Establishing a peritoneal dissemination xenograft mouse model for survival outcome assessment of experimental gastric cancer

Zhang, Changhua; Awasthi, Niranjan; Schwarz, Margaret A.; Schwarz, Roderich E.

doi:10.1016/j.jss.2012.10.052

Cited by 20 publications

(11 citation statements)

References 24 publications

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“…Zhang et al established a peritoneal dissemination xenograft mouse model for survival outcome assessment of experimental GC [26]. Given that peritoneal metastasis is the most frequent pattern of recurrence of GC [27], we next assessed tumor growth inhibition in peritoneal dissemination xenograft models.…”

Section: Resultsmentioning

confidence: 99%

MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

Lee

Chang

et al. 2016

Oncotarget

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Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2. Inhibition of MCTs by siRNA or AR-C155858 reduced cell viability and lactate uptake in GC cell lines. The effect of inhibition of MCTs on tumor growth was also confirmed in xenograft models. Furthermore, MCT inhibition in GC cells increased the sensitivity of cells to radiotherapy or chemotherapy. Compared with normal gastric tissue, no significant alterations of expression levels in tumors were identified for MCT1 and MCT2, whereas a significant increase in MCT4 expression was observed. Most importantly, MCT4 was highly overexpressed in malignant cells of acsites and its silencing resulted in reduced tumor cell proliferation and lactate uptake in malignant ascites. Our study suggests that MCT4 is a clinically relevant target in GC with peritoneal carcinomatosis.

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Section: Resultsmentioning

confidence: 99%

MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

Lee

Chang

et al. 2016

Oncotarget

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“…Animal survival studies were performed using 6- to 8-week-old female SCID mice (35). The mice were intraperitoneally injected with SNU16 (40×10 6 ) cells and body weight was measured twice a week.…”

Section: Methodsmentioning

confidence: 99%

The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer

Zhang

Awasthi

Schwarz

et al. 2013

International Journal of Oncology

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Gastric cancer is the second most common cause of cancer-related deaths worldwide. Taxanes have shown therapeutic effects against gastric cancer while also activating the PI3K/mTOR signaling pathway. We investigated the effects of NVP-BEZ235 (BEZ235), a novel dual PI3K/mTOR inhibitor, alone and in combination with nanoparticle albumin-bound (nab)-paclitaxel in experimental gastric cancer. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were performed in murine xenografts. Phosphorylated mTOR and 4E-BP1 levels were elevated in gastric cancer cells and tumor tissues by nab-paclitaxel. BEZ235 effectively inhibited cell proliferation in vitro and provided additive effects in combination with nab-paclitaxel. Furthermore, BEZ235 blocked the activated PI3K/mTOR pathway either alone or in combination with nab-paclitaxel in gastric cancer cells. BEZ235 and nab-paclitaxel caused an increase in PARP-1 and caspase-3 cleavage. Net local tumor growth inhibition for the BEZ235, nab-paclitaxel and BEZ235+nab-paclitaxel groups was 45.1, 77.9 and 97% compared to controls. The effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BEZ235 also caused a decrease in phospho-mTOR and phospho-Akt in tumor tissue lysates. Median animal survival (controls, 23 days) was 26.5 days after BEZ235 (p=0.227), 90.5 days after nab-paclitaxel (p=0.001) and 97 days in the BEZ235+nab-paclitaxel combination treatment group (p=0.001). Our findings suggest that BEZ235 exerts some antitumor effects against gastric cancer and enhances effects of nab-paclitaxel through inhibition of cell proliferation and modulation of the PI3K/mTOR pathway. This approach may represent a promising combination targeted therapy for gastric cancer.

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“…While several gastric cancer cell lines undergo peritoneal dissemination following intra-peritoneal injection in mice, almost all peritoneal tumors formed in this manner adopt a medullary pattern [13–15]. We have previously reported that fibrotic tumors can be established in a subcutaneous xenograft model using the gastric cancer cell line MKN45 in co-culture with human peritoneal mesothelial cells (HPMCs) [16].…”

Section: Introductionmentioning

confidence: 99%

Establishing a xenograft mouse model of peritoneal dissemination of gastric cancer with organ invasion and fibrosis

et al. 2017

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BackgroundThe clinical prognosis of gastric cancer with peritoneal dissemination is poor because of its chemoresistance and rich fibrosis. While several gastric cancer cell lines have been used to establish models of peritoneal dissemination by intraperitoneal injection, most peritoneal tumors that form adopt a medullary pattern in microscopic appearance. This histological finding for the model differs from that in the clinical situation. This study was performed to demonstrate the contribution of human peritoneal mesothelial cells (HPMCs) to fibrotic tumor formation and to establish a new xenograft model with high potential for peritoneal dissemination with organ invasion and extensive fibrosis.MethodsWe established four types of xenograft model: i) intraperitoneal injection of MKN45-P cells alone (control group), ii) injection of MKN45-P cells co-cultured with HPMCs (co-cultured group), iii) scratching the parietal peritoneum (parietal group), and iv) scratching the visceral peritoneum (visceral group) with a cotton swab before injection of co-cultured cells. Fibrosis, α-smooth muscle actin expression, and organ invasion by tumor cells were all assessed by immunohistochemical examination.ResultsAll mice developed abdominal swelling with peritoneal tumors and bloody ascites. Tumors of the control and co-cultured groups were not invasive or fibrotic. Contrastingly, tumors of the scratch groups exhibited rich stromal fibrosis and possessed increased α-smooth muscle actin (α-SMA) expression. In particular, the visceral group showed edematous and spreading tumors invading the intestinal wall.ConclusionWe established a model of peritoneal dissemination with organ invasion and stromal fibrosis. Formation of peritoneal dissemination required a favorable environment for cell adhesion, invasion, and growth. This model may be useful for analyzing the pathogenesis and treatment of peritoneal dissemination of gastric cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2991-9) contains supplementary material, which is available to authorized users.

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Establishing a peritoneal dissemination xenograft mouse model for survival outcome assessment of experimental gastric cancer

Cited by 20 publications

References 24 publications

MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

The dual PI3K/mTOR inhibitor NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric cancer

Establishing a xenograft mouse model of peritoneal dissemination of gastric cancer with organ invasion and fibrosis

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