Abstract
Chondrosarcoma is the second most common primary malignancy of bone, and one of the most difficult bone tumors to diagnose and treat. It is well known that increased levels of vascular endothelial growth factor-C (VEGF-C) promote active tumor lymphangiogenesis and lymphatic tumor spread to regional lymph nodes. Brain-derived neurotrophic factor (BDNF) is known to promote metastasis in human chondrosarcoma cells. Knowing more about the mechanism of BDNF in VEGF-C expression and lymphangiogenesis in human chondrosarcoma would improve our understanding as how to prevent chondrosarcoma angiogenesis and metastasis, which currently lacks effective adjuvant treatment. Here, we found that BDNF expression was at least 2.5-fold higher in the highly migratory JJ012(S10) cell line as compared with the primordial cell line (JJ012). In addition, VEGF-C expression and secretion was markedly increased in JJ012(S10) cells. Conditioned medium from JJ012(S10) cells significantly promoted migration and tube formation of human lymphatic endothelial cells (LECs), whereas knockdown of BDNF attenuated LEC migration and tube formation by suppressing VEGF-C production in JJ012(S10) cells. Mechanistic investigations indicated that BDNF facilitated VEGF-C-dependent lymphangiogenesis through the MEK/ERK/mTOR signaling pathway. We also showed that microRNA (miR)-624-3p expression was negatively regulated by BDNF via the MEK/ERK/mTOR cascade. Importantly, BDNF knockdown profoundly inhibited tumor-associated lymphangiogenesis in vivo. Further analyses identified that BDNF promoted tumor lymphangiogenesis by downregulating miR-624-3p in human chondrosarcoma tissues. In conclusion, this study is the first to reveal the mechanism underlying BDNF-induced lymphangiogenesis. We suggest that BDNF may serve as a promising therapeutic target for the restriction of VEGF-C-mediated tumor lymphangiogenesis and lymphatic metastasis.
Highlights
Chondrosarcoma is a malignant tumor composed of cartilage-producing cells
We found that JJ012 (S10) cells displayed higher Brain-derived neurotrophic factor (BDNF) and Vascular endothelial growth factor-C (VEGF-C) expression as compared with JJ012(S0) cells (Figures 1b-e)
Incubation of cells with the mitogen-activated protein kinase kinase (MEK) inhibitor antagonized BDNF-induced extracellular signal-regulated kinase (ERK) phosphorylation (Figure 3h). These results suggest that BDNF acts through the MEK/ERK pathway to enhance VEGF-C-dependent lymphangiogenesis in human chondrosarcoma cells
Summary
Chondrosarcoma is a malignant tumor composed of cartilage-producing cells. It is the second most common primary malignancy of bone and one of the most difficult bone tumors to diagnose and treat. Vascular endothelial growth factor-C (VEGF-C) makes a crucial contribution to lymphangiogenesis and metastasis.[2,3] VEGF-C is predominantly expressed and released by tumor cells, and activates the proliferation, migration, and tube formation of human lymphatic endothelial cells (LECs) via VEGF receptor-3 (VEGFR-3),[4] and that elevated VEGF-C levels are significantly correlated with lymph node metastasis and poor patient prognosis.[5] despite its importance in tumor physiology and pathology, we know very little about appropriate therapeutic targets against tumor-associated lymphangiogenesis. Received 15.3.17; revised 22.6.17; accepted 23.6.17; Edited by A Stephanou recent studies have revealed that VEGF-C is closely related to tumor stage in human chondrosarcoma,[2,3] we need to learn more about the mechanisms involved in VEGF-C-dependent lymphangiogenesis in order to fully understand the microenvironment in chondrosarcoma microenvironment. We investigated the role of BDNF in VEGF-C-dependent lymphangiogenesis, to elucidate its mechanism of action in human chondrosarcoma cells
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