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PubMed2004

Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit the growth of PPAR-gamma expressing cancer cells through terminal differentiation. However, there are few studies examining the effect of a PPAR-gamma ligand on metastatic potential of cancer cells in an animal model and the underlying molecular mechanisms. We have recently developed a rectal cancer xenograft animal model in which anti-tumor and anti-metastatic efficacy of agents can be evaluated. This study was designed to examine whether a representative PPAR-gamma ligand, thiazolidinedione (TZD), could inhibit growth and metastasis of PPAR-gamma positive HT-29 human colon cancer cells through the induction of terminal differentiation. TZD caused G1 arrest in association with a marked increase in p21Waf-1, Drg-1, and E-cadherin expression. In untreated cancer cells, fluorescence immunostaining demonstrated beta-catenin in the nucleus and/or cytoplasm; in TZD-treated cancer cells, beta-catenin localization shifted to the plasma membrane, in association with increased E-cadherin at this site and reduced tyrosine phosphorylation of beta-catenin. In addition, TZD completely inhibited lymph node and lung metastases in the xenograft animal model, and TZD inhibited growth of primary xenografts by 40%. These results suggest that TZD can function as a cytostatic anti-cancer agent to inhibit growth and metastasis of HT-29 colon cancer cells through differentiation-promoting effects. These effects involve not only modulation of the E-cadherin/beta-catenin system, but also up-regulation of Drg-1 gene expression.

Animals↗
PubMed1999

Short-term moderate aflatoxin B1 exposure has only minor effects on the gut-associated lymphoid tissue of Brown Norway rats.

Aflatoxin B1 (AFB1) is toxic to the systemic immune system in various animal species, whereas little is known about its effect on the gut-associated lymphoid tissue (GALT). It may be hypothesized that the toxicity of AFB1 and its locally generated metabolites in the intestinal tissue may result in a disturbed intestinal integrity and, subsequently, in an impaired immune response towards dietary proteins. The objective of our study was to investigate the toxic effect of short-term moderate AFB1 exposure on the intestinal epithelium and on the immune cells associated with the intestinal tract. The toxicological potential of AFB1 and its metabolites to the intestinal epithelium was determined by measuring viability and genotoxic damage in isolated jejunal epithelial cells (comet assay) after 30 min incubation in vitro. In vivo toxicology studies were carried out with Brown Norway (BN) rats, which were exposed orally once a week with AFB1 (1 x 100 microg/kg body weight (b.w.)/week) for 5 consecutive weeks. Viability and genotoxicity were measured in explanted jejunal epithelial cells. For studying the effectiveness of AFB1 on immunological parameters BN rats were treated with a high (study 1: 1 x 1 mg/kg b.w./week) or a low (study 2: 1 x 100 microg/kg b.w./week) AFB1 dose for 5 consecutive weeks with or without ovalbumin (OVA). Mesenteric lymphocytes were isolated and proliferative responsiveness, secretion of interferon-gamma, and changes in lymphocyte subpopulations as well as mucosal mast cell specific protease and anti-OVA specific antibody concentrations were measured. In vitro, AFB1 ( >30 microM) induced genotoxicity in rat jejunal epithelial cells. The oral administration of AFB1 (1 x 100 microg/kg b.w./week) did not induce DNA damage in jejunal epithelial cells. The high AFB1 dose increased the number of CD8+ and CD8/CD71 + cells in mesenteric lymph nodes. The immune response towards OVA was not affected. The low AFB1 dose only reduced the proliferative responsiveness of mesenteric lymphocytes (P < 0.05). Serum concentrations of anti-OVA specific IgE antibody, of RMCPII, and the capacity of mesenteric lymphocytes to produce interferon-gamma were not impaired by AFB1. In conclusion, exposure to moderate doses of AFB1 does not damage the intestinal epithelium and has only minor effects on the GALT. The low exposure, as it may predominantly occur in western countries, does not appear to increase the risk for sensitization to dietary antigens.

Aflatoxin B1↗
PubMed1986

Leporine acquired immune deficiency disease.

We have identified a recombinant leporipoxvirus that produces disseminated fibromas and a severe combined immune deficiency disease of sudden onset. The virus is recombinant between the SFV and the MV. MV was identified as a trace contaminant in stocks of SFV (Patuxent strain). Rabbits inoculated with the original uncloned stock of SFV prepared in vitro develop local tumors that subsequently regress. However, tumor extracts prepared from these animals, when injected into a second group of rabbits, produced MV syndrome. Rabbits with MV syndrome develop severe, usually lethal, Pasteurella or Bordetella infections and have disseminated fibroxanthosarcomas more similar to those produced by myxoma virus. The virus that induces this syndrome has been isolated by two cycles of plaque purification. This virus is indistinguishable from SFV using cross-neutralization and electron microscopy. Analyses of restriction enzyme digests of MV and plaque-purified SFV show them to be quite dissimilar and indicate that MV is recombinant between SFV and myxoma virus. This recombinational event resulted in approximately 5.5 kb of myxoma virus DNA within each of the inverted terminal repeats being replaced by a similar amount of DNA derived from the corresponding region of the SFV genome. Thus, MV contains approximately 149 kb of myxoma sequences and 11 kb of SFV sequences. Immunofluorescent studies of spleen and lymph nodes from MV-infected rabbits demonstrate that viral antigens are present predominantly in the sinusoidal lining cells in lymph nodes and in phagocytes in the splenic cords. This contrasts with the distribution of antigen observed in myxoma virus-infected rabbits where myxoma-specific antigens are present in large amounts in hyperplastic epithelium overlying tumors, particularly in the nasal mucosa and in spleen and lymph node cells. MV-infected rabbits essentially lose their lymphocyte proliferative response to T and B cell mitogens and are unable to initiate an antibody response to SRBC, as determined by a modified Jerne plaque assay. In vitro MV severely depresses the mitogen responses of normal B and T lymphocytes after two days of culture. Lymphoid cells and lysates of lymphoid cells from MV-infected rabbits will suppress mitogen- and antigen-induced responses in vitro. MV can grow in lymphocytes, but replication of MV is less efficient in lymphocytes than in RK-13 cells. Thus, MV produces a disseminated viral infection, systemic myxofibromas, and a severe combined immune deficiency in rabbits. The molecular and immunologic basis for these effects is now under study.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Development of a high metastatic orthotopic model of human renal cell carcinoma in nude mice: benefits of fragment implantation compared to cell-suspension injection.

In this study we compared the metastatic rate of human renal cell carcinoma SN12C in two orthotopic nude mouse models: surgical orthotopic implantation (SOI) of histologically intact tumor tissue and cellular orthotopic injection (COI) of cell suspensions in the kidney. The primary tumors resulting from SOI were larger and much more locally invasive than primary tumors resulting from COI. SOI generated higher metastatic expression than COI. The differences in metastatic rates in the involved organs (lung, liver, and mediastinal lymph nodes) were 2-3 fold higher in SOI compared to COI (P < 0.05). Median survival time in the SOI model was 40 days, which was significantly shorter than that of COI (68 days) (P < 0.001). Histological observation of the primary tumors from the SOI model demonstrated a much richer vascular network than the COI model. Lymph node and lung metastases were larger and more cellular in the SOI model compared to COI. We conclude that the tissue architecture of the implanted tumor tissue in the SOI model plays an important role in the initiation of primary tumor growth, invasion, and distant metastasis. This study directly demonstrates that the implantation of histologically intact tumor tissue orthotopically allows accurate expression of the clinical features of human renal cancer in nude mice. This model should be of value in cancer research and antimetastatic drug discovery for renal cancer, a currently very poorly responding malignancy.

Adult↗
PubMed1981

Prognostic value of concanavalin A reactivity of primary human breast cancer cells.

A prospective, double-blind study was carried out to determine whether activity with concanavalin A (Con A) of human breast cancer cells was related to early disease recurrence. Mammary epithelial cells were isolated from 138 primary human breast cancers. The cells were placed in culture, and their reactivity with Con A was determined with a hemadsorption assay in which human erythrocytes treated with various concentrations of Con A were incubated with the test (mammary epithelial) cells in situ. The Con A half-maximum value was determined as the concentration of Con A at which approximately 50% of the test cells adsorbed erythrocytes. Con A reactivity of the tumors was classified as high or low (half-maximum value less than or equal to 30 or greater than 30 microgram/ml, respectively). Patients were followed for 2 to 60 months after primary surgery (median, 22 months). Those patients having tumors that were highly reactive with Con A were at significantly greater risk of developing early recurrence of their cancers than were those patients with low-reactivity tumors. No correlation was found between Con A reactivity and the age of the patients, their menopausal status, the number of axillary lymph nodes infiltrated with tumor, the number of axillary lymph nodes infiltrated with tumor, the estrogen receptor content of the tumor, or the clinical stage of the disease. These data show that Con A reactivity is an independent discriminator for identifying those breast cancer patients who are at high risk of developing early recurrent disease.

Agglutination↗
PubMed1989

Clinical use of prostate specific antigen in patients with prostate cancer.

The clinical use of prostate specific antigen as a screening test for prostate cancer, as a preoperative determinant for staging of prostate cancer and to monitor response to therapy in prostatic cancer patients was evaluated in 168 men with benign prostatic hyperplasia and 231 men with prostate cancer. Only 3% of the men with benign prostatic hyperplasia had prostate specific antigen levels greater than 10 ng. per ml. compared to 44% of the men with proved prostate cancer. Preoperative prostate specific antigen levels increased with higher clinical stages of prostate cancer but there was substantial overlap among stages. Among patients with stage A1 prostate cancer who were followed expectantly none had an elevated prostate specific antigen value or metastatic disease during a followup of 15 to 120 months. After radical prostatectomy serum prostate specific antigen values decreased to undetectable levels (less than 0.6 ng. per ml.) in 89% of the patients with organ-confined disease, in 87% of those with microscopically positive margins only but in only 34% with seminal vesicles or lymph node involvement. Failure of the prostate specific antigen levels to decrease to the undetectable range after radical prostatectomy was associated with a greater likelihood of subsequent tumor recurrence. Only 3 of 18 patients (17%) treated with definitive radiation therapy had post-irradiation prostate specific antigen values of less than 0.6 ng. per ml., while in 39% the prostate specific antigens values remained greater than 4 ng. per ml. and in 4 of 18 (22%) the values were greater than 10 ng. per ml. Of patients with previously untreated stage D2 prostate cancer the mean pre-treatment prostate specific antigen value was 63.7 ng. per ml. compared to a post-hormonal therapy mean value of 31.1 ng. per ml. Of 32 patients treated with hormonal therapy 14 had stable disease, including 13 with prostate specific antigen levels of less than 10 ng. per ml. In contrast, 18 patients had progressive disease, of whom 16 had prostate specific antigen levels of more than 10 ng. per ml. We conclude that the serum prostate specific antigen assay is most useful clinically to monitor the response to therapy of prostate cancer patients.

Acid Phosphatase↗
PubMed2004

Early delayed-type hypersensitivity eosinophil infiltrates depend on T helper 2 cytokines and interferon-gamma via CXCR3 chemokines.

We investigated the role of T helper (Th)1- and Th2-type cytokines in delayed-type hypersensitivity to soluble protein antigens elicited early postimmunization. Mice were sensitized by intradermal injection without adjuvants, or subcutaneously with complete Freund's adjuvant, and subsequently ear challenged intradermally. As soon as day 3, antigen-specific eosinophil-rich responses were elicited in wild-type mice, but not in T-cell receptor-alpha-/- mice without adjuvant. Draining lymph node T cells stimulated with antigen secreted interleukin (IL)-4, IL-5 and interferon-gamma (IFN-gamma). IFN-gamma-dependent specific immunoglobulin G (IgG)2a and IL-4-dependent IgG1 were also generated. Delayed-type hypersensitivity ear swelling and local eosinophil recruitment were decreased in IL-5-/-, IL-4-/- and signal transducer and activator of transcription-6 (STAT-6)-/- mice, and with anti-IL-4 treatment of wild-type mice, suggesting Th2 mechanisms. Interestingly, responses were also decreased in IFN-gamma-/- mice, and IFN-gamma protein and the IFN-gamma-inducible CXC chemokine, IP-10, were present in 24-hr ear tissue extracts, suggesting Th1 effects. Finally, ear swelling, total histology and eosinophils were decreased in mice deficient in CXCR3, the chemokine receptor for IP-10. These results suggest that both a Th2-like (IL-5, IL-4 and STAT-6) and a Th1-like (IFN-gamma, IP-10, CXCR3) pathway contribute to eosinophil recruitment in early delayed-type hypersensitivity.

Animals↗
PubMed2001

Utility of tests for circulating melanoma cells in identifying patients who develop recurrent melanoma.

Prospective studies were carried out on 186 patients with AJCC stage I (13), II (76) and III (97 patients) melanoma before and after surgical removal of their tumour. The goal was to determine if PCR tests on blood samples for MART-1 and tyrosinase were predictive of recurrence of melanoma in a 2-year follow-up period. (PCR assays for MUC-18, p97 and gp100 were positive in blood samples from normal subjects and excluded from the study.) PCR tests for MART-1 and tyrosinase were most commonly positive in the first 3 months following surgical removal of melanoma, and three tests over this period gave maximum sensitivity in the identification of patients who subsequently developed recurrences. Positive tests for the first time in the second year of follow-up had similar predictive power. The tests identified 68.5% of patients who developed recurrences in the 2-year follow-up period. Assays for MART-1 were mainly positive in patients with locoregional recurrences, whereas tyrosinase was detected in blood samples from patients with both locoregional and disseminated recurrences. (Positivity rate for tyrosinase in 48 patients with disseminated melanoma was 60.4% compared to 14.6% for MART-1.) Tests for MART-1 and tyrosinase were strongly predictive of disease-free survival (DFS) and were more powerful predictors of DFS than lymph node status or thickness of the primary melanoma. (Hazard ratios by Cox analysis were 2.97 in patients with disseminated recurrences and 2.93 in those with locoregional recurrences.) These results indicate that PCR tests for MART-1 and tyrosinase are powerful prognostic indicators, but their practical utility for selecting patients for adjuvant therapy is limited by the high false-negative rate of approximately 30%. Intermittent shedding of melanoma cells into the circulation would appear to be the most likely explanation for the latter.

Antigens, Neoplasm↗
PubMedDate not supplied

High serum soluble E-selectin levels are associated with postoperative haematogenic recurrence in esophageal squamous cell carcinoma patients.

E-selectin has been reported to be associated with haematogenic metastasis in various cancer patients. In order to evaluate the risk of postoperative haematogenic recurrence of esophageal squamous cell carcinoma (SCC) patients, we examined the preoperative serum levels of soluble E-selectin and clinicopathological data of the patients. Preoperative serum was obtained from 135 esophageal SCC patients who received esophagectomies from 1990 to 1998. Serum soluble E-selectin levels were measured by means of enzyme linked immunoreactive synthesis assay (ELISA). The expression of sialyl Lewis A and X antigens were evaluated in 58 out of 135 patients. Thirty-five patients (25.9%) had haematogenic recurrence in their postoperative course. Serum soluble E-selectin levels of the haematogenic recurrence group (mean 55.6 ng/ml) were significantly higher than those of the non-haematogenic recurrence group (mean 41.1 ng/ml). When the cut-off level of soluble E-selectin was 56 ng/ml, the logistic regression analysis showed that high serum soluble E-selectin levels, lymph node metastasis and intraepithelial spread were associated with postoperative haematogenic recurrence of the esophageal SCC patients (OR 2.99, p=0.047, OR 4.94, p=0.009 and OR 5.0, p=0.019. respectively). Univariate analysis revealed that the patients with a high serum soluble E-selectin level tended to have poor survival (p=0.078) and Cox multivariate analysis revealed that a high serum soluble E-selectin level was a prognostic factor in esophageal SCC patients (RR 1.84, p=0.065). The patients with a high serum soluble E-selectin concomitant with expression of sialyl Lewis antigens had a significant risk of postoperative haematogenic recurrence (p=0.005). These results indicated that preoperative high serum soluble E-selectin was a risk factor in the development of postoperative haematogenic recurrence and was a prognostic factor in esophageal SCC patients.

Biomarkers, Tumor↗
PubMed2000

[Current diagnostic method, prognosis estimation and therapy of papillary thyroid cancer: recommendations of the medical universities and the National Oncologic Institute of Budapest].

Physical examination, cervical ultrasonography (US) and aspiration cytology are the mainstays of the preoperative diagnostics of papillary thyroid carcinoma. For the staging of suspected malignant cases, cervical and mediastinal CT (MRI for inconclusive results) is indicated before any surgery. The end-result of primary treatment is assessed by total-body iodine scintigraphy and the serum human thyroglobulin (hTG) level. For long-term follow-up, physical examination and the serum hTG level are the most reliable tools (6-monthly), supplemented by cervical US and chest X-ray (yearly), and total-body iodine scintigraphy (2-yearly). If these furnish positive results, further examinations may be indicated. In suspected relapses of hTG non-producing and iodine non-accumulating papillary carcinomas, 201thallium chloride or 99mTc-sesta-MIBI (methoxy-isobutyl-isonitrile) scintigraphy, and positron emission tomography with 18fluoro-deoxyglucose or 11C-methionine may be of help. For estimation of the prognosis (cause-specific survival) of the patients, the MACIS score system of the Mayo Clinic is widely accepted, the patients being divided into low-risk and intermediate/high-risk categories. The recommended standard surgical intervention is near-total thyroidectomy (2-4 g residual glandular tissue left at the upper pole of the less-involved lobe), with a central cervical lymph node dissection for diagnostic purposes. In cases of lymph node dissemination, dissection (radical, modified radical, selective or microdissection) of any of the involved compartments (central, right or left cervical, or upper mediastinal) is indicated for therapeutic reasons, the method of which is depending on the extent of the metastatic involvement. Following adequate surgical intervention, no adjuvant radioiodine therapy is indicated for low-risk cases with a tumour of less than 1 cm diameter. For other low-risk or intermediate/high-risk patients, radioiodine ablation (R0N0M0) or a therapeutic radioiodine dosage (R2N1M1) is indicated. In cases at high-risk of local/regional relapse and in radioiodine non-accumulating tumorous cases, external radiotherapy may be applied. Thyroid hormone medication in a TSH suppressive dose is indicated during the first 5 postsurgical years: the goal is to achieve a TSH level below 0.1 (determined by a 3rd generation assay). If no relapse occurs or the case is a low-risk one, following the 5 years, it is enough to maintain the TSH level in a subnormal range (0.1-0.3).

Carcinoma, Papillary↗
PubMed1987

[Colon carcinoma. Preoperative CEA, tumor differentiation and prognosis].

Investigations on 279 patients with colon carcinoma revealed an increase in the sensitivity of the CEA (carcinoembryonic antigen) test with regard to tumor stage from 42% (Dukes A) to 86% (Dukes D). Curative operable carcinoma without lymph-node or distant metastases had CEA levels up to 70 ng/ml. CEA values below 20 ng/ml had no predictive value concerning resectability at first operation. When the CEA level rose above 20 ng/ml, the proportion of curative operations fell from 83% (CEA values below 20 ng/ml) to 17%. Recurrence rate rose with the preoperative level of CEA from 22% (CEA less than 2.5 ng/ml) to 62% (CEA greater than 10 ng/ml). The resection rate at second operation had a closer relationship than at first operation to the preoperative CEA level; it fell from 50% (CEA less than 5.0 ng/ml) to 0% (CEA greater than 20 ng/ml). At operation, highly differentiated tumors were found to be at an early stage in 50% of cases, compared to 26% of G2 and 11% of G3 tumors. In 44% of dedifferentiated tumors CEA levels were above 20 ng/ml. An influence of tumor differentiation on CEA remained even after division into the individual tumor stages.

Adenocarcinoma↗
PubMed2000

Epidermal growth factor-like ligands differentially up-regulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes, with distant metastases developing in 30-40% of cases. Overexpression of the epidermal growth factor receptor (EGFR/c-erbB-1) and/or its ligands and high levels of certain matrix metalloproteinases (MMPs) have been associated with poor prognosis. The aim of this study was to examine the effects of EGFR ligands on gelatinase expression and invasion in HNSCC cell lines. We tested epidermal growth factor (EGF), transforming growth factor alpha, betacellulin, heparin-binding EGF, and amphiregulin and measured expression of gelatinases MMP-9 and MMP-2 in an established squamous carcinoma cell line (Detroit-562) and in two cell lines newly derived from patients with head and neck cancers (SIHN-005A and SIHN-006). Incubation of the cell lines with EGF-like ligands up-regulated MMP-9 (but not MMP-2) expression as measured by semiquantitative reverse transcription-PCR in a dose-dependent manner, with the effects being most marked in cells with high EGFR levels and undetectable in cells with low levels. Maximum stimulation was obtained in a concentration range of 10-100 nM. In addition, we confirmed by zymography that gelatinolytic activity consistent with MMP-9 (Mr 92,000) was up-regulated in parallel with increases in gene expression. Betacellulin (which binds both to EGFR and c-erbB-4 receptors) consistently increased MMP-9 expression and activation to a significantly greater degree than the other four ligands when tested at equimolar concentrations. In parallel with MMP-9 up-regulation, all EGF-like ligands increased tumor cell invasion through Matrigel in in vitro Transwell assays. These activities were independent of ligand effects on cell proliferation. Antagonist (ICR62) or agonist (ICR9) anti-EGFR monoclonal antibodies, respectively, inhibited or potentiated MMP-9 activity and tumor cell invasion induced by all ligands. Furthermore, a monoclonal antibody that neutralizes MMP-9 activity (Abl) also inhibited ligand-induced invasion of HNSCC. We confirmed that tumor cell lines used in these studies (and a larger series not reported here) generally expressed multiple c-erbB receptors and ligands. These results indicate that autocrine or paracrine signaling through EGFR potentiates the invasive potential of HNSCC via the selective up-regulation and activation of MMP-9. Furthermore, ligands such as betacellulin (which is commonly expressed in HNSCC), which can bind to and activate other c-erbB receptors, may be especially potent in this regard.

Antibodies, Monoclonal↗
PubMed1998

Characterisation of the primary local and systemic immune response in gnotobiotic lambs against rotavirus infection.

This study characterised the primary immune response in gnotobiotic lambs after infection with a lamb rotavirus (RV). Lambs were infected and killed over a 7 week period together with controls. RV-ELISA and neutralising antibodies were determined in serum, nasal secretions, and intestinal scrapings. RV-antibody secreting cells (ASC) were enumerated in blood. Lymphocyte proliferations were determined in blood and gut-associated lymphoid tissues and cytokine expression was analysed in jejunal Peyer's patches (JPPs) and mesenteric lymph nodes (MLNs). Infected lambs cleared the virus by 8-9 days after infection without showing any clinical signs. The first indication of a specific immune response to RV was an increased expression of IL-4 mRNA in the JPPs in the infected group compared to the control group 3 days after infection. Rotavirus-specific IgA ASC in blood and IgA antibodies in serum and nasal secretions were detected from 7 days after infection followed at 10 days after infection by RV-specific IgG ASC and antibodies. Rotavirus-specific IgA antibodies were not detected in intestinal scrapings in the first 10 days after infection, but were detected by 52 days after infection. No RV-specific neutralising antibodies were seen in the intestine during the course of the experiment.

Animals↗
PubMed1986

Humoral and cellular immunologic aspects of adjuvant and collagen arthritis in rats.

Systemic and local immunological responses of rats sensitized with either M. butyricum or native type II collagen have been evaluated. In rats exhibiting adjuvant-induced arthritis no antibodies to collagen could be detected. In animals exhibiting collagen-induced arthritis, high antibody titers developed by day 14, and could be correlated with the severity of the arthritis. Delayed type hypersensitivity (DTH) responses were measured by a 5-iodo-2'-deoxyuridine 125-I (125-IUdR) uptake assay. Arthritic scores in rats immunized with collagen were not accompanied by a positive DTH response, whereas adjuvant arthritic rats showed a positive response. T-lymphocyte cellular responses in both adjuvant- and collagen-induced arthritic rats were measured. In neither syndrome were major alterations observed in T-lymphocyte subpopulations. These results provide evidence that adjuvant-induced arthritis and type II collagen-induced arthritis are distinct entities, and that they may be discriminated by the nature of the humoral response.

Animals↗
PubMed1999

Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence.

Disseminated disease, especially to the liver, constitutes the major risk of recurrence for colorectal cancer patients. However, successful resection can still be achieved in 25-35% of colorectal cancer patients with isolated metastases. To evaluate the clinical value of occult micrometastatic disease detection in lymph nodes, we tested genetic (K-ras and p53 gene mutations) and epigenetic (p16 promoter hypermethylation) molecular markers in the perihepatic lymph nodes from colorectal cancer patients with isolated liver metastases. DNA was extracted from 21 paraffin-embedded liver metastases and 80 lymph nodes from 21 colorectal cancer patients. K-ras and p53 gene mutations were identified in DNA from liver metastases by PCR amplification followed by cycle sequencing. A sensitive oligonucleotide-mediated mismatch ligation assay was used to search for the presence of K-ras and p53 mutations to detect occult disease in 68 lymph nodes from tumors positive for these gene mutations. Promoter hypermethylation at the p16 tumor suppressor gene was examined in both liver lesions and lymph nodes by methylation-specific PCR. Sixteen of the 21 (76%) liver metastases harbored either gene point mutations or p16 promoter hypermethylation. Twelve of the 68 lymph nodes were positive for tumor cells by molecular evaluation and negative for tumor cells by histopathology and cytokeratin immunohistochemistry, whereas none were positive for tumor cells by histopathology or negative for tumor cells by molecular analysis (P = 0.0005, McNemar's test). Moreover, in three patients with lymph nodes that were histologically negative at all sites, molecular screening detected tumor DNA at one or more lymph nodes. Survival analysis showed a median survival of 1056 days for patients without evidence of lymph node involvement by molecular analysis and 165 days for patients with positive lymph nodes by this approach (P = 0.0005). These results indicate that lymph node metastasis screening in colorectal cancer patients by molecular-based techniques increases the sensitivity of tumor cell detection and can be a good predictor of recurrence in colorectal cancer patients with resectable liver metastases.

Colorectal Neoplasms↗
PubMed2002

Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells.

Chemokines and chemokine receptors play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCR4 in adult T-cell leukemia (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-immortalized T cells. Flow cytometric analysis revealed that ATL and HTLV-1-immortalized T-cell lines consistently expressed CCR4. Inducible expression of HTLV-1 transcriptional activator tax in a human T-cell line Jurkat did not, however, up-regulate CCR4 mRNA. In vitro immortalization of peripheral blood T cells led to preferential outgrowth of CD4(+) T cells expressing CCR4. We further demonstrated highly frequent expression of CCR4 in fresh ATL cells by (1) reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of CCR4 expression in peripheral blood mononuclear cells (PBMCs) from patients with ATL and healthy controls; (2) flow cytometric analysis of CCR4-expressing cells in PBMCs from patients with ATL and healthy controls; (3) CCR4 staining of routine blood smears from patients with ATL; and (4) an efficient migration of fresh ATL cells to the CCR4 ligands, TARC/CCL17 and MDC/CCL22, in chemotaxis assays. Furthermore, we detected strong signals for CCR4, TARC, and MDC in ATL skin lesions by RT-PCR. Collectively, most ATL cases have apparently derived from CD4(+) T cells expressing CCR4. It is now known that circulating CCR4(+) T cells are mostly polarized to Th2 and also contain essentially all skin-seeking memory T cells. Thus, HTLV-1-infected CCR4(+) T cells may have growth advantages by deviating host immune responses to Th2. CCR4 expression may also account for frequent infiltration of ATL into tissues such as skin and lymph nodes.

Adult↗
PubMed2001

[Spontaneous portal vein thrombosis associated with acute cytomegalovirus infection in an immunocompetent patient].

BACKGROUND: Portal vein thrombosis (PVT) generally results from a local cause (hepatocellular and pancreatic carcinoma). Spontaneous PVT related to a general cause is less common. We report here a case of spontaneous PVT associated with acute cytomegalovirus (CMV) infection in an immunocompetent patient. CASE REPORT: A 31-year-old white female was admitted with fever and lymph node enlargement. The patient was a heavy smoker and was taking oral contraception. Blood tests revealed an inflammatory syndrome. Liver enzymes were elevated (2N) and platelet count was 118 G/l. Abdominal ultrasonography disclosed partial portal thrombosis. Computed tomography did not show any evidence of a hepatic or pancreatic mass. Protein S, protein C, and anti-thrombin III levels were normal. No antiphospholipid antibodies, no mutation for factors II and V and no abnormality suggestive of paroxysmal nocturnal hemoglobinuria at flow cytometry could be demonstrated. Acute CMV infection was diagnosis with positive viremia (PCR). The patient was given anticoagulation treatment and has done well with no relapse. CONCLUSION: Cytomegalovirus, by damaging endothelial cells, is thought to trigger a cascade of events leading to deep vein thrombosis. CMV infection does not appear to act alone on endothelial cells but rather behaves as an associated factor.

Acute Disease↗
PubMed2006

Hodgkin's lymphoma cells express alternatively spliced forms of HDM2 with multiple effects on cell cycle control.

The HDM2 oncoprotein is a cellular inhibitor of p53 and is frequently deregulated in human cancer. However, the HDM2 gene encodes alternatively spliced variants whose functional significance is poorly understood. We had previously reported the detection of alternative HDM2 forms in Hodgkin's lymphoma (HL)-derived cell lines. Here, we have cloned several of these transcripts, including the previously described HDM2-A, -B and -C (which encode the COOH terminus of HDM2), and two novel variants (HDM2-HL1 and -HL2) containing a complete p53 interaction domain. Real-time PCR assays demonstrated that HDM2-A and -B were selectively expressed by HL cell lines and primary tumors, compared with their non-neoplastic counterparts. In transient transfection experiments, alternatively spliced HDM2 isoforms were partially or totally localized within the cytoplasm. HDM2-HL2 was able to inhibit transactivation of a p53-inducible reporter construct and induced a partial relocalization of p53 to the cytoplasm. Expression of HDM2-A and -B caused the activation of p53/p21 and induced growth arrest in primary cells, but also increased the expression levels of cyclins D1 and E. Other possible genes regulated by HDM2-A and -B were identified using cDNA microarray technology. These results imply that HDM2 isoforms may have multiple effects on cell cycle control, and provide insight into the mechanisms through which these molecules contribute to tumorigenesis.

Alternative Splicing↗