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Open Access Research article

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

Alanna Ruddell12*, Alexandra Croft2, Karen Kelly-Spratt1, Momoko Furuya1 and Christopher J Kemp13

Author Affiliations

1 Fred Hutchinson Cancer Research Center, Seattle, WA, USA

2 Department of Comparative Medicine, University of Washington School of Medicine, 1959 NE Pacific St., Box 357190, Seattle, WA 98195, USA

3 Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA

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BMC Cancer 2014, 14:354  doi:10.1186/1471-2407-14-354

Published: 21 May 2014

Abstract

Background

Tumors 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.

Methods

The 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.

Results

Each 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.

Conclusions

Implanted 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.

Keywords:
Melanoma; Carcinoma; Lymphangiogenesis; Lymphatic vessel; Angiogenesis; Blood vessel