No abstract

In lung cancer, antiangiogenic strategies targeting tumor-derived endothelial cells (TECs) afford a survival advantage, but the characteristics of TECs have not been comprehensively elucidated. Herein, high-purity (> 98%) TECs were obtained, and these cells retained expression of EC markers and exhibited high viability. ITRAQ-2DLC-MS/MS was performed to profile the proteome and the heterogeneity of ECs. Only 31 of 1820 identified proteins were differentially expressed between adenocarcinoma (ADC)- and squamous cell carcinoma (SCC)-derived TECs (TEC-A and TEC-S, respectively), and cadherin-2 (CDH2) was the most significantly upregulated protein in TEC-A samples. Positive immunostaining for CDH2 (score > 3) was significantly more frequent in the endothelium of ADC tissues than in that of SCC tissues. Loss- or gain-of-function analysis showed that CDH2 significantly promoted in vitro and in vivo angiogenesis and sensitivity to the antagonist exherin. The MAPK/ERK and MAPK/JNK signaling pathways may play crucial roles in CDH2-induced HIF-1α/VEGF-mediated angiogenesis. Moreover, high CDH2 expression in TECs was significantly associated with tumor stage, visceral pleural metastasis, and decreased overall survival in patients with ADC but not SCC. Together, these data indicate the importance of CDH2 in angiogenesis and highlight its potential both for antiangiogenic therapy and as a candidate prognostic marker for ADC. Electronic supplementary material The online version of this article (10.1186/s12943-019-0987-1) contains supplementary material, which is available to authorized users.

As there are conflicting reports regarding the association between obstructive sleep apnoea (OSA) and cancer incidence and mortality, a meta-analysis was performed to evaluate whether OSA is independently associated with cancer incidence and mortality. Pubmed, EMBASE and Web of Science were searched up until November 2014. Studies that assessed OSA and the future risk of cancer incidence or mortality were included. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated. Subgroup analysis was conducted based on the polysomnographic variable, apnoea-hypopnoea index. Six studies, which involved 114 105 participants, were pooled in this meta-analysis. Fixed-effects analysis showed the pooled adjusted HR of cancer incidence as 0.91 (95% CI, 0.74-1.13; P = 0.408) for mild OSA, 1.07 (95% CI, 0.86-1.33; P = 0.552) for moderate OSA and 1.03 (95% CI, 0.85-1.26; P = 0.743) for severe OSA. Random-effects analysis demonstrated neither mild OSA (adjusted HR, 0.79; 95% CI, 0.46-1.34; P = 0.381), moderate OSA (adjusted HR, 1.92; 95% CI, 0.63-5.88; P = 0.251) nor severe OSA (adjusted HR, 2.09; 95% CI, 0.45-9.81; P = 0.349) correlated with cancer mortality. This meta-analysis indicates that OSA is not independently associated with cancer incidence and mortality according to currently available data. Additional experimental and human research is required to determine the exact association between OSA and cancer.

Angiogenesis and vascular maturation play important roles in tumorigenesis and tumor development. The expression of neuropilin 1 (NRP1) is closely associated with angiogenesis in tumors; however, the molecular mechanisms of action in angiogenesis and tumor maturation, as well as the potential clinical value of NRP1 remain unclear. The importance of NRP1 expression in tumor progression was determined using The Cancer Genome Atlas (TCGA) database analysis. Gain- and loss-of-function experiments of NRP1 were performed in vascular endothelial cells (ECs) to investigate the functions in angiogenesis. CCK-8, flow cytometry, Transwell experiments and a series of in vitro experiments were used to detect cell functions. A combination of angiogenesis antibody arrays and RNA-Seq analyses were performed to reveal the proangiogenic mechanisms of action. The function of semaphorin 4D (SEMA4D) was also investigated separately. NRP1 mRNA levels were significantly increased in primary tumors compared with normal tissues based on TCGA data (P<0.01) and were associated with tumor development in patients. Gain- and loss-of-function experiments highlighted the function of NRP1 in promoting EC proliferation, motility and capillary-like tube formation and in reducing apoptosis. NRP1 overexpression led to significantly decreased EC markers (PECAM-1, angiogenin, PIGF and MMP-9) expression levels and reduced the vascular maturity. MAPK7, TPM1, RRBP1, PTPRK, HSP90A, PRKD2, PFKFB3, RGS4 and SPARC were revealed to play important roles in this process. SEMA4D was revealed to be a key protein associated with NRP1 in ECs. These data indicated that NRP1-promoted angiogenesis may be induced at the cost of reducing maturity of the ECs. NRP1 may also be a therapeutic target for antiangiogenic strategies and a candidate prognostic marker for tumors.