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.
Highlights
Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they can induce lymphatic vessel growth to facilitate fluid drainage and metastasis
Peritumoral blood and lymphatic vessels are enlarged Prominent red-colored blood vessels surround B16-F10 melanoma tumors implanted in the flank of syngeneic C57Bl/6 wild-type mice (Figure 1a), often growing toward regional draining Lymph node (LN)
Other abnormal red-colored vessels (ODD) variably appeared in adjacent regions of the flank skin in regions that normally do not contain large blood vessels (Figure 1c). These phenotypes of increased superficial epigastric blood vessel (SE), IF, and ODD vessel growth were identified in all twelve of the tumor-bearing mice analyzed in this study. We tested whether this angiogenesis involves lymphatic vessels, as the SE blood vessel between the ING and AX LNs tracks with a major lymphatic vessel draining from the ING LN [31]
Summary
Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they 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. VEGF-A, placental growth factor), as well as lymphangiogenesis (VEGF-C, −D), the resulting vessels are highly abnormal relative to those of embryos [17,18], presumably due to aberrant signaling [9,19] These vessels can actively increase blood circulation and lymph drainage, or they can become so abnormal that they are unable to transport blood [20] or lymph [14,21]
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