Exosomes have great potential to be drug delivery vehicles due to their natural material transportation properties, intrinsic long-term circulatory capability, and excellent biocompatibility, which are suitable for delivering a variety of chemicals, proteins, nucleic acids, and gene therapeutic agents. However, an effective method of loading specific protein agents into exosomes for absorption by target cells is still lacking. The application potential of exosome is still limited. In this review, we discussed the methods for loading specific treating molecules (proteins, nucleic acids and small chemicals) into exosomes, the design strategies for cell and tissue targeting, and the factors for exosome formation. This review can be used as a reference for further research as well as for the development of therapeutic exosomes.

BackgroundOCT4 and BIRC5 are preferentially expressed in human cancer cells and mediate cancer cell survival and tumor maintenance. However, the molecular mechanism that regulates OCT4 and BIRC5 expression is not well characterized.MethodsBy manipulating OCT4 and BIRC5 expression in hepatocellular carcinoma (HCC) cell lines, the regulatory mechanism of OCT4 on BIRC5 and CCND1 were investigated.ResultsIncreasing or decreasing OCT4 expression could enhance or suppress BIRC5 expression, respectively, by regulating the activity of BIRC5 promoter. Because there is no binding site for OCT4 within BIRC5 promoter, the effect of OCT4 on BIRC5 promoter is indirect. An octamer motif for OCT4 in the CCND1 promoter has directly and partly participated in the regulation of CCND1 promoter activity, suggesting that OCT4 also could upregulated the expression of CCND1. Co-suppression of OCT4 and BIRC5 induced cancer cell apoptosis and cell cycle arrest, thereby efficiently inhibiting the proliferative activity of cancer cells and suppressing the growth of HCC xenogrfts in nude mice.ConclusionOCT4 can upregulate BIRC5 and CCND1 expression by increasing their promoter activity. These factors collusively promotes HCC cell proliferation, and co-suppression of OCT4 and BIRC5 is potentially beneficial for HCC treatment.

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BackgroundOCT4 and Survivin are important factors for cancer cell proliferation, renewal and dedifferentiation, and correlate with resistance to radiotherapy and chemotherapy in most human cancers, but their regulatory mechanisms are not well known.Methodology/Principal FindingsIn this study, 50 patients with esophageal squamous cell carcinoma (ESCC) were retrospectively analyzed. OCT4 was expressed in 13 cases (26%), and survivin was positively expressed in 31 cases (62%), examined by immunochemistry. OCT4 was found to be an independent predictive factor for median survival time, and the patients from the subgroup with both high expression of OCT4 and Survivin had the worst prognosis investigated by log-rank test. To further explore the molecular regulatory mechanism between OCT4 and Survivin, we constructed the specific small hairpin RNA (shRNA)-expressing vectors targeting OCT4 or/and Survivin and manipulated the expression of OCT4 and Survivin. By Western blotting and RT-PCR, we found that OCT4 could up-regulate Survivin expression in the esophageal cancer cell lines Eca109 and TE1. Simultaneously knockdown of OCT4 and Survivin expression induced cell apoptosis and G2-phase decrease of cell cycle by flow cytometry, and finally exerted an enhanced anti-proliferation potency in Eca109 and TE1 cell lines by MTT assay.ConclusionsThis study shows that OCT4 and Survivin expression were correlated with poor survival in patients with ESCC. OCT4 and Survivin may be regarded as targets in ESCC biotherapy.

We previously identified serine protease HtrA1 as a down-regulated gene in epithelial ovarian cancer (EOC), but the functional consequence of loss of HtrA1 in EOC remains largely unclear. Here, we report that loss of HtrA1 attenuates anoikis - a critical physiological barrier for tumor metastasis. In response to loss of anchorage, HtrA1 expression was up-regulated in SKOV3 cells, resulting in autocatalytic activation of HtrA1. Stable knockdown of HtrA1 in SKOV3 and TOV21G cells resulted in resistance to anoikis due to enhanced activation of EGFR/AKT pathway. In suspended SKOV3 cells, enhanced expression of HtrA1 inhibited EGFR/AKT pathway, leading to increased cell death, while protease inactive mutant HtrA1 failed to result in either the inhibition of EGFR/AKT pathway or increased cell death, suggesting the requirement of HtrA1 protease activity in regulating anoikis. Immunoprecipitation and immunofluorescence assays revealed that HtrA1 interacted with EGFR not only on the cell membrane but also in the nucleus. Most importantly, down-regulation of HtrA1 significantly enhanced the peritoneal dissemination of SKOV3ip1 cells in NOD/SCID mice, with increased p-EGFR level in corresponding tumor nodules compared to that in xenografts originated from the control cells. Taken together, these data reveal for the first time a novel function of HtrA1 in promoting anoikis by attenuating activation of EGFR/AKT pathway that may contribute to its metastasis suppression capacity, thus providing a possible explanation for the aggressive nature of human ovarian tumors with down-regulated HtrA1.

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Costunolide (CE) and dehydrocostuslactone (DE) are derived from many species of medicinal plants, such as Saussurea lappa Decne and Laurus nobilis L. They have been reported for their wide spectrum of biological effects, including anti-inflammatory, anticancer, antiviral, antimicrobial, antifungal, antioxidant, antidiabetic, antiulcer, and anthelmintic activities. In recent years, they have caused extensive interest in researchers due to their potential anti-cancer activities for various types of cancer, and their anti-cancer mechanisms, including causing cell cycle arrest, inducing apoptosis and differentiation, promoting the aggregation of microtubule protein, inhibiting the activity of telomerase, inhibiting metastasis and invasion, reversing multidrug resistance, restraining angiogenesis has been studied. This review will summarize anti-cancer activities and associated molecular mechanisms of these two compounds for the purpose of promoting their research and application.

Conditionally replicating adenoviruses (CRAd) can replicate specifically in cancer cells and lyse them. The CRAds were widely used in the preclinical and clinical studies of cancer therapy. We hypothesize that more precisely regulated replication of CRAds may further improve the vector safety profile and enhance its antitumor efficacy.