Lymphatic pathophysiology of tumors

Abstract

Lymph node metastases have a negative impact on cancer survival, but the mechanisms for lymphatic metastasis are not well understood. The universal finding in solid tumors of an absence of functional lymphatic vessels seems paradoxical, as cancer cells do travel through lymphatics in order to disseminate. In order to address some of these issues, this thesis proposes two etiologies for the absence of functional lymphatic vessels in solid tumors. The first hypothesis addresses whether Vascular Endothelial Growth Factor-C (VEGF-C), a lymphangiogenic factor, was sufficient to induce lymphatic function in tumors. The overexpression of VEGF-C in tumors leads to an increase in lymph node metastasis as well as structures that positively stain for lymphatic markers, but does not induce functional lymphatics within the tumor. Thus VEGF-C is not sufficient to grow functional lymphatic vessels in tumors. The second hypothesis addresses whether mechanical forces generated by the proliferation of cancer cells in a confined space compress lymphatic vessels in tumors. The mechanical forces inside of the tumor were reduced by the selective killing of human cancer cells grown in mice by Diphtheria Toxin. Tumor cell death leads to an increase in the fraction of lymphatics with open lumen. In addition, lymphatic vessels with open lumen are surrounded by a lower cellular density than collapsed vessels. Thus, relieving solid stress allows lymphatic vessels to open. However, function was not restored in these vessels. This is presumably due to the inability of the lymphatic vessels to completely open along its entire length, leaving focal areas of lymphatic collapse. Compressive forces are common to all growing tumors, giving credence to the mechanical etiology of the absence of functional lymphatic vessels in tumors, regardless of tumor type or organ site.

(cont.) These findings lead to an interesting question: Does cancer treatment in humans relieve the mechanical compression allowing lymphatic and blood vessels to open? Furthermore, would the resumption of function of compressed blood and lymphatic vessels lead to a paradoxical increase in metastasis? These questions require further investigation.