics could be observed inside tumours. However, during the last 2 years, several studies have demonstrated the existence of intratumoral lymphatics using experimental xenotransplanted tumour models (34, 35, 148-150).

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