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  • colon cancer  (14)
  • 1
    ISSN: 1573-7276
    Keywords: DNA ; colon cancer ; comparative genomic hybridization ; metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Understanding the genetic elements controlling the process of tumor metastasis to distant organ sites such as the liver may be the key to improving survivorship from colon cancer. By using standard cytogenetic techniques in combination with comparative genomic hybridization, multiple genetic imbalances within three human colon cancer cell lines previously selected for differences in liver-metastatic behavior were identified. The entire genome of one poorly metastatic cell line (KM12C) was compared directly with that of two highly metastatic cell lines (KM12SM, KM12L4A) derived from it. A number of chromosomal gains (8q, 12g15, 20q11.2) and losses (5p13, 6p21.3, 18) were common to all three cell lines and are likely related to early tumor development rather than to the selection process used to generate cell lines of increased metastatic potential. Chromosomal imbalances detected only in the highly metastatic cell lines were also observed. KM12SM showed losses of portions of 2p22, 2824.3→2q32.2, 4p15.3→cen, 4q24 without the 13q and 15q22.3 gains noted for KM12C. Both gains (1p31.3→1p21, 2822→2q33, 3cen→3q26.2, 5q14→5q23, 6cen→6q23) and losses (16p, 17p, 17q, 19p, 19q, 22q) were observed for KM12L4A but not for the other two cell lines. Identification of these alterations provides valuable insight into the process of experimental liver metastasis and is a first step towards mapping genes linked to the terminal phases of human colon cancer progression.
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  • 2
    ISSN: 1573-7276
    Keywords: chemotaxis ; colon cancer ; fibronectin ; metastasis ; tumorigenicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract CT 26 murine colon carcinoma cells demonstrated directional migration (chemotaxis) in response to fibronectin (FN). Sub-lines were derived by positive and negative selection to FN across Transwell filters of 8 mm pore size. The FL6 sub-line (positively selected) demonstrated a significantly increased chemotactic response (P 〈 0.01) to FN compared with parental CT 26 cells, while the FU7 sub-line (negatively selected) showed a reduced chemotactic response to FN (P 〈 0.01). Comparable levels of a4, a5, av and b1 integrins, which mediate FN attachment, were expressed on positively and negatively selected sub-lines and parental CT 26 cells. Activation of integrins with Mn 2+ suggested that the integrins expressed on FL6 cells were in the fully activated state; in contrast FU7 cells displayed only partially activated integrins. Cell attachment and integrin activation status of the sub-lines correlated with their chemotactic response to FN. In vivo FL6 cells showed a significantly reduced tumour growth rate s.c. and a reduction in the number of lung colonies formed following i.v. injection compared with parental CT 26 and FU7 cells. In contrast FU7 cells displayed a sig-nificant increase in s.c. tumour growth and the number of lung colonies when compared with the parental line and FL6 sub-line. The results indicate that interaction between integrin receptors expressed on cancer cells and FN plays a central role in the chemotactic response of CT 26 colon carcinoma cells, and that in this model cells selected for chemotaxis to FN displayed a reduced malignant potential.© Kluwer Academic Publishers 1998
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  • 3
    ISSN: 1573-7276
    Keywords: beta-galactosidase ; CC531 ; chemiluminescence ; colon cancer ; liver metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Disseminated colon carcinoma metastases in the liver are associated with low cure rates and constitute a serious therapeutic problem. Appropriate experimental models which mimic metastases development and outgrowth can provide insight into the mechanism of this lethal process and facilitate the finding of new approaches for its control. We established an orthotopic liver metastases model based on CC531 rat colon adenocarcinoma cells which were transfected with a β-galactosidase gene as marker to facilitate their detection. Intraportal injection of CC531-lac-Z cells resulted in a rapid and locally aggressive growth within the liver and was characterised by a tumour volume doubling time of 20 h and abundant angiogenesis. A commercially available chemi-luminescence assay allowed rapid, quantitative and sensitive detection of the diffusely growing tumour cells. Immunogenicity of CC531-lac-Z cells induced by the marker gene was significantly reduced by co-administering the tumour cells with matrigel. Within an observation period of three weeks following tumour cell injection only 6% of the animals showed lung involvement, thus indicating a specific homing of CC531-lac-Z cells to the liver. This period appears long enough to allow therapeutic manipulations at various stages of tumour growth in the liver. It is envisaged that the model will have applications for various therapeutic strategies.
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  • 4
    ISSN: 1573-7276
    Keywords: colon cancer ; liver metastasis ; histologically intact tumor tissue ; nude mice ; partial hepatectomy ; surgical implantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Partial hepatectomy has been widely employed in clinical practice as the therapy of choice for primary and metastatic liver tumors. However, the recurrence rate after the treatment remains high, which is most likely due to the growth of residual microscopic lesions. Previous studies in murine models demonstrated that a 70% hepatectomy significantly accelerated the growth of ectopically implanted tumors. In this study, we reported the effect of partial hepatectomy on the growth of two human colon cancers (Co-3 and AC3603) implanted in the liver of nude mice using the technique of surgical implantation of histologically intact tumor tissue. Our results showed a dramatic acceleration of tumor growth following 30% partial hepatectomy, which resembles clinical procedures. Tumor volumes were assessed with calipers on day-15 by abdominal palpation and on day-30 at autopsy by direct measurement. For both Co-3 and AC3603, tumor volumes in the hepatectomized animals were significantly larger than the control at the above two time points (P〈0.001). The results demonstrate the stimulating effect of partial hepatectomy directly on the tumor growth in the liver, in contrast to previous studies on ectopic tumors. Furthermore, since conservative partial hepatectomy (30%) is normally used in clinical practice for surgical treatment of liver metastasis, the animal models presented here should be useful for the clinical investigation of the high recurrence rate of liver metastasis following partial hepatectomy.
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  • 5
    ISSN: 1573-7276
    Keywords: cell motility ; cilostazol ; colon cancer ; invasion ; phosphodiesterase type III
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Metastasis of cancer cells is initiated by the cellular migration into extracellular matrix and surrounding vessels. We previously showed that elevation of cAMP levels in cancer cells suppressed trans-cellular migration in vitro. Drugs that can elevate cAMP levels in cancer cells effectively may be applied to prevent metastasis in cancer patients. Cilostazol, an oral anti-platelet drug, is a specific cAMP phosphodiesterase type III inhibitor and has been clinically used to treat thrombosis patients. In chemotaxis assay, cellular migration of human colon cancer cells, DLD-1, was induced by 10 μg/ml of soluble fibronectin or 10% of fetal bovine serum (FBS). Treatment with cilostazol (50 μM) suppressed 92.3% or 84.6% of the migration in control cells, respectively. When DLD-1 cells were stimulated by soluble fibronectin in phagokinetic assay, migration assessed by the area of gold particle phagocytosis track was induced and cilostazol also decreased 67.3% of the cellular migration in control cells. Furthermore, in the trans-cellular migration assay, cilostazol suppressed cancer cell invasion induced by FBS. Thus, cilostazol can suppress colon cancer cell motility and might be effective as an anti-metastasis drug for cancer patients.
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  • 6
    ISSN: 1573-7276
    Keywords: colon cancer ; fat storing cell ; fish oil ; immunohistochemistry ; metastasis ; myofibroblast
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recently, it was demonstrated that dietary Ω-3 polyunsaturated fatty acids (PUFAs) induce 10-fold more metastases in number and 1000-fold in volume in an animal model of colon cancer metastasis in rat liver. It was observed that tumors of rats on a fish oil diet lacked peritumoral stroma unlike tumors in livers of rats on a low fat diet or a diet containing Ω-6 PUFAs. In the present study, only one-third of the tumors in livers of rats on Ω-3 PUFA diet contained peritumoral stroma, whereas peritumoral stroma was present in 87% of the tumors in livers of rats on low fat diet. To explain these findings, we tested the hypothesis that fish oil exerts a direct inhibiting effect on the formation of extracellular matrix in tumor stroma as a consequence of blocking transformation of fat storing cells into myofibroblasts. It was found with immunohistochemical analysis of desmin as marker for fat storing cells and α-smooth muscle actin as marker for myofibroblasts that numbers of myofibroblasts were higher in tumors containing intratumoral stroma only than in tumors containing both peritumoral and intratumoral stroma. As most of the tumors in fish oil-treated rats contained intratumoral stroma only, this suggests that transformation of fat storing cells into myofibroblasts was highest in tumor stroma of fish oil-treated rats. Therefore, it is unlikely that the lack of stroma around tumors in fish oil-treated rats is due to inhibition of transformation of fat storing cells into myofibroblasts, but lack of peritumoral stroma is rather a consequence of rapid development of tumors in livers of fish oil-treated rats.
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  • 7
    ISSN: 1573-7276
    Keywords: cAMP ; colon cancer ; DLD-1 ; phosphodiesterase ; rolipram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To investigate mechanisms for regulation of intracellular cAMP involved in cancer cell invasion, phosphodiesterase (PDE) activity in a colon cancer cell line, DLD-1, was studied. Activities of PDE 2, 4, and 5 were detected in DLD-1 cells by pharmacological approach. Specific and cell permeable inhibitors for those PDEs were used to determine which PDE is responsible for cAMP turnover involved in cancer cell motility. Treatment of DLD-1 cells with rolipram and Ro-20-1724, inhibitors for PDE 4, elevated intracellular cAMP contents three to five times of control. EHNA, an inhibitor for PDE 2, and zaprinast, an inhibitor for PDE 5, did not affect cAMP levels. To assess cellular motility, we utilized chemotaxis assay. EHNA and zaprinast did not suppress serum-induced chemotaxis. In contrast, rolipram and Ro-20-1724, suppressed chemotaxis in a dose dependent fashion. These suggest that PDE 4 plays a critical role in regulating intracellular cAMP levels of colon cancer cells and is involved in cancer invasion. PDE 4 can be a novel target of anti-invasion drug.
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  • 8
    ISSN: 1573-7276
    Keywords: colon cancer ; immunotherapy ; matrix proteins ; metastasis ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The colon adenocarcinoma cell line CC531 was adopted as a model for immunotherapeutical treatment of experimental colorectal metastases in a syngeneic rat model. We studied the presence and localization of T and natural killer cells, vessels and matrix proteins in in vivo growing CC531 tumours by immunohistochemistry. CC531 tumours were induced either in the lungs by injecting CC531 tumour cells into a tail vein or in the liver by injection of CC531 tumour cells under the liver capsule or into a mesenteric vein. All 3 tumour types were composed of islets of tightly apposed tumour cells surrounded by abundantly present tumour-stroma which contained tumour vessels and matrix proteins. Some of these matrix proteins, especially laminin and collagen IV formed a basal membrane-like structure around the tumour nodules. This structure was most pronounced in mesenteric vein-induced liver tumours and less prominent in subcapsular-induced liver tumours and tail vein-induced lung tumours. Tumour-infiltrating lymphocytes of both T and natural killer cell origin were found in the tumours, but predominantly in the tumour stroma, separated from the islets of tumour cells by the basal membrane-like structure. We hypothesize that the matrix proteins of these tumours play an ambivalent role: they may provide a substratum for migration of effector cells into the tumour stroma but may also provide a barrier preventing direct contact between tumour target cells and immune effector cells.
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  • 9
    ISSN: 1573-7276
    Keywords: colon cancer ; Kupffer cells ; liver ; metastasis ; pit cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: The present study was performed to investigate processes involved in circumvention of the immune system by advanced stages of tumor growth in the liver. The efficacy of Kupffer cells and pit cells against cancer cells was tested in vivo in an experimental model of colon carcinoma metastasis in rat liver. Liver tumors were induced by administration of CC531 colon cancer cells into the vena portae. After 3 weeks, livers were obtained and partly fixed for electron microscopic procedures or frozen in liquid nitrogen for enzyme and immunohistochemistry at the light microscope level. The activation status of Kupffer cells was studied by expression of la-antigen (MHC class II) and by measurement of glucose-6-phosphate dehydrogenase (G6PDH) activity in the cells in situ as a measure of production of reactive oxygen species. Large numbers of Kupffer cells were found in liver parenchyma surrounding colon carcinomas when compared with levels in control livers, but these cells were not activated. Large numbers of activated monocytes and macrophages, cytotoxic T cells but only a few pit cells were found to be recruited to the boundary between liver parenchyma and tumors or their stroma. In those areas where cancer cells invaded liver parenchyma, only newly recruited macrophages and some Kupffer cells were present but few cytotoxic T cells or pit cells were found. The low activation status of Kupffer cells both in terms of production of reactive oxygen species and Ia-antigen expression and the absence of significant numbers of pit cells at tumor sites suggest that Kupffer cells and pit cells do not play a significant role in advanced stages of tumor growth. High levels of prostaglandin E2 were detected in the parenchyma of livers containing tumors and transforming growth factor β was detected in the stroma of the tumors, therefore suggest that cytotoxicity of newly recruited monocytes, macrophages and cytotoxic T cells may be limited in these stages because of local production of these immunosuppressive factors.
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  • 10
    ISSN: 1573-7276
    Keywords: colon cancer ; liver metastatic model ; nude mice ; surgical orthotopic implantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An ultra-high metastatic model of human colon cancer was developed in order to represent highly malignant patient disease for which there is no current model. Surgical orthotopic implantation (SOI) of a histologically intact liver metastasis fragment derived from a surgical specimen of a patient with metastatic colon cancer was initially implanted in the colon, liver and subcutaneously in nude mice. This tumor did not metastasize for the first 10 passages. At the eleventh passage, the tumor exhibited metastasis from the colon to the liver, spleen, and lymph nodes. At this time, two selective passages were carried out by transplanting resulting liver metastases in the nude mice to the colon of additional nude mice. After these two passages, the tumor became stably ultra-metastatic and was termed AC3488UM. One-hundred percent of mice transplanted with AC3488UM with SOI to the colon exhibited local growth, regional invasion, and spontaneous metastasis to the liver, lymph nodes, and spleen. While the maximum size of the primary tumor was 0.9 g, the metastatic liver was over 9 times the weight of the normal liver with the maximum weight of the metastatic liver over 12 g. Liver metastases were detected by the tenth day after transplantation in all animals. Half the animals died of metastatic tumor 25 days after transplantation. Histological characteristics of AC3488UM tumor were poorly differentiated adenocarcinoma of colon. Mutant p53 is expressed heterogeneously in the primary tumor and more homogeneously in the liver metastasis suggesting a possible role of p53 in the liver metastasis. The human origin of AC3488UM was confirmed by positive fluorescence staining for in situ hybridization of human DNA. The AC3488 human colon-tumor model with its ultra-high metastatic capability in each transplanted animal, short latency and a short median survival period is different from any known human colon cancer model and will be an important tool for the study of and development of new therapy for highly metastatic human colon cancer.
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