Lymphatic Endothelial Markers and Tumor Lymphangiogenesis Assessment in Human Breast Cancer

Abstract

Metastasis via lymphatic vessels or blood vessels is the leading cause of death for breast cancer, and lymphangiogenesis and angiogenesis are critical prerequisites for the tumor invasion–metastasis cascade. The research progress for tumor lymphangiogenesis has tended to lag behind that for angiogenesis due to the lack of specific markers. With the discovery of lymphatic endothelial cell (LEC) markers, growing evidence demonstrates that the LEC plays an active role in lymphatic formation and remodeling, tumor cell growth, invasion and intravasation, tumor–microenvironment remodeling, and antitumor immunity. However, some studies have drawn controversial conclusions due to the variation in the LEC markers and lymphangiogenesis assessments used. In this study, we review recent findings on tumor lymphangiogenesis, the most commonly used LEC markers, and parameters for lymphangiogenesis assessments, such as the lymphatic vessel density and lymphatic vessel invasion in human breast cancer. An in-depth understanding of tumor lymphangiogenesis and LEC markers can help to illustrate the mechanisms and distinct roles of lymphangiogenesis in breast cancer progression, which will help in exploring novel potential predictive biomarkers and therapeutic targets for breast cancer.

Transcriptomic and Functional Evidence for Differential Effects of MCF-7 Breast Cancer Cell-Secretome on Vascular and Lymphatic Endothelial Cell Growth

“…Angiogenesis and lymphangiogenesis play a dynamic role in facilitating breast tumor growth and metastasis [7,17]. The role of angiogenesis in supporting tumor growth has been intensively studied and is well-established.…”

“…However, relatively less is known regarding the role/contribution of lymphangiogenesis/LECs in BC, except for its role in immune cancer cell-counteraction and metastasis. The presence of LECs in tumors has led to the belief that similar to angiogenesis, lymphangiogenesis results from existing lymphatic vessels, which evolved following PROX-1 expression in ECs [7,17]. The tumor's microenvironment and BC-derived paracrine factors are thought to promote lymphangiogenesis.…”

“…However, recent findings suggest that tumor LECs may be of different origins. Some tumor-associated LECs express non-venous origins, such as mesenchymal origin [7,17], and marrow-derived progenitors with markers for myeloid LEC progenitors. Interestingly, the presence of TIE-2-expressing monocytes within lymphatic vessels of BC has also been reported [7,17].…”

“…Importantly, their structure and functional characteristics vary considerably from VECs [7]. The increased lymphatic vessel density in tumors is largely due to growth of pre-existing conduits [15,16]; however, some tumor-associated LECs are documented to be of non-venous origin and of mesenchymal origin [17,18]. Unlike the blood vessels, discrepant findings with regard to increased lymphatic vessel density and tumor growth/metastasis have been reported [17,18].…”

“…Moreover, the impact of BC-derived paracrine factors on VEC and LEC genes remains poorly documented. Since discrepant findings with regard to role of lymphatic vessels in metastasis have been reported, together with the fact that the lymphatic system acts as an immune sink to cleanse the cancer cells [19,22] and intra-tumoral lymphatic vessels appear collapsed and dysfunctional [17], it is important to study the effects of BC-driven changes in LECs and VECs. Apart from signal transduction pathways (MAPK and Akt), EC metabolism and mitochondrial activity have also emerged as key players in regulating vascular and lymphatic angiogenesis [30][31][32][33][34].…”