Pathophysiological and anatomical basis of lymphatic transit of cancer cells and role of the lymphatic system: a review of published literature

Abstract

Cancer metastasis involves dissemination of malignant cells from the primary tumor, via local lymphatic vessels to gain access to systemic circulation, while evading the destruction by immune cells, followed by successful extravasation and initiation of malignant growth in the distant organ. Despite the obvious contribution of the lymphatic system to the metastatic spread of cancer, basic research regarding the mechanisms leading to tumor dissemination via lymphatic vessels has been limited for years. Recent identification of molecular growth factors of lymphangiogenesis have led to new advances in our understanding of the underlying mechanisms of tumor metastasis. These growth factors have enabled scientists to better identify peritumoral lymphatics and to visualize precisely the ingrowth of tumor cells into the lumen of lymphatic capillaries. Moreover, it has been shown that these molecular markers secreted from a primary tumor can induce lymphangiogenesis in close regional lymph nodes, even prior to tumor cells arrival, which may facilitate metastasis spread. Comprehensive research of the multiplex interactions between tumor cells, lymphatics and the immune system will be crucial to further enhance the development of therapeutic and prognostic approaches to cancer. This review presents the ontogeny and anatomy of the lymphatic vasculature, discuss the immunological, molecular and physiological control of lymphatic vessel function, and explore the contribution of the lymphatic system to the development of metastases.

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“…The primary cause of cancer-related deaths worldwide is metastasis [6,7]. In the majority of human malignancies, the initial step involves metastatic spread to sentinel lymph nodes [8,9]. It has been proposed that there is a link between tumor lymphangiogenesis and lymph node metastases in various types of human cancer [10].…”

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“…The lymphatic vessels transport immune cells throughout the body. Cancer cells can exploit these vessels to migrate to nearby lymph nodes and regional lymph nodes, evade the self-destruction meditated by immune cells, and eventually to distant organs and initiate tumorigenesis in those metastatic sites 5 . The distribution of metastatic sites for a given primary tumor is not arbitrary, but rather dictated by several factors such as the anatomical location, the origin of the cell, and molecular subtypes 6 .…”