title: Neuropilin-2 mediates lymphangiogenesis of colorectal carcinoma via a VEGFC/VEGFR3 independent signaling.
abstract: Lymphangiogenesis critically contributes to the lymphatic metastasis of colorectal carcinomas (CRCs), but the underlying mechanism of CRC lymphangiogenesis remains largely elusive. We have previously demonstrated that Semaphorin-3F (SEMA3F) is critically involved in CRC metastasis, and the receptor of SEMA3F, neuropilin-2 (NRP2), originally described as an axon guiding chemorepulsant implicated in nerve development, has been suggested in promoting lymphangiogenesis via acting as an obligate co-receptor of VEGFR3 cooperatively enhancing the activity of VEGF-C. Our present study revealed that in colorectal carcinomas, NRP2 expression levels of tumor-associated lymphatic endothelial cells (LECs) are significantly correlated with the density of tumor lymphatic vessels. In vitro, activation of NRP2 in LECs substantially facilitates their migration, sprouting, and tubulogenesis capacity via regulating the rearrangement of cytoskeleton polarity. In vivo model further showed that in the xenografts generated from SEMA3F knockdown CRC cells, NRP2 is substantially activated in tumor-associated LECs, resulting in a significantly increased tumor lymphangiogenesis. Further evidence demonstrated that CRC cell induces the activation of NRP2 in LECs to promote tumor lymphangiogenesis via integrinα9β1/FAK/Erk pathway independent VEGF-C/VEGFR3 signaling. Our study for the first time revealed the novel molecular mechanism of NRP2-mediated-lymphangiogenesis in CRCs, suggesting NRP2 as a potential therapeutic target in preventing lymphatic metastasis of CRCs.
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Ou
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zha
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Rong-Bin
authors.initials: RB
authors.lastname: Zhou
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; Department of oncology, FuLing Central Hospital, Chongqing 408000, China. Electronic address: qizhou112@163.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. Electronic address: lianghoujie@sina.com.
authors.forename: Hou-Jie
authors.initials: HJ
authors.lastname: Liang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D042583:Lymphangiogenesis / Q000235:genetics; D051379:Mice; D039943:Neuropilin-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C541973:ITGA9 protein, human; D019012:Integrin beta1; D016023:Integrins; D039943:Neuropilin-2; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020830:rac1 GTP-Binding Protein
keywords: Colorectal carcinoma; Cytoskeleton; Focal adhesion kinase; Lymphatic metastasis; Vasculogenesis