Development of Lymphatic Vessels: Tumour Lymphangiogenesis and Lymphatic Invasion

Abstract

In human solid cancer, the lymph node status is the most important prognostic indicator for the clinical outcome of patients. Follow-up data has shown that about 80% of metastasis follows an orderly pattern of progression via the lymphatic network while about 20% systemic metastasis occurs, bypassing the lymphatic system. Over the past few years, advances have been made in understanding the cellular and molecular aspects of physiological lymphangiogenesis and tumour-induced lymphangiogenesis, and the majority of studies point out to a positive correlation between tumour-induced lymphangiogenesis and lymphatic metastasis. However, the impact of intra- and peritumoural lymphatics on the tumour biology and the first steps of lymphatic metastasis, i.e. the invasion of tumour cells into the lymphatic vessels, are not well understood. We will give an outline of i. the physiological process of lymphangiogenesis, ii. tumour-induced lymphangiogenesis and lymphatic metastasis, iii. lymphatic invasion and the common pathways of tumour-lymphangiogenesis and lymphatic invasion. The growing interest in this topic has brought up a number of new molecular players in the field, which may provide the basis for a rational therapy against the process of lymphatic dissemination of tumour cells.

Similarities and differences of human and experimental mouse lymphangiomas

“…Genes that are dysregulated in lymphangiomas are unknown, and only very recently we have provided evidence for up-regulation of VEGFR-2 and -3 in lymphangioma LECs (Norgall et al, 2007). Due to recent advantages in lymphangiogenesis research (Wilting et al, 2005), it can be expected that our understanding of the molecular mechanisms involved in normal and aberrant development of lymphatics will increase rapidly. In order to test the effectiveness of new therapeutics in vivo, animal models for lymphangiomas are needed.…”

“…3B), whereas LECs generally appeared to be MMP2-negative. It has been shown that Vascular Endothelial Growth Factor-C and -D (VEGF-C/-D) are critical regulators of embryonic and tumor-induced lymphangiogenesis (Wilting et al, 2005). Human VEGF-C and -D bind VEGF receptors (R)-2 (KDR) and -3 (Flt-4) with high affinity.…”

Clever-1/Stabilin-1 Controls Cancer Growth and Metastasis

“…The cells, which can intravasate into the preexisting or tumor-induced neoangiogenic blood or lymphatic vessels, can form metastases in draining lymph nodes (LN) and at distant sites. Because of differences in the endothelial and vessel wall structure, lymphatic vessels likely offer pathways of lower resistance for migrating cells, which is associated with the fact that approximately 80% of metastasizing tumors preferentially spread via the lymphatic system (2).…”

Basement membrane protein distribution in LYVE-1-immunoreactive lymphatic vessels of normal tissues and ovarian carcinomas

“…The impairment of these functions leads to lymphoedema and disturbances in immune responses (Oliver and Alitalo 2005;Randolph et al 2005;Zawieja 2005). Lymphatic vessels are the main routes for the intravasation and dissemination of cancer cells, with lymph node metastasis being a prognostic factor for the clinical outcome in human carcinomas (Cao 2005;Oliver and Alitalo 2005;Wilting et al 2005).…”