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      Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis.

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          Abstract

          Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.

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          The pre-metastatic niche: finding common ground.

          Jaclyn Sceneay, Mark Smyth, Andreas Möller (2013)
          It is rapidly becoming evident that the formation of tumor-promoting pre-metastatic niches in secondary organs adds a previously unrecognized degree of complexity to the challenge of curing metastatic disease. Primary tumor cells orchestrate pre-metastatic niche formation through secretion of a variety of cytokines and growth factors that promote mobilization and recruitment of bone marrow-derived cells to future metastatic sites. Hypoxia within the primary tumor, and secretion of specific microvesicles termed exosomes, are emerging as important processes and vehicles for tumor-derived factors to modulate pre-metastatic sites. It has also come to light that reduced immune surveillance is a novel mechanism through which primary tumors create favorable niches in secondary organs. This review provides an overview of our current understanding of underlying mechanisms of pre-metastatic niche formation and highlights the common links as well as discrepancies between independent studies. Furthermore, the possible clinical implications, links to metastatic persistence and dormancy, and novel approaches for treatment of metastatic disease through reversal of pre-metastatic niche formation are identified and explored.
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            KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis

            Meera Murgai, Wei Ju, Matthew Eason … (2017)
            A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche composed of hematopoietic cells, stromal cells, and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesize that perivascular cells similarly regulate tumor cell fate at metastatic sites. Using perivascular cell-specific and pericyte-specific lineage-tracing models, we trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC/pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration, and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically-switched perivascular cells promotes a less differentiated state characterized by enhanced ECM production that establishes a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreases pre-metastatic niche formation and metastasis. Our data reveal a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncover novel strategies for limiting metastasis.
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              The exosomes in tumor immunity.

              Yanfang Liu, Yan-Yan Gu, Xuetao Cao (2015)
              Exosomes are a kind of nanometric membrane vesicles and can be released by almost all kinds of cells, including cancer cells. As the important mediators in intercellular communications, exosomes mediate exchange of protein and genetic material derived from parental cells. Emerging evidences show that exosomes secreted by either host cells or cancer cells are involved in tumor initiation, growth, invasion and metastasis. Moreover, communications between immune cells and cancer cells via exosomes play dual roles in modulating tumor immunity. In this review, we focus on exosome-mediated immunosuppression via inhibition of antitumor responses elicited by immune cells (DCs, NK cells, CD4(+) and CD8(+) T cells, etc.) and induction of immunosuppressive or regulatory cell populations (MDSCs, Tregs and Bregs). Transfer of cytokines, microRNAs (miRNAs) and functional mRNAs by tumor-derived exosomes (TEXs) is crucial in the immune escape. Furthermore, exosomes secreted from several kinds of immune cells (DCs, CD4(+) and CD8(+) Tregs) also participate in immunosuppression. On the other hand, we summarize the current application of DC-derived and modified tumor-derived exosomes as tumor vaccines. The potential challenges about exosome-based vaccines for clinical application are also discussed.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature communications
                Publisher: Springer Science and Business Media LLC
                ISSN (Electronic): 2041-1723
                ISSN (Print): 2041-1723
                Publication date (Electronic): December 19 2018
                Volume: 9
                Issue: 1
                Affiliations
                [1 ] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, People's Republic of China.
                [2 ] Department of Pathology, Southern Medical University, Guangzhou, 510515, Guangdong Province, People's Republic of China.
                [3 ] Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong province, People's Republic of China.
                [4 ] Department of Pathology, Dongguan People's hospital, Dongguan, Guangdong Province, People's Republic of China.
                [5 ] Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, Guangdong Province, People's Republic of China.
                [6 ] Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, People's Republic of China.
                [7 ] Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, People's Republic of China. redsnow007@hotmail.com.
                [8 ] Department of Pathology, Southern Medical University, Guangzhou, 510515, Guangdong Province, People's Republic of China. redsnow007@hotmail.com.
                [9 ] Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, Guangdong province, People's Republic of China. redsnow007@hotmail.com.
                Article
                Publisher Item ID: 10.1038/s41467-018-07810-w
                DOI: 10.1038/s41467-018-07810-w
                PMC ID: 6300604
                PubMed ID: 30568162
                SO-VID: 884ac459-98ab-4498-b469-e596871da71f
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