Role of lymphangiogenesis and lymphangiogenic factors during pancreatic cancer progression and lymphatic spread.

Treatment options for ductal adenocarcinoma of the pancreas are limited by early lymphatic spread, but the lymphatic vessels in pancreatic carcinoma have not been studied to date. Here, we present a histomorphological analysis of lymphatic vessels in pancreatic cancer resection specimens. Both intratumoral and peritumoral tissue were devoid of active lymphangiogenesis. Intratumoral lymphatics were frequently collapsed and non-functional, whereas peritumoral lymphatic vessels were enlarged, and numerous lymphatic vessels were seen in metastases. In addition, we screened pancreatic cancer tissue and pancreatic carcinoma cell lines for mRNA expression of the lymphangiogenic growth factor, VEGF-C; its receptor, VEGFR-3/flt4; and Prox1, a transcription factor essential for embryonic development of both lymphatic vessels and the pancreatic bud. VEGF-C was abundantly expressed in pancreatic cancer tissue and -cell lines and VEGFR-3/flt4 was expressed in cancer stromal cells. Prox1 was strongly expressed in the normal exocrine pancreas but significantly reduced in pancreatic cancer specimens from patients with short survival rates. Well-differentiated cell lines displayed higher levels of Prox1 mRNA than poorly differentiated ones. These results suggest that active lymphangiogenesis is not required for lymphovascular spread of pancreatic cancer. VEGF-C may promote local tumor growth via paracrine signaling to stromal cells expressing VEGFR-3 and support the entry of cancer cells into peritumoral lymphatics. Furthermore, loss of Prox1 function may be a driving force behind pancreatic carcinoma progression.