RESUMO
The majority of patients with epithelial ovarian cancer are diagnosed at a late stage when the peritoneal metastases exist; however, there is little knowledge of the metastatic process in this disease setting. In this study, we report the identification of the long noncoding RNA LINC00092 as a nodal driver of metastatic progression mediated by cancer-associated fibroblasts (CAF). Prometastatic properties of CAFs in vitro and in vivo were found to associate with elevated expression of the chemokine CXCL14. In clinical specimens, elevated levels of CXCL14 in CAFs also correlated with poor prognosis. Notably, CXCL14-high CAFs mediated upregulation of LINC00092 in ovarian cancer cells, the levels of which also correlated with poor prognosis in patients. Mechanistic studies showed that LINC00092 bound a glycolytic enzyme, the fructose-2,6-biphosphatase PFKFB2, thereby promoting metastasis by altering glycolysis and sustaining the local supportive function of CAFs. Overall, our study uncovered a positive feedback loop in the metabolism of CXCL14-positive CAFs and ovarian cancer cells that is critical for metastatic progression. Cancer Res; 77(6); 1369-82. ©2017 AACR.
Assuntos
Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/patologia , Glicólise/fisiologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Fosfofrutoquinase-2/metabolismo , RNA Longo não Codificante/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Fibroblastos Associados a Câncer/metabolismo , Movimento Celular , Proliferação de Células , Quimiocinas CXC/metabolismo , Progressão da Doença , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Prognóstico , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Long noncoding RNAs (lncRNAs) are transcribed by genomic regions (exceeding 200 nucleotides in length) that do not encode proteins. While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, lncRNAs control pleiotropic cancer phenotypes through interactions with other cellular molecules including DNA, protein, and RNA. Recent studies have demonstrated that dysregulation of lncRNAs is influential in proliferation, angiogenesis, metastasis, invasion, apoptosis, stemness, and genome instability in colorectal cancer (CRC), with consequent clinical implications. In this review, we explicate the roles of different lncRNAs in CRC, and the potential implications for their clinical application.
Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Apoptose/genética , Proliferação de Células/genética , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Instabilidade Genômica/genética , Humanos , Modelos Genéticos , Neovascularização Patológica/genéticaRESUMO
Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently, with poor prognosis. However, the molecular mechanisms underlying ovarian cancer metastasis still remain unelucidated. The tumor microenvironment, consisting of stromal cells (including fibroblasts, macrophages, regulatory T cells, myeloid-derived suppressor cells, endothelial cells, pericytes and platelets), the extracellular matrix component (EMC) (including inflammatory cytokines, chemokines, matrix metalloproteinases, integrins, and other secreted molecules) and exosomes (small extracellular vesicles loaded with molecules), establishes an autocrine-paracrine communication circuit that reinforces invasion and cancer cell metastasis via reciprocal signaling. Recent evidences have unraveled the significant contribution of tumor microenvironment to ovarian cancer metastasis. In this review, we provide a comprehensive landscape of the reciprocity between tumor stroma and ovarian cancer cells upon metastasis, aiming to offer novel clues on the development of novel diagnostic biomarkers and therapeutic targets for ovarian cancer in future clinical practice.