Xiaolan Su

SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin

SARI, also called as BATF2, belongs to the BATF family and has been implicated in cancer cell growth inhibition. However, the role and mechanism of SARI in tumour angiogenesis are elusive. Here we demonstrate that SARI deficiency facilitates AOM/DSS-induced colonic tumorigenesis in mice. We show that SARI is a novel inhibitor of colon tumour growth and angiogenesis in mice. Antibody array and HUVEC-related assays indicate that VEGF has an essential role in SARI-controlled inhibition of angiogenesis. Furthermore, Co-IP/PAGE/mass spectrometry indicates that SARI directly targets ceruloplasmin (Cp), and induces protease degradation of Cp, thereby inhibiting the activity of the HIF-1α/VEGF axis. Tissue microarray results indicate that SARI expression inversely correlates with poor clinical outcomes in colon cancer patients. Collectively, our results indicate that SARI is a potential target for therapy by inhibiting angiogenesis through the reduction of VEGF expression and is a prognostic indicator for patients with colon cancer.

Anti-TNF-α monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis.

Tumor necrosis factor-alpha (TNF-α) antagonists have shown remarkable efficacy in psoriasis; however, the precise mechanisms of action of TNF-α blocking agents mainly focus on their neutralizing TNF-α and its anti-inflammatory effects. In this study, we generated a humanized anti-TNF-α monoclonal antibody (IBI303) and suggested a potential mechanism of anti-TNF-α therapy for psoriasis. The results of SPR and ELISA indicated that IBI303 has a good affinity to TNF-α. In vitro, it could suppress TNF-α-induced cytotoxicity in WEHI164 cells. In vivo, administration of IBI303 to K14-VEGF transgenic mice led to a significant treatment efficiency in psoriasis in a dose-dependent manner. IHC staining and cytokines-ELISA indicated that TNF-α inhibition strongly reduced inflammatory cells infiltration and pro-inflammatory cytokines release, accompanied by suppression of inflamed dermal blood vessels. Mechanistically, in order to explain the anti-angiogenesis effect of anti-TNF-α antibody, the production of cytokine in macrophage conditional medium was measured by ELISA. The result indicated that the massive secretion of TNF-α stimulated by LPS in RAW264.7 cell supernatant was markedly neutralized in a dose-response manner by IBI303, moreover, the expression of NF-κB p65 was down-regulated. Mouse endothelial cell tube formation assay showed that anti-TNF-α could inhibit blood vessels formation directly and indirectly. Collectively, our study suggested a kind of antipsoriatic mechanism of TNF-α inhibitors that is the dual inhibition of inflammation and angiogenesis.

Synthesis, characterization, and antitumor evaluation of the albumin-SN38 conjugate.

7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of irinotecan, exerts a 100-fold to 1000-fold higher effect than irinotecan itself against several tumor cell lines. However, the water insolubility of SN38 has prevented its direct use as an antitumor drug in the clinic. To improve the water solubility and antitumor efficacy, SN38 was covalently attached to the only free sulfhydryl at cysteine-34 on the BSA site specifically through a thiol-binding linker to form a prodrug BSA–SN38 conjugate (BSA : SN38=1 : 1). The water solubility of this conjugate was similar to albumin using the current method. Also, SN38 loading in this conjugate became controllable. Size-exclusion chromatography purification and UV characterization of the SDS-PAGE electrophoresis product were carried out. Then, an MTT assay was carried out to test the antitumor effect of this conjugate on five colon cancer cell lines in vitro. The 72 h IC50 values of the BSA–SN38 conjugate ranged from 1.5 to 6.1 &mgr;mol/l. A colorectal peritoneal carcinomatosis model in mice was established to determine the intraperitoneal chemotherapy effect of the BSA–SN38 conjugate. The BSA–SN38 conjugate at an SN38 equivalent dose of 10 mg/kg/day was administrated every 4 days. Eighteen days after manipulation, the mice were euthanized and the tumors in the abdominal cavity were collected and weighed. Tumors in the BSA–SN38 conjugate treatment group (m=0.21±0.15 g) were found to be significantly (P=5) lighter than those in the NS control group (m=4.74±0.73 g). The results indicated that this water-soluble BSA–SN38 conjugate exerted a strong antitumor effect on colorectal carcinoma.

Human Adipose-Derived Mesenchymal Stem Cell-Secreted CXCL1 and CXCL8 Facilitate Breast Tumor Growth By Promoting Angiogenesis

Autologous adipose tissue or adipose tissue with additive adipose‐derived mesenchymal stem cells (ADSCs) is used in the breast reconstruction of breast cancer patients who undergo mastectomy. ADSCs play an important role in the angiogenesis and adipogenesis, which make it much better than other materials. However, ADSCs may promote residual tumor cells to proliferate or metastasize, and the mechanism is still not fully understood. In this study, we demonstrated that human ADSCs (hADSCs) could facilitate tumor cells growth after co‐injection with MCF7 and ZR‐75‐30 breast cancer cells (BCCs) by promoting angiogenesis, but hADSCs showed limited effect on the growth of MDA‐MB‐231 BCCs. Intriguingly, compared with ZR‐75‐30 tumor cells, MCF7 tumor cells were more potentially promoted by hADSCs in the aspects of angiogenesis and proliferation. Consistent with this, cytokine and angiogenesis array analyses showed that after co‐injection with hADSCs, the CXCL1 and CXCL8 concentration were significantly increased in MCF7 tumor, but only moderately increased in ZR‐75‐30 tumor and did not increase in MDA‐MB‐231 tumor. Furthermore, we found that CXCL1/8 were mainly derived from hADSCs and could increase the migration and tube formation of human umbilical vein endothelial cells (HUVECs) by signaling via their receptors CXCR1 and CXCR2. A CXCR1/2‐specific antagonist (SCH527123) attenuated the angiogenesis and tumor growth in vivo. Our findings suggest that CXCL1/8 secreted by hADSCs could promote breast cancer angiogenesis and therefore provide better understanding of safety concerns regarding the clinical application of hADSCs and suggestion in further novel therapeutic options. Stem Cells 2017;35:2060–2070

Synthesis, characterization and targeting chemotherapy for ovarian cancer of trastuzumab-SN-38 conjugates

Antibody-drug conjugates (ADCs), combining monoclonal antibody with high cytotoxicity chemotherapeutic drug (warhead), have been successfully applied for clinical cancer therapy. Linker technology to select and design linker connecting warhead with antibody, is critical to the success of therapeutic ADCs. In this study, three kinds of linkers were designed to connect SN-38, the bioactive metabolite of the anticancer drug irinotecan (CPT-11), which is 100-1000 times more potent than CPT-11, with the anti-HER2 antibody trastuzumab to prepare three different ADC conjugates (T-SN38 A, B and C). Meanwhile, we compared the anti-ovarian cancer effect of these three T-SN38 conjugates with trastuzumab in vitro and in vivo. Our in vitro results showed that T-SN38 A, B and C (drug-to-antibody ratio, DAR=3.7, 3.2, 3.4) were 2 to 3 times as cytotoxic as SN-38, and the IC50 for these three conjugates on SKOV-3 cell line at 72 h were 5.2 ± 0.3, 4.4 ± 0.7, and 5.1 ± 0.4 nM respectively. In our in vivo studies, T-SN38 conjugates had well targeting ability for tumor tissue and all three of them had much higher anti-ovarian cancer potency than trastuzumab. Among of them, T-SN38 B, which coupled SN-38 with trastuzumab by a carbonate bond, has the best anti-ovarian cancer potency. In conclusion, the novel HER2-targeting ADCs T-SN38 have great potential for HER2-positive ovarian cancer. Moreover, the SN-38-Linkers designed in this study can also be used to connect with other antibodies for the therapy of other cancers.

Efficient inhibition of intraperitoneal ovarian cancer growth in nude mice by liposomal delivery of short hairpin RNA against STAT3

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the tumor formation, prognosis and chemoresistance of ovarian cancer. Our goal was to investigate the effect of silencing STAT3 on ovarian cancer cell apoptosis, proliferation, angiogenesis and expression of key targets in vitro and in vivo.

Proteomic analysis of the interleukin-4 (IL-4) response in hepatitis B virus-positive human hepatocelluar carcinoma cell line HepG2.2.15†

Hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. In recent decades, significant progress toward understanding the molecular virology and pathogenesis of HBV infection has been made. In addition, multiple treatment modalities have been developed for persons with HBV infection. In the present study, we demonstrated that IL‐4 inhibits the expression of hepatitis B surface antigen and hepatitis B e antigen in a HBV stably transfected hepatocellular carcinoma cell line (HepG2.2.15). To reveal the anti‐HBV mechanism of IL‐4 by proteomics, 2‐DE and MS technology were utilized to profile global changes in protein expression in HepG2.2.15 cells after IL‐4 treatment. A total of 56 differentially expressed proteins were identified in IL‐4‐treated HepG2.2.15 cells. To find out the interaction of these changed proteins by bioinformatics, signaling network analysis with the STRING tool showed that the identified proteins are primarily involved in transcription and proteolysis. Taken together, these results offer valuable clues for understanding the molecular mechanisms of the IL‐4‐mediated anti‐HBV response.

IL-35 recombinant protein reverses inflammatory bowel disease and psoriasis through regulation of inflammatory cytokines and immune cells.

Interleukin‐35 (IL‐35), a member of the IL‐12 family, functions as a new anti‐inflammatory factor involved in arthritis, psoriasis, inflammatory bowel disease (IBD) and other immune diseases. Although IL‐35 can significantly prevent the development of inflammation in many diseases, there have been no early studies accounting for the role of IL‐35 recombinant protein in IBD and psoriasis. In this study, we assessed the therapeutic potential of IL‐35 recombinant protein in three well‐known mouse models: the dextransulfate sodium (DSS)‐induced colitis mouse model, the keratin14 (K14)‐vascular endothelial growth factor A (VEGF‐A)‐transgenic (Tg) psoriasis mouse model and the imiquimod (IMQ)‐induced psoriasis mouse model. Our results indicated that IL‐35 recombinant protein can slow down the pathologic process in DSS‐induced acute colitis mouse model by decreasing the infiltrations of macrophages, CD4+T and CD8+T cells and by promoting the infiltration of Treg cells. Further analysis demonstrated that IL‐35 recombinant protein may regulate inflammation through promoting the secretion of IL‐10 and inhibiting the expression of pro‐inflammatory cytokines such as IL‐6, TNF‐α and IL‐17 in acute colitis model. In addition, lower dose of IL‐35 recombinant protein could achieve long‐term treatment effects as TNF‐α monoclonal antibody did in the psoriasis mouse. In summary, the remarkable therapeutic effects of IL‐35 recombinant protein in acute colitis and psoriasis mouse models indicated that IL‐35 recombinant protein had a variety of anti‐inflammatory effects and was expected to become an effective candidate drug for the treatment of inflammatory diseases.

Correction: High ECT2 expression is an independent prognostic factor for poor overall survival and recurrence-free survival in non-small cell lung adenocarcinoma

[This corrects the article DOI: 10.1371/journal.pone.0187356.].

Establishment and characterization of intraperitoneal xenograft models by co-injection of human tumor cells and extracellular matrix gel

Establishing a feasible intraperitoneal (i.p.) xenograft model in nude mice is a good strategy to evaluate the antitumor effect of drugs in vivo. However, the manipulation of human cancer cells in establishing a stable peritoneal carcinomatosis model in nude mice is problematic. In the present study, the ovarian and colorectal peritoneal tumor models were successfully established in nude mice by co-injection of human tumor cells and extracellular matrix gel. In ovarian tumor models, the mean number tumor nodes was significantly higher in the experimental group (intraperitoneal tumor cell co-injection with ECM gel) compared with the PBS control group on the 30th day (21.0±3.0 vs. 3.6±2.5; P<0.05). The same results were observed in the colorectal peritoneal tumor models on the 28th day. The colorectal peritoneal tumor model was further used to evaluate the chemotherapy effect of irinotecan (CPT-11). The mean weight of peritoneal tumor nodes in CPT-11 treatment group was significantly less than that of the control group (0.81±0.16 vs. 2.18±0.21 g; P<0.05). The results confirmed the value of these i.p. xenograft models in nude mice as efficient and feasible tools for preclinical evaluation.