VEGF‐D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma

Abstract

Lymphatic spread is an important clinical determinant for the prognosis of hepatocellular carcinoma (HCC), but little is known about the control of lymphangiogenesis in HCC. We addressed expression and biological role of the pro‐(lymph), angiogenic protein VEGF‐D in this tumor entity. Using immunohistochemistry and in situ hybridization on specimens of HCC, cirrhotic and normal liver we found abundant expression of VEGF‐D exclusively in the tumor cells. The cognate receptor VEGFR‐3 was detected on blood and lymphatic vessels. By clinicopathological analysis VEGF‐D expression was correlated with pT‐stage of the primary, lymph node metastasis and lymphangiosis carcinomatosa. Three out of 4 human HCC cell lines expressed and secreted VEGF‐D. To approach its biological function, VEGF‐D deficient SKHep‐1 cells were stably transfected with VEGF‐D cDNA and effects on tumor progression were determined in vivo. Compared to mock‐transfected controls, subcutaneous tumors derived from VEGF‐D expressing cells were larger and more frequently metastasized to regional lymph nodes. VEGF‐D expressing tumors exhibited increased microvessel density and increased abundance of peri‐ and intratumoral lymphatics, as assessed by immunostaining for CD31 and for LYVE‐1 and/or podoplanin, respectively. Furthermore, coexpression of the soluble extracellular VEGFR‐3 domain blocked VEGF‐D‐induced tumor growth and lymphatic spread via reduction of angiogenesis and lymphangiogenesis. In the orthotopic approach, VEGF‐D expression resulted in an increased rate of intra‐ and extrahepatic as well as lymph node metastasis. In conclusion, our study suggests that expression of VEGF‐D is involved in growth and lymphatic spread of HCC. Therefore, VEGF‐D might represent a therapeutic target in HCC. © 2008 Wiley‐Liss, Inc.

Radiomics Features of Multiparametric MRI as Novel Prognostic Factors in Advanced Nasopharyngeal Carcinoma

“…However, we unexpectedly found that cases with lymph node metastasis had a lower mean value of CET1-w_5_fos_median than did cases without lymph node metastasis. Almost all previous studies have reported the contrary result that angiogenesis is positively correlated with lymph node metastasis (48)(49)(50). The reason for this discrepancy may be NPC patients often experienced lymph node metastasis even in the low-stage (stage I-II).…”

Clinical Significance of Microvessel Count in Patients with Metastatic Liver Cancer Originating from Colorectal Carcinoma

“…12 Metastatic liver cancer also expresses angiogenic factors such as vascular endothelial growth factor (VEGF) and microvessel counts. 9,13 Levels of these angiogenic factors may affect patient survival.…”

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].…”

“…Similarly, adenoviral or transgenic overexpression of VEGF-D corrects defective lymphangiogenesis in airway inflammation in wild type mice [26] or in the skin of VEGF-C +/-lymphedema mice [14]. Vice versa, strategies to prevent VEGF-C/D mediated signaling block tumor (lymph)angiogenesis and metastasis in cancer, or lymphangiogenesis in corneal inflammation [5,21,23,27,28]. …”