Abstract
Semaphorins play important regulatory roles in diverse processes such as axon guidance, angiogenesis, and immune responses. We find that semaphorin-3C (sema3C) induces the collapse of the cytoskeleton of lymphatic endothelial cells (LEC) in a neuropilin-2-, plexin-D1-, and plexin-A1-dependent manner, while most other semaphorins, including antiangiogenic semaphorins such as sema3A do not. Sema3C is cleaved, like other class-3 semaphorins, by furin-like pro-protein convertases (FPPC). Cleaved sema3C (p65-Sema3C) was unable to induce the collapse of the cytoskeleton of LEC. FPPC are strongly upregulated in tumor cells. In order to examine the effects of full-length sema3C on tumor progression, we therefore generated an active point mutated furin cleavage-resistant sema3C (FR-sema3C). FR-sema3C inhibited potently proliferation of LEC and to a lesser extent proliferation of human umbilical vein-derived endothelial cells. FR-sema3C also inhibited VEGF-C-induced phosphorylation of VEGFR-3, ERK1/2, and AKT. Expression of recombinant FR-sema3C in metastatic, triple-negative LM2-4 breast cancer cells did not affect their migration or proliferation in vitro. However, tumors derived from FR-sema3C-expressing LM2-4 cells implanted in mammary fat pads developed at a slower rate, contained a lower concentration of blood vessels and lymph vessels, and metastasized much less effectively to lymph nodes. Interestingly, p65-Sema3C, but not FR-sema3C, rendered A549 lung cancer cells resistant to serum deprivation, suggesting that previously reported protumorigenic activities of sema3C may be due to p65-Sema3C produced by tumor cells. Our observations suggest that FR-sema3C may be further developed into a novel antitumorigenic drug.
Highlights
Tumor metastasis to lymph nodes represents the first step of dissemination in head and neck tumors and in breast cancer tumors, and is a major prognostic indicator for disease progression [1,2,3,4]
We show that ectopic expression of a furin cleavage-resistant point mutated www.aacrjournals.org sema3C (FR-sema3C) in tumors derived from LM2-4 breast cancer cells implanted in mammary fat pads inhibits tumor lymphangiogenesis and the metastatic spread of tumor cells to lymph nodes
The expression patterns of the type-A plexins were similar between Human umbilical vein–derived endothelial cells (HUVEC) [and other primary human endothelial cell types (Supplementary Fig. S1C)] and lymphatic endothelial cells (LEC) except that plexin-A4 was not expressed at all in LEC, and plexins A1 and D1 seemed to be more abundant in LEC (Supplementary Fig. S1B)
Summary
Tumor metastasis to lymph nodes represents the first step of dissemination in head and neck tumors and in breast cancer tumors, and is a major prognostic indicator for disease progression [1,2,3,4]. Tumor cells can enter the vascular circulation via the thoracic lymphatic duct [3]. The metastatic spread of tumor cells to lymph nodes is enhanced following the induction of tumor lymphangiogenesis, which is driven by lymphangiogenic factors such as VEGF-C and VEGF-D [5,6,7]. The metastatic spread of tumor cells to lymph nodes can be enhanced by cytokines such as CCL21, CXC12 (SDF-1), and CCL1 that recruit tumor cells to lymph vessels [4]. VEGF-D was found to promote the dilation of collecting lymphatics by upregulation of prostaglandin production, thereby promoting the passage of tumor cells to lymph nodes [8]. The class-3 semaphorins were initially characterized as axon guidance factors [9]. Class-3 semaphorins, with the exception of sema3E, which binds directly to the plexin-D1 receptor, bind
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
