How cancer cells cross lymphatic endothelium?

Abstract

The lymphatic microcirculation is a key component of metastatic spread providing a pathway for cancer cell dissemination, and the endothelium seems to enhance or promote the invasiveness of certain cancer cells. Furthermore, some tumors secrete lymphangiogenic growth factors acting on the lymphatic vasculature to facilitate metastasis. This study, based on 875 ultrastructural serial sections and 9 three-dimensional reconstructions of 28 initial lymphatics, clarify the transmigration mechanism of cancer cells from the extravascular matrix to the lumen of initial lymphatics. The lymphatic identification and distribution were assessed by transmission electron microscopy and immunohistochemistry (D2-40 and LYVE-1 markers) in experimental murine tumor mass (T84 adenocarcinoma, B16 melanoma, and transgenic prostate adenocarcinoma). The initial lymphatics were detectable in peritumoral connective tissue showing an endothelium lacking of continuous basal membrane. Twenty-nine invasive phenotype cancer cells were detected to migrate from the extravascular matrix of peritumoral connective tissue towards the initial lymphatic taking firm adhesion with the abluminal endothelial wall. The ultrastructural feature analysis and their reconstruction showed a cancer cell passage through the interdigitating and overlapping interendothelial contacts of the lymphatic vessels, without evidences of endothelial barrier degradation indicating the plasticity of endothelial cells. This study provide concrete contribution on the mechanism underlying the interactions between cancer cell and lymphatic endothelium, demonstrating a cancer cell transmigratory pathway. The discovery of the molecular mechanisms controlling these interactions could lead to new therapeutic strategies to reduce metastatic diffusion.