Data from Inhibition of miR-328–3p Impairs Cancer Stem Cell Function and Prevents Metastasis in Ovarian Cancer
Amit SrivastavaAnanya BanerjeeTiantian CuiChunhua HanShurui CaiLu LiuDayong WuRi CuiZaibo LiXiaoli ZhangGuozhen XieKaruppaiyah SelvendiranSrinivas PatnaikAdam R. KarpfJinsong LiuDavid E. CohnQi-En Wang
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<div>Abstract<p>Cancer stem cells (CSC) play a central role in cancer metastasis and development of drug resistance. miRNA are important in regulating CSC properties and are considered potential therapeutic targets. Here we report that miR-328–3p (miR-328) is significantly upregulated in ovarian CSC. High expression of miR-328 maintained CSC properties by directly targeting DNA damage binding protein 2, which has been shown previously to inhibit ovarian CSC. Reduced activity of ERK signaling in ovarian CSC, mainly due to a low level of reactive oxygen species, contributed to the enhanced expression of miR-328 and maintenance of CSC. Inhibition of miR-328 in mouse orthotopic ovarian xenografts impeded tumor growth and prevented tumor metastasis. In summary, our findings provide a novel mechanism underlying maintenance of the CSC population in ovarian cancer and suggest that targeted inhibition of miR-328 could be exploited for the eradication of CSC and aversion of tumor metastasis in ovarian cancer.</p>Significance:<p>These findings present inhibition of miR-328 as a novel strategy for efficient elimination of CSC to prevent tumor metastasis and recurrence in patients with epithelial ovarian cancer.</p></div>Abstract Most patients with ovarian cancer present with widely metastatic disease. Although epithelial ovarian cancer was widely believed to metastasize via direct surface spread, the distribution of metastasis from the primary tumor is not completely random. Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. We have used parabiosis model systems that demonstrate preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis. Citation Format: Anil K. Sood. Hematogenous metastasis of ovarian cancer: Rethinking mode of spread. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA23.
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Metastasis is incontrovertibly linked to poor cancer patient survival. Cancer treatments that inhibit metastasis are predicted to improve cancer patient outcomes by preventing cancer dissemination. However, to control metastasis in patients necessitates an understanding of the biological drivers of metastasis. Drivers of metastasis can be thought of as factors that promote tumour dissemination, required at least for a part of the metastatic process. Yet, presently specific molecular drivers of metastasis largely remain unidentified, and very little evidence for ubiquitous metastasis-specific driver gene mutations has been identified to date (1,2).
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An outline of the mechanism of cancer metastasis is presented from a molecular biological point of view, and the present state and future possibility of prediction about cancer metastasis in clinical cases is described. Cancer metastasis is developed through multiple steps. With the progress of studies on the mechanism of metastasis, the effort to predict cancer metastasis in clinical cases has progressed. Metastasis is formed in concern with many factors, so it may be highly difficult to explain clinical metastasis by a single factor. It will be important to comprehensively put many factors into consideration. For the preoperative diagnosis of the potential of metastasis, examination of specimens from endoscopic biopsy or blood serum will become more important.
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Metastasis is one of the most distinct but complicated biological phenomena in cancer. It is hard to decide the most important prospect which must be performed at the present as well as in future studies on cancer metastasis. However, the final goal of the studies on metastasis can be simply concluded as that metastasis should be prevented before dissemination. In this review, we discussed several points to do research in metastasis.
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The spread of cancer cells in the body -'metastasis,' is a challenging issue for cancer patients and for cancer research. From a clinical point of view, the majority of the cancer-related deaths in patients who suffer from solid cancers are metastasis-related. Although this life threatening consequence in cancer is recognised almost immediately at the time of diagnosis, the current-state-of-knowledge on the mechanisms and effective ways to combat cancer metastasis in clinical settings is far from being realized. Thus, making the necessity of continuing research into cancer metastasis evermore demanding and critical. This issue of the journal is directed toward consideration of some of the salient aspects of cancer metastasis, with a focus on recent progress of the molecular and cellular mechanisms of cancer invasion and metastasis.
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Cancer as an historical disease is known to occur since several hundred years and still prevails till date as one of the most feared diseases. Its occurrence and/or progression are considered as the outcome of the series of accumulated ocogenic changes in the cell those transform it from benign to invasive or metastatic. It has been observed that most of the metastatic cancers are not curable and the available drugs focus on steadying the tumour growth to prevent further metastasis. Metastasis remains the cause of around 90% of the cancer deaths. Fundamental understanding of metastasis and recent advancements in metastasis driven cancer research may help to strengthen and bring in practice the new and advanced approaches for cancer treatment. In view of this, we review in detail the molecular mechanism of metastasis, problems in diagnosing and treating metastasis, and recent developments in cancer biology. Future efforts in order to unveil the unpredicted and uncontrolled metastasis of cancer cells have also been summarised.
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Abstract Most solid tumors have now been reported to contain stem cell‐like cells called cancer stem cells (CSCs). These cells are endowed with high tumorigenic capacity and may be the cells that drive tumor formation, maintain tumor homeostasis, and mediate tumor metastasis. Since these self‐renewing cancer cells may be the sole population to develop a primary tumor, it is predicted that CSCs may also represent the lethal seeds of metastasis, as supported by a flurry of recent studies on the relationship between CSCs and metastasis. Herein, we summarize current knowledge of stem/progenitor cells and CSCs, especially in the context of normal human prostate and prostate cancer. We further update the recently gained knowledge on the involvement of CSCs in metastasis. We also discuss the fundamental influence of tumor microenvironment on the manifestation of CSCs and metastasis. Finally, we discuss the clinical implication of CSC‐based therapy. J. Surg. Oncol. 2011;103:558–562. © 2011 Wiley‐Liss, Inc.
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