Patient-derived xenograft (PDX) models are created by engraftment of patient tumor tissues into immunocompetent mice. Since a PDX model retains the characteristics of the primary patient tumor including gene expression profiles and drug responses, it has become the most reliable in vivo human cancer model. The engraftment rate increases with the introduction of Non-obese diabetic Severe combined immunodeficiency (NOD/SCID)-based immunocompromised mice, especially the NK-deficient NOD strains NOD/SCID/interleukin-2 receptor gamma chain(IL2Rγ)null (NOG/NSG) and NOD/SCID/Jak3(Janus kinase 3)null (NOJ). Success rates differ with tumor origin: gastrointestinal tumors acquire a higher engraftment rate, while the rate is lower for breast cancers. Subcutaneous transplantation is the most popular method to establish PDX, but some tumors require specific environments, e.g., orthotropic or renal capsule transplantation. Human hormone treatment is necessary to establish hormone-dependent cancers such as prostate and breast cancers. PDX mice with human hematopoietic and immune systems (humanized PDX) are powerful tools for the analysis of tumor–immune system interaction and evaluation of immunotherapy response. A PDX biobank equipped with patients’ clinical data, gene-expression patterns, mutational statuses, tumor tissue architects, and drug responsiveness will be an authoritative resource for developing specific tumor biomarkers for chemotherapeutic predictions, creating individualized therapy, and establishing precise cancer medicine.

Increased glucose utilization is a feature of cancer cells to support cell survival, proliferation, and metastasis. An association between diabetes mellitus and cancer progression was previously demonstrated in cancers including cholangiocarcinoma (CCA). This study was aimed to determine the effects of high glucose on protein O-GlcNAcylation and metastatic potentials of CCA cells. Two pairs each of the parental low metastatic and highly metastatic CCA sublines were cultured in normal (5.6 mM) or high (25 mM) glucose media. The migration and invasion abilities were determined and underlying mechanisms were explored. Results revealed that high glucose promoted migration and invasion of CCA cells that were more pronounced in the highly metastatic sublines. Concomitantly, high glucose increased global O-GlcNAcylated proteins, the expressions of vimentin, hexokinase, glucosamine-fructose-6-phosphate amidotransferase (GFAT) and O-GlcNAc transferase of CCA cells. The glucose level that promoted migration/invasion was shown to be potentiated by the induction of GFAT, O-GlcNAcylation and an increase of O-GlcNAcylated vimentin and vimentin expression. Treatment with a GFAT inhibitor reduced global O-GlcNAcylated proteins, vimentin expression, and alleviated cell migration. Altogether, these results suggested the role of high glucose enhanced CCA metastasis via modulation of O-GlcNAcylation, through the expressions of GFAT and vimentin.

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Cholangiocarcinoma (CCA) is a major cause of cancer deaths in northeast Thailand. It is aggressive, highly metastatic, and responds poorly to traditional chemotherapy. We demonstrated the potential for Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania cepharantha, to treat CCA. CEP significantly inhibited growth of human CCA cell lines in a dose-and time-dependent manner, regardless of the histologic type of tumor origin. Increasing cell apoptosis via caspase-3 and capase-9 activation was demonstrated in CEP-treated cells. We found that CEP controlled the growth of CCA cells through nuclear factorkappa B (NF-jB) inactivation by inhibiting nuclear translocation. CEP treatment effectively reduced tumor size in CCA-inoculated mice without serious side effects. CEP also increased cell apoptosis in primary histocultures of CCA patients' tissues; this was demonstrated by immunohistochemistry using TUNEL staining. Our results suggest that CEP possesses therapeutic potential against human CCA. (Cancer Sci 2010; 101: 1590-1595) C holangiocarcinoma (CCA) is an aggressive and lethal cancer arising from biliary epithelia within either the intrahepatic or extrahepatic biliary tracts. This cancer is rare worldwide but it is the most common liver cancer in northeast Thailand. Several conditions associated with chronic inflammation have been identified as risk factors for CCA. Infection with the liver fluke Opisthorchis viverrini is the most common risk factor for CCA in Thailand and in Southeast Asia; whereas Clonochis sinensis infection is the general risk for CCA in East Asia. For non-liver fluke-associated CCA, primary sclerosing cholangitis is the predisposing factor in Western countries.(1) According to our research, there were no significant differences in the clinical features and biological behaviors of these three different etiologic CCAs; however, differences in the molecular signature of CCAs from different etiologic CCAs were recognized. A comparison of gene expression profiles for mass-forming CCA (from Thai Opisthorchis viverrini-related CCA) and Japanese (nonliver fluke-related CCA) revealed that the liver fluke-related CCA exhibited increased expression of genes involved in xenobiotic metabolism, whereas those of non-fluke-related CCA showed enhanced genes related to growth factor signaling. (2) Early detection of CCA is difficult since there are no specific symptoms during the early stages of tumor development. Consequently, the majority of CCA patients present with advanced incurable disease so these people are not good candidates for curative surgery. Even in those who have undergone complete surgical resection, recurrence is common and the 5-year survival rate unfavorable.(3,4) Novel treatment strategies directed against this malignancy are, therefore, urgently needed.Cepharanthin (CEP), a biscoclaurine alkaloid extracted from the roots of Stephania cepharantha Hayata, is widely used in Japan for the treatment of various acute and chronic diseases without any serious side effects.(5) It...