Yi You

Comparison Different Methods of Intraoperative and Intraperitoneal Chemotherapy for Patients with Gastric Cancer: A Meta-analysis

PURPOSE To investigate the efficacy and safety of intraperitoneal chemotherapy (IPC) for patients with gastric cancer and to compare effects between different regimens of IPC. METHOD Randomized controlled trials comparing the effects of surgery plus intraperitoneal chemotherapy with surgery alone or comparing the efficacy between different regimens of intraperitoneal chemotherapy were searched for in Medline, Embase, Pubmed, the Cochrane Library and the Chinese BioMedical Disc and so on by two independent reviewers. After quality assessment and data extraction, data were pooled for meta-analysis using RevMan5.16 software. Tests of interaction were used to test for differences of effects among subgroups grouped according to different IPC regimens. RESULTS Fifteen RCTs with a total of 1713 patients with gastric cancer were included for quality assessment and data extraction. Ten studies were judged to be of fair quality and entered into meta-analysis. Hyperthermic intraoperative intraperitoneal chemotherapy (HR=0.60, P<0.01), hyperthermic intraoperative intraperitoneal chemotherapy plus postoperative intraperitoneal chemotherapy (HR=0.47, P<0.01) and normothermic intraoperative intraperitoneal chemotherapy (HR=0.70, P=0.01) were associated with a significant improvement in overall survival. Tests of interaction showed that hyperthermia and additional postoperative intraperitoneal chemotherapy did not impact on its effect. Further analysis revealed that intraperitoneal chemotherapy remarkably decrease the rate of postoperative hepatic metastasis by 73% (OR=0.27, 95% CI=0.12 to 0.67, P<0.01). However, intraperitoneal chemotherapy increased risks of marrow depression (OR=5.74, P<0.01), fever (OR=3.67, P=0.02) and intra-abdominal abscess (OR=3.57, P<0.01). CONCLUSION The present meta-analysis demonstrates that hyperthermic intraoperative intraperitoneal chemotherapy and normothermic intraoperative intraperitoneal chemotherapy should be recommended to treat patients with gastric cancer because of improvement in overall survival. However, it is noteworthy that intraperitoneal chemotherapy can increase the risks of marrow depression, intra-abdominal abscesses, and fever.

TRIM24 is upregulated in human gastric cancer and promotes gastric cancer cell growth and chemoresistance

The tripartite motif protein tripartite motif-containing 24 (TRIM24) is involved in human cancer progression. However, the expression pattern and biological roles of TRIM24 in human gastric cancer have not been studied. Here, we report that expression of TRIM24 protein was upregulated in 65 of 133 gastric cancer specimens. TRIM24 upregulation positively correlated with clinical stage, local invasion, and poor patient prognosis. We overexpressed TRIM24 by transfection in SGC-7901 cells and used an siRNA strategy to knock down TRIM24 in MKN-1 cells. MTT and colony formation assays showed that transfection of TRIM24 plasmid accelerated, while its depletion inhibited cell proliferation rate. TRIM24 overxpression also induced chemoresistance to 5-FU in gastric cancer cells. Further analysis showed that TRIM24 overexpression upregulated cyclin D1 and Akt phosphorylation. Akt inhibitor LY294002 reversed the role of TRIM24 on chemoresistance. In conclusion, our study shows that TRIM24 is overexpressed in human gastric cancer and accelerates cell growth as well as induce chemoresistance, possibly through the Akt pathway.

Milky spot macrophages remodeled by gastric cancer cells promote peritoneal mesothelial cell injury

Peritoneal dissemination (PD) is the most frequent metastatic pattern of advanced gastric cancer (GC) and the main cause of death in GC patients. Human peritoneal mesothelial cell (HPMC) injury induced by gastric cancer cells (GCCs) and GCC outgrowths supported by peritoneal milky spot macrophages (PMSMs) are the key events during gastric cancer peritoneal dissemination (GCPD). In this study, we investigated whether PMSMs remodeled by GCC can induce HPMC injury and create a favorable microenvironment for GCPD. We established a tumor-associated macrophage (TAM) model using in vitro cell coculture. Normal macrophages cocultured with GCCs down-regulated expression of antigen-presenting surface molecules CD80, CD86, and MHC-II, but, notably, they up-regulated expression of phagocytic scavenger receptor CD206, which is similar to the M2 macrophage phenotype. In further experiments, various experimental methods were applied to detect the injurious effect of TAMs on HPMCs in another TAM-HPMC coculture. Our results showed that GCCs can induce HPMC apoptosis by unregulated apoptosis associated with cleaved caspase3, cleaved caspase9, and p21 proteins. HPMC growth ceased, and both early- and late-stage apoptosis were observed. Additionally, GCCs can induce HPMC fibrosis via increased expression of epithelial cell marker E-cadherin and decreased expression of mesenchymal cell marker α-SMA. Our results demonstrate that, in the GCPD process, PMSMs were remodeled by GCCs, resulting in phenotypic and functional transformation. In turn, this transformation induced HPMC injury and provided a favorable microenvironment for GCC anchorage and growth. These results may provide new insight into the mechanisms of GCPD.

Transforming growth factor-beta1 signaling blockade attenuates gastric cancer cell-induced peritoneal mesothelial cell fibrosis and alleviates peritoneal dissemination both in vitro and in vivo

Peritoneal dissemination is the most frequent metastatic pattern of advanced gastric cancer and the main cause of death in gastric cancer patients. Transforming growth factor-beta1 (TGF- ß1), one of the most potent fibrotic stimuli for human peritoneal mesothelial cells, has been shown to play an important role in this process. In this study, we investigated the effect of TGF- ß1 signaling blockade in gastric cancer cell (GCC)-induced human peritoneal mesothelial cell (HPMC) fibrosis. HPMCs were cocultured with the high TGF- ß1 expressing GCC line SGC-7901 and various TGF- ß1 signaling inhibitors or SGC-7901 transfected with TGF-ß1-specific siRNA. HPMC fibrosis was monitored on the basis of morphology. Expression of the epithelial cell marker, E-cadherin, and the mesenchymal marker, α-smooth muscle actin (α-SMA), was evaluated by Western blotting and immunofluorescence confocal imaging. GCC adhesion to HPMC was also assayed. In nude mouse tumor model, the peritoneal fibrotic status was monitored by immunofluorescent confocal imaging and Masson’s trichrome staining; formation of metastatic nodular and ascites fluid was also evaluated. Our study demonstrated that GCC expressing high levels of TGF-ß1 induced HMPC fibrosis, which is characterized by both upregulation of E-cadherin and downregulation of α-SMA. Furthermore, HPMC monolayers fibrosis was reversed by TGF- ß1 signaling blockade. In vivo, the TGF- ß1 receptor inhibitor SB-431542 partially attenuated early-stage gastric cancer peritoneal dissemination (GCPD). In conclusion, our study confirms the significance of TGFß1 signaling blockade in attenuating GCPD and may provide a therapeutic target for clinical therapy.

The mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa shift peritoneal milky spot macrophages towards an M1 phenotype to dampen peritoneal dissemination.

Peritoneal dissemination (PD) of tumor cells is the most frequent pattern of gastric cancer recurrence and the leading cause of death. Peritoneal milky spots are deemed as the site of origin of gastric cancer PD wherein the main cellular components are macrophages. A vaccine derived from the mannose-sensitive hemagglutination pilus strain of Pseudomonas aeruginosa (PA-MSHA) has exhibit strong immune modulatory properties. In the present study, we tested the hypothesis whether the PA-MSHA vaccine activated peritoneal milky spot macrophages (PMSM) in a manner that would attenuate PD. It was observed that PA-MSHA activated PMSM towards a classical activation phenotype via a toll-like receptor4/9-dependent mechanism, which increased interleukin-12 levels and promoted the expression of co-stimulatory and antigen-presenting molecules like CD80, CD86, and MHC-II (P < 0.05). In addition, PA-MSHA-treated PMSM exhibited strong nonspecific antitumor effects in both contact-dependent and contact-independent modes of action (P < 0.05). In mice treated with PA-MSHA before inoculating gastric cancer cells, we noted alleviated PD toward the untreated mice. In conclusion, our findings demonstrated that PA-MSHA can stimulate PMSM towards an M1 phenotype and that activated PMSM inhibit gastric cancer growth and PD both in vitro and in vivo. The results of the current study provide a mechanistic insight that is relevant to the potential application of PA-MSHA in the treatment of gastric cancer-mediated PD.