Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis

Abstract

Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor lymphangiogenesis and metastasis.

Vascular patterns in reactive lymphoid tissue and in non-Hodgkin's lymphoma

“…Efforts have been made to exclude them on morphological examination but the recent identification of the molecule Lyve 1 and the raising of a specific antibody against this protein (Skobe et al, 2001), which is specifically expressed on lymphatic vessels, will allow this to be properly investigated in normal and neoplastic lymph nodes in future studies.…”

Targeting lymphangiogenesis to prevent tumour metastasis

“…One approach has involved expressing VEGF-C or VEGF-D in tumour cells and monitoring the effects on lymphatic vessels within or adjacent to solid tumours as well as assessing the degree to which tumour cells spread to lymph nodes. For example, expression of VEGF-C in breast cancer cells increased intratumoural lymphangiogenesis and metastasis to lymph nodes and lung after injection into mice (Skobe et al, 2001b). In other models, expression of VEGF-C in breast cancer cells promoted growth of tumour-associated lymphatics (Skobe et al, 2001a), that were in some cases infiltrated with tumour cells , and metastatic spread to lymph nodes (Mattila et al, 2002).…”

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…The lymphangiogenic factor Vascular Endothelial Growth Factor-C (VEGF-C), secreted by tumor-associated macrophages or tumor cells themselves, leads to increased LVD in the tumor microenvironment and in lymph nodes (LNs), correlating with increased metastasis and poor prognosis. 14-20 However, the mechanisms by which lymphangiogenesis promotes disease progression are not well understood. While increased LVD provide more surface area for tumor cells to enter the lymph and thereby migrate to distant sites, recent studies have highlighted additional important mechanisms.…”