Cellular microparticles are vesicular plasma membrane fragments with a diameter of 100-1,000 nanometres that are shed by cells in response to various physiological and artificial stimuli. Here we demonstrate that tumour cell-derived microparticles can be used as vectors to deliver chemotherapeutic drugs. We show that tumour cells incubated with chemotherapeutic drugs package these drugs into microparticles, which can be collected and used to effectively kill tumour cells in murine tumour models without typical side effects. We describe several mechanisms involved in this process, including uptake of drug-containing microparticles by tumour cells, synthesis of additional drug-packaging microparticles by these cells that contribute to the cytotoxic effect and the inhibition of drug efflux from tumour cells. This study highlights a novel drug delivery strategy with potential clinical application.

Despite the evidence for the role of inflammation in cancer initiation, promotion, and progression, the precise mechanism by which the inflammation within tumor is orchestrated by inflammatory cells remains to be determined. Here IntroductionChronic inflammation, a "promoting force" in the tumor microenvironment, has long been known to be commonly braided with the initiation, promotion, and progression of tumorigenesis. [1][2][3][4][5] To date, however, it is still incompletely understood how the inflammation in the tumor microenvironment is orchestrated by inflammatory cells. Recently, mast cells were highlighted as not only a major participator but also an important regulator of inflammation, 6,7 and their accumulation in tumors has also been well documented, [8][9][10][11][12][13] implying that mast cells may possibly play an important role in orchestrating the inflammation in tumors.The tumor microenvironment is regarded as a "smoldering" inflammation site in which a lot of cytokines, chemokines, and enzymes mediate the inflammatory process and drive malignant progression. 14,15 Among them, TNF-␣, IL-6, VEGF, iNOS, Cox-2, and MMP-9 are of particular interest. [15][16][17][18] Coincidentally, all of them can be produced by mast cells. However, the tumor microenvironment is also characterized by its immunoediting from immunosurveillance to immunosuppression. 19 Mast cells have been found to play a critical role in the suppression of immune reactions. 20 They not only produce inhibitory cytokine IL-10, 21 but they also are essential for the immune tolerance mediated by regulatory T (Treg) cells. 22 Thus, mast cell infiltration into tumor may possibly remodel tumor microenvironment and profoundly influence tumor behavior by participating and regulating inflammatory and immune reactions. However, although some studies have shown that mast cells promote tumor angiogenesis and tumor growth because of their properties as inflammatory cells, [23][24][25] the roles of mast cells in tumor progression have been incompletely understood so far. Several key questions remain unclear, especially how mast cells are recruited into the tumor site and whether they can remodel the tumor microenvironment.Mast cell migration to the tumor site and the following activation may be the prerequisite for their promoting effect on tumors. In this regard, stem cell factor (SCF) is possibly involved, because SCF triggers the c-Kit signaling pathway for the differentiation, migration, maturation, and survival of mast cells. 26 In the present study, we investigated the relation of mast cells and SCF in tumor progression and showed that SCF recruited and activated mast cells, the activated mast cells remodeled the tumor microenvironment by intensifying inflammation and immunosuppression, the tumor cell NF-B and AP-1 activities were augmented, and the suppression of T cells and natural killer (NK) cells was exacerbated in such remodeled microenvironments. These findings provide a new insight into the role of mast cells in tumors and the relati...

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IL-17 is a pivotal proinflammatory molecule in asthmatics. However, the cellular source of IL-17 in asthma has not been identified to date. In this study, we report that macrophages rather than Th17 cells are the main producer of IL-17 in allergic inflammation related to asthma. After OVA challenge in a mouse model mimicking allergic asthma, the increased IL-17+ cells in the lung were mainly CD11b+F4/80+ macrophages, instead of T cells or others. Importantly, IL-17+ alveolar macrophages (AMs), but not IL-17+ interstitial macrophages, were significantly increased after allergen challenge. The increase of IL-17+ AMs was not due to the influx of IL-17+ macrophages from circulation or other tissues, but ascribed to the activation of AMs by mediator(s) secreted by IgE/OVA-activated mast cells. Depleting alveolar macrophages or neutralizing IL-17 prevented the initiation of OVA-induced asthma-related inflammation by inhibiting the increase of inflammatory cells and inflammatory factors in bronchoalveolar lavage fluid. Th2 cytokine IL-10 could down-regulate IL-17 expression in alveolar macrophages. The increased IL-17 and the decreased IL-10 in bronchoalveolar lavage fluid were further confirmed in asthmatic patients. These findings suggest that IL-17 is mainly produced by macrophages but not Th17 cells in allergic inflammation related to asthma. Mast cell-released mediators up-regulate the expression of IL-17 by macrophages, whereas IL-10 down-regulates IL-17 expression.

Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates diverse cellular functions. It has been found that CD4 þ CD25 þ regulatory T (T REG ) cells exert their suppressor function by transferring cAMP to responder T cells. Here, we show that miR-142-3p regulates the production of cAMP by targeting adenylyl cyclase (AC) 9 messenger RNA in CD4 þ CD25 À T cells and CD4 þ CD25 þ T REG cells. miR-142-3p limits the level of cAMP in CD4 þ CD25 À T cells by inhibiting AC9 production, whereas forkhead box P3 (FOXP3) downregulates miR-142-3p to keep the AC9/cAMP pathway active in CD4 þ CD25 þ T REG cells. These findings reveal a new molecular mechanism through which CD4 þ CD25 þ T REG cells contain a high level of cAMP for their suppressor function, and also suggest that the microRNA controlling AC expression might restrict the final level of cAMP in various types of cells.