Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis

Abstract

Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor‐C (VEGF‐C) is a recently described lymphangiogenic factor. Increased expression of VEGF‐C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF‐C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF‐C expression, driven by the rat insulin promoter (Rip), is targeted to β‐cells of the endocrine pancreas. In contrast to wild‐type mice, which lack peri‐insular lymphatics, RipVEGF‐C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic β‐cell tumours that are neither lymphangiogenic nor metastatic. Double‐transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of β‐cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF‐C‐induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.

Calcium carbonate nanoparticle delivering vascular endothelial growth factor-C siRNA effectively inhibits lymphangiogenesis and growth of gastric cancer in vivo

“…25 For gastric tumors, as for many others, VEGF-C is considered the prominent inducer of tumor lymphangiogenesis. Consequently, a tumor therapy targeting VEGF-C would be particularly efficacious in the treatment of gastric tumor.…”

“…for 10 min, and it protects DNA from degradation in 10% FBS and 10% newborn bovine serum at 37 1C for 12 h. Furthermore, we found that the optimal ratio of CaCO 3 nanoparticle to DNA is 15:1, and the maximal gene expression is observed 48 h after transfection. The CaCO 3 Abbreviations: PBS, phosphate-buffered saline; siRNA, small interfering RNA; VEGF-C, vascular endothelial growth factor-C.…”

“…This family comprises VEGF-A, -B, -C, -D and -E, which are specific members of this family known to be required for cancer progression and metastasis. 2,3 Among the VEGF family, VEGF-C has recently been found to induce not only angiogenesis, but also lymphangiogenesis, via both VEGF receptor (VEGFR)-2 and VEGFR-3. [4][5][6] Expression of VEGFR-3 is highly restricted to lymphatic endothelial cells and stimulated by only VEGF-C and -D. [7][8][9] VEGF-C overexpression in breast cancer potently increases intratumoral lymphangiogenesis, resulting in enhanced metastasis to regional lymph nodes.…”

“…The silencing mechanism is triggered by double-stranded RNA that causes specific degradation of the homologous target mRNA. [24][25][26][27] This new approach has been successfully applied to inhibit virus replication 28 and tumorigenicity. 29 Recent reports have described DNA vector-based strategies for delivery of small interfering RNA (siRNA) into mammalian cells.…”

Targeting lymphangiogenesis to prevent tumour metastasis

“…In other models, expression of VEGF-C in breast cancer cells promoted growth of tumour-associated lymphatics (Skobe et al, 2001a), that were in some cases infiltrated with tumour cells , and metastatic spread to lymph nodes (Mattila et al, 2002). In a transgenic mouse model of pancreatic cancer, expression of VEGF-C in tumour cells led to extensive lymphangiogenesis associated with the tumours and metastases in draining lymph nodes (Mandriota et al, 2001). Expression of VEGF-D in tumour cells of a mouse xenograft model promoted formation of intratumoural lymphatics, angiogenesis, tumour growth and metastasis to lymph nodes ).…”