Biomimetic black phosphorus nanosheets codeliver CDK9 and BRD4 inhibitors for gastric cancer targeted therapy.

Combining the BRD4 and CDK9 inhibitors can trigger the significant down-regulation of the MYC oncogene as well as anti-apoptotic genes and induce tumor cell apoptosis by synergistically impairing RNA synthesis in cancer cells. However, the lack of tumor-targeting capacity and the different pharmacokinetic curves of these two inhibitors may impair the antitumor activity of simultaneous CDK9 and BRD4 inhibition. Herein, CDK9 inhibitor (CI) and BRD4 inhibitor (BI) were codelivered by macrophage membrane-encapsulated black phosphorus nanosheets (M@BP) for the treatment of gastric cancer (GC) via the high expression of BRD4 and CDK9. BP with prominent biocompatibility exhibited a high drug loading efficiency for both CI and BI and could efficiently decrease the expression of the MYC oncogene. More importantly, BP could also serve as a phototherapy agent collaborating with CDK9 and BRD4 inhibition for GC therapy upon near-infrared (NIR) irradiation. Furthermore, the introduction of a macrophage membrane endowed BP with tumor-targeting ability, which could simultaneously deliver CI and BI to tumor tissues. In a murine orthotopic GC model, M@BP could efficiently target and accumulate in the tumor tissues, exhibiting an excellent photothermal effect. The tumor growth monitoring demonstrated that the combination of CI and BI codelivered by M@BP significantly inhibited the tumor progress than the single inhibitors, and the inhibition effect could be further enhanced upon NIR irradiation. Taken together, M@BP with tumor-targeting capacity and high drug loading efficiency for CI and BI could efficiently block the activation of CDK9 and BRD4, exhibiting excellent antitumor activity under NIR irradiation without systemic toxicity in an orthotopic GC model.

MicroRNA-370-3p shuttled by breast cancer cell-derived extracellular vesicles induces fibroblast activation through the CYLD/Nf-κB axis to promote breast cancer progression.

Breast cancer is a malignancy arising in the mammary epithelial tissues. Recent studies have indicated the abundance of microRNAs (miRNAs) in extracellular vesicles (EVs), and their interactions have been illustrated to exert crucial roles in the cell-to-cell communication. The present study focused on investigating whether EV-delivered miR-370-3p affects breast cancer. Initially, the miR-370-3p expression pattern was examined in the cancer-associated fibroblasts (CAFs), normal fibroblasts (NFs), and cancerous cells-derived EVs. The relation of miR-370-3p to CYLD was assessed using luciferase activity assay. Afterwards, based on ectopic expression and depletion experiments in the MCF-7 breast cancer cells, we evaluated stemness, migration, invasion, and sphere formation ability, and EMT, accompanied with measurement on the expression patterns of pro-inflammatory factors and nuclear factor-kappa B (NF-κB) signaling-related genes. Finally, tumorigenesis and proliferation were analyzed in vivo using a nude mouse xenograft model. The in vitro experiments revealed that breast cancer cell-derived EVs promoted NF activation, while activated fibroblasts contributed to enhanced stemness, migration, invasion, as well as EMT of cancerous cells. In addition, EVs could transfer miR-370-3p from breast cancer cells to NFs, and EV-encapsulated miR-370-3p was also found to facilitate fibroblast activation. Mechanistically, EV-encapsulated miR-370-3p downregulated the expression of CYLD through binding to its 3'UTR and activated the NF-κB signaling pathway, thereby promoting the cellular functions in vitro and in vivo in breast cancer. Taken together, EVs secreted by breast cancer cells could carry miR-370-3p to aggravate breast cancer through downregulating CYLD expression and activating the NF-κB signaling pathway.

The circular RNA circEIF3M promotes breast cancer progression by promoting cyclin D1 expression.

We investigated the function of circular RNA circEIF3M (hsa_circ_0003119) in triple-negative breast cancer. The expression profiles of circRNAs in 3 specimens of triple-negative breast cancer tissues with adjacent nontumor tissues were analyzed by RNA-sequencing. We verified the oncogenic role of circEIF3M in triple-negative breast cancer through a series of biological function experiments. It was found that circEIF3M was markedly upregulated in triple-negative breast cancer as compared to adjacent nontumor tissue, and that circEIF3M promoted triple-negative breast cancer cell proliferation, migration, and invasion. Mechanistic analysis indicated that circEIF3M may act as a competing endogenous RNA for miR-33a that relieves the inhibitory effect of miR-33a on its target cyclin D1. These findings showed that circEIF3M promotes triple-negative breast cancer progression via the circEIF3M/ miR-33a/ cyclin D1 axis.

Prognostic Value of Chemotherapy-Induced Amenorrhea in Breast Cancer: a Meta-Analysis.

BACKGROUND: There is still a great deal of controversy with regard to the prognostic role of chemotherapy- induced amenorrhea (CIA) in breast cancer patients. To confirm whether CIA can serve as a useful factor in predicting clinical effects of systemic adjuvant chemotherapy, we performed this meta-analysis. MATERIALS AND METHODS: Relevant studies were identified using PubMed, and Embase databases. Eligible study results were pooled and summary hazard ratios (HRs) with corresponding confidence intervals (CIs) were calculated. Subgroup analyses and an assessment of publication bias were also conducted. RESULTS: A total of 8,333 patients from 11 published studies were identified through searching the databases. The pooled HRs for disease-free survival (DFS) suggested that CIA was associated with a significant reduction in the risk of recurrence, especially in patients with hormone receptor-positive lesions (overall HR=0.65, 95%CI 0.53-0.80, I2= 41.3%). When the five studies reporting the HR for overall survival (OS) were pooled (n=4193), a favorable trend was found (HR=0.69, 95%CI 0.52-0.91, I2= 51.6%). No publication bias was observed in this study. CONCLUSIONS: This meta-analysis suggests that CIA predicts a better outcome in premenopausal hormone receptor-positive breast cancer patients.

Lack of prognostic value of human epidermal growth factor-like receptor 2 status in inflammatory breast cancer (IBC): a meta-analysis.

Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer which is more likely to be her-2/ neu amplified. While the her-2/neu status has been utilised to predict prognosis, the published data are inconsistent. The present meta-analysis was conducted to determine whether the her-2/neu status predicts outcomes. Papers were selected from the PubMed database based on defined inclusion and exclusion criteria. Parameters such as total patients, follow-up time and outcome statistics (i.e. overall survival (OS), relapse-free survival (RFS) were collected. The analysis included 6 studies with 2,838 IBC patients. The summary hazards ratio (HR) estimating the association of OS with HER-2-positive disease was 0.96 (95% confidence interval (95%CI: 0.85-1.10)), with similar findings for RFS (HR=0.81, 95%CI: 0.61-1.09). No obvious statistical heterogeneity was detected. This meta-analysis suggests that HER-2-positive status is not an independent adverse prognostic factor for survival among IBC patient cases.

Oncoplastic breast conserving surgery with nipple-areolar preservation for centrally located breast cancer: a retrospective cohort study.

A compariosn was made of survival outcomes of oncoplastic breast conserving therapy (oBCT) with nipple- areolar (NAC) preservation in women with centrally located breast cancer (CLBC) undergoing modified radical mastectomy (MRM) in China in a matched retrospective cohort study. We used a database including patients who received oBCT (n=91) or MRM (n=182) from 2003 to 2013 in our hospital. Matching was conducted according to five variables: age at diagnosis, axillary lymph node status, hormone receptor status, human epidermal growth factor-like receptor 2 status (HER-2) and tumor stage. The match ratio was 1:2. Median follow-up times for the oBCT and MRM groups were 83 and 81 months, respectively. There were no significant differences in 87-month overall, local, or distant recurrence-free survival between patients with oBCT and MRM (89%vs.90%; 93%vs.95%; 91%vs.92%;). For appropriate breast cancer patients, oBCT for CLBC is oncologically safe, oncoplastic techniques improving cosmetic outcomes.

Inhibition of tumor angiogenesis in lung cancer by T4 phage surface displaying mVEGFR2 vaccine.

Vascular endothelial growth factor (VEGF) has been known as a potential vasculogenic and angiogenic factor and its receptor (VEGFR2) is a major receptor to response to the angiogenic activity of VEGF. The technique that to break the immune tolerance of "self-antigens" associated with angiogenesis is an attractive approach for cancer therapy with T4 phage display system. In this experiment, mouse VEGFR2 was constructed on T4 phage nanometer-particle surface as a recombinant vaccine. T4-mVEGFR2 recombinant vaccine was identified by PCR and western blot assay. Immunotherapy with T4-mVEGFR2 was confirmed by protective immunity against Lewis lung carcinoma (LLC) in mice. The antibody against mVEGFR2 was detected by ELISPOT, ELISA and Dot ELISA. The inhibitive effects against angiogenesis were studied using CD31 and CD105 via histological analysis. VEGF-mediated endothelial cells proliferation and tube formation were inhibited in vitro by immunoglobulin induced by T4-mVEGFR2. The antitumor activity was substantiated from the adoptive transfer of the purified immunoglobulin. Antitumor activity and autoantibody production of mVEGFR2 could be neutralized by the depletion of CD4+T lymphocytes. These studies strongly suggest that T4-mVEGFR2 recombinant vaccine might be a promising antitumor approach.

Antitumor activity of endogenous mFlt4 displayed on a T4 phage nanoparticle surface.

AIM: Flt4 plays a key role in promoting tumor metastasis by stimulating solid tumor lymphangiogenesis. In this study, mouse Flt4 (mFlt4) was displayed on T4 phage in order to explore the feasibility of breaking immune tolerance to "self-antigens" and to evaluate the phage's antitumor activity. METHODS: A T4 phage nanometer particle expressing mFlt4 on the surface was constructed for evaluation as a recombinant vaccine. The presence of the mFlt4 gene in the T4-mFlt4 recombinant vaccine was verified by PCR and Western blot analysis. The immunotherapeutic potential of T4-mFlt4 was tested in mice injected with Lewis lung carcinoma (LLC) cells. Anti-Flt4 antibody producing B cells were detected by ELISPOT. The effects of T4-mFlt4 on lymphatic metastasis and lymphangiogenesis were investigated in a mouse antimetastasis assay and by Flt4 and CD105 immunohistochemistry. RESULTS: The T4-mFlt4 recombinant vaccine demonstrated antitumor activity and elicited autoantibodies against mFlt4. Mice carrying LLC-derived tumors exhibited prolonged survival when given the vaccine compared with control-treated animals. The vaccine also inhibited lymphangiogenesis and tumor metastasis in the mouse models. However, T4-mFlt4 was not observed to inhibit tumor growth. CONCLUSION: The T4-mFlt4 recombinant vaccine induced protective antitumor immunity and antimetastasis against LLC. Induction of an autoimmune response directed against tumor progression merits further study as a new strategy for immunotherapy in cancer.