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Orthotopic Transplantation (orthotopic + transplantation)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Mesenchymal stem cells enhance growth and metastasis of colon cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 10 2010
Kei Shinagawa
Abstract Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed-cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed ,-smooth muscle actin and platelet-derived growth factor receptor-, as carcinoma-associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells. [source]

Cardiac hypertrophy and failure: lessons learned from genetically engineered mice

ACTA PHYSIOLOGICA, Issue 1 2001
Y. Takeishi
Congestive heart failure is a major and growing public health problem. Because of improved survival of myocardial infarction patients produced by thrombolytic therapy or per-cutaneous revascularization it represents the only form of cardiovascular disease with significantly increased incidence and prevalence. Clinicians view this clinical syndrome as the final common pathway of diverse pathologies such as myocardial infarction and haemodynamic overload. Insights into mechanisms for heart failure historically derived from physiological and biochemical studies which identified compensatory adaptations for the haemodynamic burden associated with the pathological condition including utilization of the Frank Starling mechanism, augmentation of muscle mass, and neurohormonal activation to increase contractility. Therapy has largely been phenomenological and designed to prevent or limit the deleterious effects of these compensatory processes. More recently insights from molecular and cell biology have contributed to a more mechanistic understanding of potential causes of cardiac hypertrophy and failure. Many different analytical approaches have been employed for this purpose. These include the use of conventional animal models which permit serial observation of the onset and progression of heart failure and a sequential analysis of underlying biochemical and molecular events. Neonatal murine cardiomyocytes have been a powerful tool to examine in vitro subcellular mechanisms devoid of the confounding functional effects of multicellular preparations and heterogeneity of cell type. Finally, significant progress has been made by utilizing tissue from human cardiomyopathic hearts explanted at the time of orthotopic transplantation. Each of these methods has significant advantages and disadvantages. Arguably the greatest advance in our understanding of cardiac hypertrophy and failure over the past decade has been the exploitation of genetically engineered mice as biological reagents to study in vivo the effects of alterations in the murine genome. The power of this approach, in principle, derives from the ability to precisely overexpress or ablate a gene of interest and examine the phenotypic consequences in a cardiac specific post-natal manner. In contrast to conventional animal models of human disease which employ some form of environmental stress, genetic engineering involves a signal known molecular perturbation which produces the phenotype. [source]

Antitumor activity of ALK1 in pancreatic carcinoma cells

INTERNATIONAL JOURNAL OF CANCER, Issue 8 2007
Hendrik Ungefroren
Abstract In this study, the authors investigated the expression of activin receptor-like kinase 1 (ALK1) in pancreatic carcinoma and evaluated its potential role as a tumor suppressor in vitro and in vivo. Endogenous ALK1 expression was demonstrated by immunohistochemistry in both pancreatic tumor tissue and peritumoral normal tissue from 6 patients and by RT-PCR in 8/12 established pancreatic cancer cell lines. Ectopic expression of a constitutively active (ca) ALK1 mutant in TGF-, sensitive PANC-1 and COLO-357 cells augmented transcriptional activation of a Smad2/3 responsive reporter, and slowed down basal growth in vitro. Both effects were further enhanced by TGF-,/ALK5 stimulation, suggesting largely independent nuclear Smad signaling by both type I receptors. Upon orthotopic transplantation of PANC-1-caALK1 into immunodeficient mice, tumor size was strongly reduced and was associated with a lower microvessel density in the PANC-1-caALK1-derived tumors. In vitro, this mutant efficiently blocked TGF-,-induced epithelial-to-mesenchymal transdifferentiation and suppressed TGF-,/ALK5-mediated activation of the p38 MAPK pathway. Mechanistically, caALK1 silenced MyD118, an immediate TGF-, target gene whose protein product, GADD45,, couples Smad signaling to p38 activation. These results show that ALK1 activation in pancreatic tumor cells is antioncogenic by inducing ALK5-independent growth inhibition and by blocking TGF-,/ALK5-mediated epithelial-to-mesenchymal transdifferentiation and, possibly, invasion and metastatic progression. © 2007 Wiley-Liss, Inc. [source]

Liver Transplantation Using Liver Grafts Preserved Under High Pressure

ARTIFICIAL ORGANS, Issue 10 2005
Takuya Ueno
Abstract: To extend organ preservation time, we attempted to establish a unique method of maintaining a preservation solution in a stable unfrozen state below its freezing point by pressurizing the solution. Livers removed from Lewis rats (RT1l) were stored in UW solution pressurized at the prescribed pressure. After the termination of preservation, orthotopic liver transplantation was performed. Experiment 1: Liver grafts were pressurized up to 30, 40, 50, and 70 MPa and preserved at 0°C for 60 min. Experiment 2: Liver grafts were compressed at a rate of 1.32 or 0.04 MPa/s to 35 MPa and preserved for 60 min at 0°C. Experiments 3 and 4: Liver grafts were pressurized up to 5, 10, 20, and 30 MPa and preserved at ,2°C (Exp. 3), ,3°C or ,4°C (Exp. 4) for 5 h. All rats transplanted with livers pressurized up to 30 MPa (Exp. 1), all rats in the 5 MPa and control groups at ,2°C (Exp. 3), and all rats in the 5 MPa group at ,3°C (Exp. 4) survived for 2 weeks. In light microscopy, diffuse hemorrhage and vacuolar degeneration of hepatocytes were observed in a pressure-dependent manner. Liver grafts preserved under pressurized, subzero nonfrozen condition have sufficient function to sustain the life of rats after orthotopic transplantation. [source]

Expression of HNFs and C/EBP, is correlated with immunocytochemical differentiation of cell lines derived from human hepatocellular carcinomas, hepatoblastomas and immortalized hepatocytes

CANCER SCIENCE, Issue 9 2003
Tadashi Ishiyama
Objective assessment of the differentiation grade of hepatocellular carcinomas (HCCs) is important for evaluation of the pathological diagnosis, prognosis and therapeutic treatment. Differentiation of hepatocytes is reflected by their expression of hepatic functional proteins in the mouse embryo, and liver-enriched transcription factors (LETFs) have been shown to regulate hepatic functional genes strictly. Previous reports demonstrated that the level of LETF expression is altered in HCC or preneoplastic nodules compared with noncancerous tissues. Therefore, LETF expression levels might be useful as a measure of HCC maturation. In this study, to clarify the correlation between the expression of LETFs and the differentiation grade of HCCs, we performed a quantitative analysis of the mRNA expressions of HNFs and C/EBP, using real-time reverse-transcription PCR and immunocytochemical analysis for hepatic functional proteins in twelve cell lines. Furthermore, we examined orthotopic transplantations of the HCC cell lines in C.B-17/Icrj-scid/scid mice and characterized the histologic and cytologic differentiation of the tumors that developed. Our results showed that comprehensive expressions of HNF-3,, HNF-4,, HNF-1,, and C/EBP, were specific to HCCs with well-differentiated function and morphology. Furthermore, among these four transcription factors, HNF-4, and HNF-1, expressions showed synchronism and had a close relation with HCC differentiation. These in vitro results were confirmed in tumors developed in SCID mice in vivo. These findings suggested that HNF-4, and HNF-1, are useful markers to assess the degree of HCC differentiation, which we suggest could be evaluated objectively by the quantitative analysis of HNFs and C/EBP, in HCCs. [source]