Review
The biological significance of lymphangiogenesis in human tumours

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Abstract

Increasing evidence indicates that lymphangiogenesis in cancer is an important factor in promoting tumour progression and metastasis. The discovery of immunohistochemical markers for lymphatic vessels' identification as well as the characterization of lymphatic-specific growth factors and receptors afforded insight into the mechanisms involved in new lymphatic vessel formation and the process of lymphatic-borne metastasis. Quantitative assessment of lymphangiogenesis in malignant tumours has emerged as a promising prognostic indicator, although there are conflicting results on the impact of lymphatic vessel density to predict lymph nodal metastases and overall survival. Solid tumours were recently found to induce new lymphatic vessel growth in draining lymph nodes before the onset of metastasis and therefore lymphangiogenesis in the lymph nodes has gained great interest. This review highlights advances in our understanding of the mechanisms by which lymphangiogenesis in tumours and lymph nodes enhances metastases and reports the potential implications of these developments in cancer therapeutics.

Introduction

The lymphatic vascular system mediates tissue fluid homeostasis by providing an important route for fluid and protein transport, serves as conduit for fat absorption from the gut and for the transport of lymphocytes and antigen-presenting cells to regional lymph nodes where specific immune responses are initiated. Interest in basic lymphatic research was recently boosted by the increasing evidence that the lymphatic vasculature plays an active role in the lymph nodal and systemic metastasis of human cancer. The discovery of various molecular markers allowing the distinction of blood and lymphatic vessels as well as the characterization of lymphatic-specific growth factors and receptors afforded insight into the mechanisms of tumour lymphangiogenesis. Furthermore, genome-wide analyses of the lymphatic endothelial transcriptome, contemporary technological advances in microscopic imaging of lymphatics and the availability of an increasing number of sophisticated in vitro and in vivo models have greatly facilitated the unravelling of lymphatic biology and lymphatic-borne metastases. This expanded knowledge, focus of the present review, offers promise for the development of novel cancer therapies specifically targeting dissemination through the lymphatic network.

Section snippets

Development of the lymphatic system

In contrast to the blood vascular system, the lymphatic system is open ended and serves as a drainage system by collecting interstitial fluid, proteins and macromolecules in the periphery and by transporting them back to the subclavian veins in the nuchal region. In the gut, lymphatic vessels also play an important role in the uptake of dietary fats. Furthermore, lymphatic vessels attract antigen-presenting cells and other immune cells from peripheral tissues to the draining lymph nodes. The

Lymphangiogenic growth factors and their receptors

Because of their common origin, lymphangiogenesis as well as angiogenesis relay on the interplay of several growth factors and receptors (Figure 2). Members of the VEGF family, VEGF-C and VEGF-D, are thus far the best characterized lymphangiogenic factors that bind the VEGFR-3 specifically expressed on LEC, and the VEGF-C/VEGF-D/VEGFR-3 axis constitutes the signal transduction system for lymphatic endothelial cell growth, migration, and survival.14, 15 In addition to VEGF-C and VEGF-D, also

Specific markers of the lymphatic endothelium

Although much progress has been made in recent years in identifying molecules specifically expressed on lymphatic and blood vessels, none of these markers are exclusively or homogeneously expressed on tumour lymphatics in both physiological and pathologic conditions, therefore a combination of markers is needed to identify tumour-associated lymphatic vessels in a reliable manner (Table 1). The heterogeneity of expression of markers in both blood and lymphatic vessels reflects underlying

Current concepts on lymphatic-borne metastases

Several human cancers metastasize at least initially through the lymphatic route and lymph node metastasis is currently a major determinant for patients staging and clinical management. Great efforts have been undertaken to understand which are the processes involved in metastatic dissemination via the lymphatic route, how neoplastic cells interact with the lymphatic vasculature, and what significance this has on determining the development of systemic metastases.

Microscopic studies

Tumour (peripheral tissue) lymphangiogenesis and its prognostic significance

In the last two decades, the prognostic significance of lymphatic vascular density (LVD) in primary human tumours has been the object of extensive debate and conflicting results have been reported on the impact of LVD to predict lymph nodal metastases and overall survival (Table 2).

In head and neck cancer, high intratumoural LVD was associated with a higher risk for local relapse and dismal prognosis34, 35 as well as with nodal metastases36, 37, 38, 39 and grade.40 We also demonstrated that

Lymph node lymphangiogenesis

In the past few years, it has become clear that tumour-induced lymph node lymphangiogenesis gives a major contributor to the process of tumour metastasis,25, 81, 82 although the exact molecular mechanisms remain largely unexplored. The pre-metastatic lymphatic dilation or remodelling in tumour-draining lymph nodes driven by VEGF-A and VEGF-C was demonstrated in spontaneous metastatic models of melanoma, nasopharyngeal carcinoma, murine developing lymphomas, transgenic mouse models of chemically

Therapeutic implications

Delineation of the in vivo mediators of tumour lymphangiogenesis has identified potential targets for the therapeutic blockade of lymphatic cancer spread, as well for markers predicting disease progression. Promising cancer therapeutic strategies aimed to inhibit tumour-cell entry into initial lymphatics and restrict the metastatic spread of cancer can derive from targeting the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling axis. The chemokine system could likely be targeted simultaneously

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