Lymphangiogenesis and Cancer

Abstract

Historically, lymphatic vessels were considered passive participants in tumor metastasis by simply providing channels for tumor cells to transit to draining lymph nodes. The discovery of several key lymphatic-specific molecular markers and an increased availability of in vitro and in vivo experimental systems to study lymphatic biology have however highlighted a much more complex, active role for the lymphatic vasculature in metastatic tumor spread. This review will briefly describe the lymphatic system and lymphangiogenesis and then focus on the role of the lymphatic system in cancer metastasis. The progression of our understanding from the lymphatic system as a somewhat passive conduit for metastasis to an active participant in metastatic tumor dissemination, regulated by a complex array of lymphangiogenic factors, chemokines, and immune cell subsets, will be described.

Interaction of tumor cells and lymphatic vessels in cancer progression

“…97 --99 For a more detailed review on the chemoattraction of tumor cells and the immunomodulatory effects of lymphatic factors and lymphatic endothelium, the reader is referred to a recent review by Christiansen and Detmar. 100 How do tumor cells reach lymph nodes? Increased interstitial pressure within tumors has been proposed to be the driving force for movement of the cells and fluid within the lymphatic drainage pathway.…”

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.…”

Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis

“…While the lymphatic vascular system has traditionally been thought to only play a passive role in cancer metastasis, with preexisting lymphatic vessels serving as mere conduits for invading tumor cells, there is increasing evidence that malignant tumors can actively induce the growth of lymphatic vessels. This process, termed tumor lymphangiogenesis, has been found to promote metastatic spread to sentinel lymph nodes and beyond (1). Increased tumor lymphangiogenesis is positively correlated with an increased incidence of sentinel lymph node metastasis and with reduced overall survival in several types of human cancers (1,2).…”

“…This process, termed tumor lymphangiogenesis, has been found to promote metastatic spread to sentinel lymph nodes and beyond (1). Increased tumor lymphangiogenesis is positively correlated with an increased incidence of sentinel lymph node metastasis and with reduced overall survival in several types of human cancers (1,2). Importantly, tumor-induced lymphangiogenesis also occurs in the tumor-draining sentinel lymph nodes, sometimes even before metastatic spread (3).…”

“…The lymphatic vascular system drains interstitial fluids and cells to the lymph nodes and also serves as a major route for disseminating cancer cells. Indeed, the tumor-draining sentinel lymph node represents the first site of metastasis in the majority of epithelial cancers and malignant melanomas (1), and the presence of sentinel lymph node metastases is an important negative prognostic indicator and also has an impact on the choice of cancer therapy. While the lymphatic vascular system has traditionally been thought to only play a passive role in cancer metastasis, with preexisting lymphatic vessels serving as mere conduits for invading tumor cells, there is increasing evidence that malignant tumors can actively induce the growth of lymphatic vessels.…”