Tumour angiogenesis regulation by the miR-200 family

Abstract

The miR-200 family is well known to inhibit the epithelial–mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent.

Improving vascular maturation using noncoding RNAs increases antitumor effect of chemotherapy

“…We silenced miRs in ECs using miR inhibitors and RNAifect reagent (Qiagen) as described in the supplemental methods. VEGFR1 and VEGFR2 were silenced in RF24 cells and annexin A2 in HMVECs was silenced with either control or target siRNAs using Lipofectamine 2000 reagent (Invitrogen) as described previously (33). The expression of annexin A2, miRs, and tight junction proteins was determined using quantitative real-time PCR and Western blot analyses as described previously (34,35).…”

Association of microRNA-93, 190, 200b and Receptor Status in Core Biopsies from Stage III Breast Cancer Patients

“…Almog et al (2012Almog et al ( , 2013 emphasized the role of miR-NA-190 in the reversal of fast-growing angiogenic tumors toward prolonged tumor dormancy. Pecot et al (2013) and Li et al (2013) emphasized the critical role of miRNA-200 in regulating epithelial-to-mesenchymal transition, which are key processes in invasion, progression, and metastasis. Lim et al (2013), in a study of pleural effusion or ascites samples in stage IV breast cancer patients, added to these observations and demonstrated the involvement of the miRNA-200 family in the process of nonstem to a stem-like phenotypic conversion.…”

Focal adhesion kinase

“…In these cases, other mediators of angiogenesis (e.g., platelet-derived growth factor, fibroblast growth factor, the polycomb group protein enhance Zeste homolog 2 [EZH2], notch family, the angiopoietin [Ang]-TIE system, and the miR-200 family of miRNA) are likely to play a role. 37,38 There is a small but growing body of literature that initial tumor response to anti-angiogenic therapy may paradoxically be followed by enhanced tumor progression by promoting an invasive phenotype. Experimental models have recently shown that tumors can develop anti-VEGF escape programs associated with metastatic dissemination to lymph nodes and distant sites.…”