The aim of this study was to investigate the inhibitory effect of TSU68 [(Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid; SU6668], an inhibitor of vascular endothelial growth factor receptor 2, plateletderived growth factor receptor B, and fibroblast growth factor receptor 1 (FGFR1), on colon cancer liver metastasis, and to test the hypothesis that TSU68 modulates the microenvironment in the liver before the formation of metastasis. First, we implanted the highly metastatic human colon cancer TK-4 orthotopically into the cecal walls of nude mice, followed by twice-daily administration of TSU68 (400 mg/kg/d) or vehicle. Five weeks of treatment with TSU68 significantly inhibited liver metastasis compared with the control group (P < 0.001). Next, we analyzed the gene expression profile in premetastatic liver using microarrays. Microarray and quantitative reverse transcription-PCR analysis showed that mRNA levels for the chemokine CXCL1 were significantly increased in tumorbearing mice compared with non-tumor-bearing mice. Moreover, CXCL1 expression was significantly decreased by TSU68 treatment. CXCR2 expression was detected predominantly on tumor cells in orthotopic tumors compared with ectopic tumors. The number of migrating neutrophils in premetastatic liver was significantly decreased in the TSU68-treated group (P < 0.001). The amount of interleukin-12 (IL-12) p40 in the portal vein was significantly decreased by TSU68 (P = 0.02). Blockade of both CXCR2 and IL-12 p40 with a neutralizing antibody significantly inhibited liver metastasis. These results suggest that the CXCL1/CXCR2 axis is important in cancer metastasis and that TSU68 may modulate the premetastatic niche in the target organ through suppression of the inflammatory response, which might be an alternative mechanism used by antiangiogenic agents. [Cancer Res 2008;68(23):9754-62]
BackgroundTotal gastrectomy is a relatively difficult and invasive procedure among gastrointestinal surgeries, and major morbidities following total gastrectomy can be serious and fatal. This study aimed to develop and validate preoperative risk models of morbidities associated with total gastrectomy using a Japanese web-based nationwide registry.MethodsThe national clinical database was used to retrieve the records of 39,253 patients who underwent total gastrectomy in 1,841 hospitals between January 1, 2011 and December 31, 2012.ResultsMean patient age was 69.1 years, and 73.8% of the patients were male. The overall morbidity rate was 21.5%, which included 8.1% with surgical site infection (SSI), 4.5% with anastomotic leak, 5.0% with pancreatic fistula, 3.7% with pneumonia, 1.9% with prolonged ventilation, and 1.2% with renal failure. Sex, splenectomy, and Brinkman index were selected as common risk factors for SSI, anastomotic leak, and pancreatic fistula. Pancreatectomy was the most significant preoperative risk factor in the risk model of SSI and pancreatic fistula. Need of assistance with activities of daily living, chronic obstructive pulmonary disease, previous cerebrovascular disease, American Society of Anesthesiologists score class 3 and over, presence of esophageal cancer, and body mass index more than 25 were selected as common risk factors for pneumonia, prolonged ventilation over 48 h, and renal failure.ConclusionsWe have created the first reported risk models of morbidities associated with total gastrectomy, using a Japanese nationwide database. The risk models developed in this study may be useful to preoperatively predict operative morbidities in patients undergoing total gastrectomy.Electronic supplementary materialThe online version of this article (doi:10.1007/s10120-017-0706-9) contains supplementary material, which is available to authorized users.
Intraoperative indocyanine green (ICG) lymphography was performed on a 62-year-old man, who was diagnosed to have chylothorax after an esophagectomy for esophageal cancer. After exploration of the thorax, a slowly increasing effusion was identified in the mediastinal space above the diaphragm, but the exact site of the lymph fistula could not be identified. By injecting 1.5 ml of ICG subcutaneously at the bilateral inguinal region, fluorescence images of the lymph flow in the thoracic cavity were obtained using a near-infrared camera system. The detected leakage point was sutured and the chyle ooze stopped. The postoperative course was uneventful. The patient was discharged on the 16th postoperative day. This is the first report using ICG fluorescence lymphography for the successful intraoperative detection of the exact site of a fistula causing chylothorax.
Tumor angiogenesis plays a critical role in colorectal cancer progression. Recent randomized clinical trials have revealed the additive effect of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)‐A, to conventional chemotherapy in the improved survival of patients with metastatic colorectal cancer. However, a number of preclinical reports indicate the development of resistance to anti‐angiogenic therapy. In this study, we addressed the effects of anti‐VEGF antibodies on the growth and malignant behavior of colorectal cancer cells. TK‐4, a solid tumor strain derived from a colon cancer patient, was subcutaneously or orthotopically implanted into nude mice. Short‐term administration of anti‐VEGF antibodies inhibited the growth of cecal tumors at day 14 by suppressing mitosis, but prolonged treatment resulted in the recovery of cellular proliferation and suppression of apoptosis at day 35. Intratumoral hypoxia induced by anti‐VEGF antibody treatment resulted in activation of hypoxia inducible factor‐1α protein and an increased number of aldehyde dehydrogenase 1‐positive tumor cells. In microarray analysis, stanniocalcin 2 (STC2) was the most highly upregulated gene in anti‐VEGF antibody‐treated tumors. In vitro analyses showed that the growth and migration of SW480 colon cancer cells under hypoxic conditions were significantly inhibited by knockdown of STC2. In vivo serial transplantation of TK‐4 revealed that long‐term administration of anti‐VEGF antibodies increased the tumorigenicity of colon cancers and accelerated tumor growth when transplanted into secondary recipient mice. Our data provide a potential molecular explanation for the limited clinical effectiveness of anti‐VEGF antibodies.
Background:Tumour stroma has important roles in the development of colorectal cancer (CRC) metastasis. We aimed to clarify the roles of microRNAs (miRNAs) and their target genes in CRC stroma in the development of liver metastasis.Methods:Tumour stroma was isolated from formalin-fixed, paraffin-embedded tissues of primary CRCs with or without liver metastasis by laser capture microdissection, and miRNA expression was analysed using TaqMan miRNA arrays.Results:Hierarchical clustering classified 16 CRCs into two groups according to the existence of synchronous liver metastasis. Combinatory target prediction identified tenascin C as a predicted target of miR-198, one of the top 10 miRNAs downregulated in tumour stroma of CRCs with synchronous liver metastasis. Immunohistochemical analysis of tenascin C in 139 primary CRCs revealed that a high staining intensity was correlated with synchronous liver metastasis (P<0.001). Univariate and multivariate analyses revealed that the tenascin C staining intensity was an independent prognostic factor to predict postoperative overall survival (P=0.005; n=139) and liver metastasis-free survival (P=0.001; n=128).Conclusions:Alterations of miRNAs in CRC stroma appear to form a metastasis-permissive environment that can elevate tenascin C to promote liver metastasis. Tenascin C in primary CRC stroma has the potential to be a novel biomarker to predict postoperative prognosis.
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