Tumors induce coordinate growth of artery, vein, and lymphatic vessel triads

Abstract

BackgroundTumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other.MethodsThe murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes. Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels.ResultsEach peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection. The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors.ConclusionsImplanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads. Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes.

Quantitative Imaging In Vivo of Functioning Lymphatic Vessels Around Human Melanoma and Benign Nevi

“…In a recent study the large blood vessels in the vicinity of B16‐F10 melanomas were always functional; lymphatic vessels, however, were sometimes blocked. Blocked lymph drainage was readily identified upon necropsy after Evans Blue subcutaneous injection and this blockade could be confirmed by subcutaneous injection of Texas Red Dextran followed by immunostaining analysis . In light of the above discussion, it seems possible that a novel mechanism for blocked lymphatic drainage around malignant tumors awaits identification.…”

“…As demonstrated by Ruddell et al . in their murine B16‐F10 melanoma model, 4 of 12 mice showed blocked lymph drainage on the tumor‐draining side but LNs did not necessarily contain visible melanoma metastases. As the number of patients with metastatic melanoma in our human study was small and the follow‐up time limited, this facet of the study must be considered preliminary.…”

Tumor-induced lymph node alterations detected by MRI lymphography using gadolinium nanoparticles

“…The mechanism for this inhibition remains to be determined. Animal studies have shown that large tumors or metastases can divert or block lymph drainage 43 44 , however in this model the small foot tumors are located at some distance from the inguinal LNs. Moreover, none of the LNs contained gross metastases at this early stage, so that metastasis does not explain this shunting effect.…”

The Lymphatic Endothelial mCLCA1 Antibody Induces Proliferation and Growth of Lymph Node Lymphatic Sinuses

“…Unlike LYVE-1, which is down-regulated in response to inflammation [ 34 ], mCLCA1 expression on LECs is not impacted by TNF-α/IL-1β stimulation, suggesting that it is a useful marker of normal as well as inflamed LECs [ 30 ]. mCLCA1 is also expressed on collecting and initial lymphatic vessels [ 35 ] as well as on splenic red pulp stromal cells and thymic medullary stromal epithelial cells [ 12 ]. Our in vitro studies have identified a role for mCLCA1 as an interacting partner for LFA1 to mediate lymphocyte adhesion to LECs, as treatment of LECs with the 10.1.1 Ab significantly reduced lymphocyte adhesion [ 30 ].…”