Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis

Abstract

Early lymph node metastasis is common in pancreatic ductal adenocarcinoma (PDAC). The present study has examined the relationship of lymphatic spread to lymph vessel development and the expression of lymphangiogenic cytokines in a series of well-characterized PDACs. The hot spot method revealed the intratumoural and peritumoural lymphatic vessel density (LVD) to be slightly higher in PDACs than in the normal pancreas. The average intratumoural LVD, however, was strikingly decreased. There was no overexpression of vascular endothelial growth factor (VEGF)-C and VEGF-D in PDACs compared with the normal pancreas. LVD and expression of lymphangiogenic cytokines were not related to any of the biological tumour features or to patient survival. Three orthotopic nude mouse PDAC models did not reveal any increase in tumour-associated LVD, despite a high rate of lymph node metastasis. Lymph vessel proliferation was comparable in PDAC and chronic pancreatitis, in both humans and mice. In conclusion, increased lymphangiogenic activity is not required for and does not significantly affect the lymphatic spread of PDAC. The reduced number of human and murine intratumoural lymph vessels indicates that lymphatic metastasis takes place predominantly via peritumoural lymphatic vessels. The weak expression of lymphangiogenic cytokines in neoplastic cells and lymphatic vessel proliferation in peritumoural regions and chronic pancreatitis indicate that inflammation may be the reason for the low rate of lymphangiogenesis.

Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma

“…7,12 Some studies have shown an inverse correlation between tumor aggressiveness and intratumoral lymphatic vessel density. 4,9,10,11 These results suggest that intratumoral lymphatic vessels, especially in the tumor center, are destructed by the tumor growth and the lymphatic vessel is preserved in the tumor border in intrahepatic cholangiocarcinoma. In the current study, tumor invasion into the lymphatic vessels was frequently detected in the tumor periphery or in the peritumoral area.…”

“…Like our result, lymphangiogenesis do not always occur in breast cancers. 11,44 It was demonstrated that increased lymphangiogenic activity is not required for the lymphatic spread in pancreatic ductal adenocarcinoma, 7,9 and prostatic adenocarcinoma. 8,22 Several studies showed that increased lymphatic perimeters and areas were found to be correlated with presence of lymphatic metastasis.…”

“…1,2 Several types of human cancer can induce the formation of lymphatic vessels, [3][4][5][6] whereas other cancers do not actively induce lymphangiogenesis and simply invade existing lymphatic vessels. [7][8][9][10][11][12][13] A positive relationship between the intratumoral or peritumoral lymphatic vessel density and lymphatic spreads has been reported in head and neck squamous cell carcinoma, 3,14,15 cutaneous melanoma, 16,17 lung cancer, 18 and pancreatic endocrine tumor. 19,20 Vascular endothelial growth factor-C (VEGF-C) has been found to be the common lymphangiogenetic factor, acting predominantly via VEGF receptor-3 (VEGFR-3), which is expressed by lymphatic endothelial cells, 21 and VEGF-C strongly promoted the growth of tumor-associated lymphatic vessels.…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…Expression of the lymphangiogenic factors VEGF-C and -D is significantly correlated with lymphangiogenesis (tumoral and nodal) and LN metastasis in a variety of primary tumors including thyroid, prostate, gastric, colorectal, lung and breast in both human and animal models [17,20,116,117]. Although VEGF-C is well-correlated with cancer metastasis, the requirement for tumor lymphangiogenesis is controversial, and there is evidence that VEGF-C can promote metastasis in the absence of tumor lymphangiogenesis [118][119][120][121][122][123]. VEGF-C can also attract macrophages [124] that can alter the tumor microenvironment to promote invasion.…”

In vivo imaging of lymphatic vessels in development, wound healing, inflammation, and tumor metastasis

“…Tumor invasion to regional lymph nodes is often the first sign of tumor metastasis and a marker of poor prognosis. Stimulation of growth and dilation of preexisting lymphatic vessels by the tumor facilitates tumor spread via the lymphatics (5-7) and the contribution of intratumoral lymphangiogenesis may depend on tumor type (8)(9)(10)(11)(12). Moreover, lymphangiogenic growth factors produced by the tumor may induce sinusoidal hyperplasia in the regional lymph node and this process may further contribute to tumor metastasis (13)(14)(15).…”