Ao Zhi, Yu Shilong, Qian Pin, Gao Wenhong, Guo Ruiling, Dong Xiaoxiao, Xu Jianping, Zhang Ruijie, Jiang Chaowen, Ji Fuyun, Qian Guisheng
Institute of Respiratory Disease, Xinqiao Hospital, The Third Military Medical University, Chongqing, 400037, China.
Institute of Field Internal Medicine, Xinqiao Hospital, The Third Military Medical University, Chongqing, 400037, China.
Biomed Pharmacother. 2017 Mar;87:539-547. doi: 10.1016/j.biopha.2016.12.110. Epub 2017 Jan 9.
Fibromodulin (FMOD), an ECM small leucine-rich proteoglycan (SLRP), was reported to promote angiogenesis not only during wound healing, but also in optical and cutaneous angiogenesis-dependent diseases. However, whether it plays important roles in tumor angiogenesis remains unclear. To explore the role of FMOD in tumor angiogenesis of human small cell lung cancer (SCLC), initially the study analyzed the relationship of FMOD expression in cancer tissues of SCLC with clinical characteristics. The analysis revealed that the positive FMOD expression was significantly associated with extensive stage of SCLC and higher vascular density. In mouse models, xenograft tumors developed with FMOD-silenced H446 cells (H446-shFMOD) exhibited slowed growth rate, decreased microvessel density, and reduced blood perfusion related to that of controls (H446-shCON). Additionally, compared with that of controls, the decreased secretion of FMOD in conditioned medium (CM) from H446-shFMOD inhibited proliferation, migration, and invasion of human umbilical vessel endothelial cells (HUVECs). Moreover, the decreased secretion of FMOD downregulated the expression of VEGF, TGF-β1, FGF-2, and PDGF-B in HUVECs. The findings strongly suggested that the autocrine FMOD of cancer cells may promote tumor angiogenesis of SCLC by upregulating the expression of angiogenic factors that act in concert to facilitate the angiogenic phenotype of endothelial cells as a proangiogenic factor. Therefore, silencing FMOD may be a potentially clinical therapy for repressing tumor angiogenesis.
纤维调节素（FMOD）是一种细胞外基质富含亮氨酸的小分子蛋白聚糖（SLRP），据报道，它不仅在伤口愈合过程中促进血管生成，还在眼部和皮肤血管生成依赖性疾病中发挥作用。然而，它是否在肿瘤血管生成中起重要作用仍不清楚。为了探究FMOD在人小细胞肺癌（SCLC）肿瘤血管生成中的作用，该研究首先分析了SCLC癌组织中FMOD表达与临床特征的关系。分析显示，FMOD阳性表达与SCLC的广泛期和较高的血管密度显著相关。在小鼠模型中，用FMOD沉默的H446细胞（H446-shFMOD）形成的异种移植肿瘤生长速度减慢，微血管密度降低，与对照组（H446-shCON）相比，血液灌注减少。此外，与对照组相比，H446-shFMOD条件培养基（CM）中FMOD分泌减少抑制了人脐静脉内皮细胞（HUVECs）的增殖、迁移和侵袭。而且，FMOD分泌减少下调了HUVECs中VEGF、TGF-β1、FGF-2和PDGF-B的表达。这些发现强烈表明，癌细胞的自分泌FMOD可能通过上调血管生成因子的表达来促进SCLC的肿瘤血管生成，这些血管生成因子协同作用以促进内皮细胞的血管生成表型，作为一种促血管生成因子。因此，沉默FMOD可能是一种潜在的抑制肿瘤血管生成的临床治疗方法。
