Distinct Roles of Vascular Endothelial Growth Factor-D in Lymphangiogenesis and Metastasis

Abstract

In many human carcinomas, expression of the lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) correlates with up-regulated lymphangiogenesis and regional lymph node metastasis. Here, we have used the Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis to investigate the functional role of VEGF-D in the induction of lymphangiogenesis and tumor progression. Expression of VEGF-D in beta cells of single-transgenic Rip1VEGF-D mice resulted in the formation of peri-insular lymphatic lacunae, often containing leukocyte accumulations and blood hemorrhages. When these mice were crossed to Rip1Tag2 mice, VEGF-D-expressing tumors also exhibited peritumoral lymphangiogenesis with lymphocyte accumulations and hemorrhages, and they frequently developed lymph node and lung metastases. Notably, tumor outgrowth and blood microvessel density were significantly reduced in VEGF-D-expressing tumors. Our results demonstrate that VEGF-D induces lymphangiogenesis, promotes metastasis to lymph nodes and lungs, and yet represses hemangiogenesis and tumor outgrowth. Because a comparable transgenic expression of vascular endothelial growth factor-C (VEGF-C) in Rip1Tag2 has been shown previously to provoke lymphangiogenesis and lymph node metastasis in the absence of any distant metastasis, leukocyte infiltration, or angiogenesis-suppressing effects, these results reveal further functional differences between VEGF-D and VEGF-C.

FOXC2 Expression is Associated with Tumor Proliferation and Invasion Potential in Oral Tongue Squamous Cell Carcinoma

“…Angiogenesis and lymphangiogenesis are also crucial for tumor progression and nodal metastasis in OSCC [10]. Some of the main angiogenic and lymphangiogenic factors have been identified as vascular endothelial growth factor (VEGF)-A and VEGF receptor(VEGFR) 2, as well as the VEGF-C/-D and VFGFR3 systems, respectively [15,16].…”

VEGF‐D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis

“…Expression levels of VEGF-D and VEGF-C correlate with lymph node metastasis in several human cancers [15,16], and addition or overexpression of exogenous VEGF-C or VEGF-D induces lymphatic growth and tumor metastasis in preclinical cancer models [17][18][19][20][21][22][23][24][25]. Addition of exogenous VEGF-D or VEGF-C also induces the formation of functional, mature collecting lymphatic collecting lymphatic vessels in mice [6].…”

Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer

“…Stacker et al [13] subsequently demonstrated in a mouse model that lymphatic spread was also associated with the expression of (VEGF-D) by the tumor. Kopfstein et al [14] further showed in a transgenic mouse model that VEGF-D, as it was expressed by the tumor cells, induced tumor lymphangiogenesis, lymph node metastasis and promoted metastasis to the lungs. Moreover, in a variety of human cancers, including gastric, pancreatic, lung, colorectal, breast and ovary, elevated tumoral VEGF-C and VEGF-D expression correlates with an increased incidence of regional lymph node metastasis and poor prognosis [15][16][17][18][19][20].…”