Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The E-cadherin/catenin cell adhesion system is often down-regulated in epithelial tumors. This is thought to play an important role in cancer invasion and metastasis, and restoration of this system may suppress metastatic spread of cancer. In this study, the effects of a Ras farnesylation inhibitor (FTI-277) on E-cadherin-mediated cell-cell adhesion and metastatic potential were examined. In cell aggregation assays, FTI-277 stimulated aggregation of colon, liver and breast cancer cells. In vitro cultures of cancer cells showed that FTI-277 induced strong cell-cell contact. Immunoblotting analysis showed that FTI-277 increased E-cadherin/catenin (alpha, beta and gamma) expression and strongly stabilized E-cadherin/catenin with the actin cytoskeleton. Northern blotting studies indicated that the observed increase in the E-cadherin/catenin protein content was due to increased expression of their genes. After inoculation of the spleens of mice with severe combined immunodeficiency (SCID) with cancer cells, FTI-277 treatment for 3 weeks markedly reduced splenic primary tumor growth and the rate of liver metastasis compared with control counterparts. Our data demonstrate that FTI-277 can activate functioning of the E-cadherin-mediated cell adhesion system, which is associated with suppression of cancer cell metastasis. Therefore, selective inhibition of Ras activation may be useful for preventing cancer metastasis.
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PMID:Ras farnesylation inhibitor FTI-277 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. 1235 56

We expressed the full-length CD44v2-10 isoform in SKHep1 cells, a nonmetastatic human hepatocellular carcinoma cell line that does not express any endogenous CD44v isoforms. In SCID mice, expression of CD44v2-10 by SKHep1 cells had no effect on s.c. primary tumor development but caused pulmonary metastases in 41% (7 of 17) of animals compared with control SKHep1 cells (0 of 16; P < 0.01). CD44v2-10 expression by SKHep1 cells resulted in enhanced heparan sulfate (HS) attachment and an enhanced capacity to bind heparin-binding growth factors. Mutation of the v3 domain to prevent HS attachment and growth factor binding abolished the metastatic phenotype, demonstrating that HS modification of CD44v2-10 plays a critical role in the development of metastases in this model. However, in vitro proliferation, motility, and invasion were not altered by CD44v2-10 expression.
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PMID:Expression of the CD44v2-10 isoform confers a metastatic phenotype: importance of the heparan sulfate attachment site CD44v3. 1259 43

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. The generation of immortalized primary prostate cancer cells that will accurately reflect the in situ characteristics of malignant epithelium is greatly needed. We have successfully established a neoplastic immortalized human prostate epithelial (HPE) cell culture derived from a primary tumor. The RC-9 cells transduced through infection with a retrovirus vector expressing the E6 and E7 genes (E6E7) of human papilloma virus-16 (HPV-16) are currently growing well at passage 40, whereas RC-9 cells senesced at passage 7. RC-9/E6E7 cells exhibit epithelial morphology and high level of telomerase activity. More importantly, these immortalized cells produced tumors (SCID5038D) when inoculated into SCID mice. RC-9/E6E7 cells and SCID-5038D cells exhibit a high level of telomerase activity and androgen-responsiveness when treated with R1881. Expression of prostate specific antigen (PSA), androgen receptor (AR), prostate stem cell antigen (PSCA), an androgen-regulated prostate specific gene (NKX3.1), p16, cytokeratins 8, 15 and HPV-16 E6 gene was detected in both of these cells. RC-9/E6E7 and SCID5038D cells also showed growth inhibition when exposed to retinoic acid and transforming growth factor (TGF)-beta1, potent inhibitors of prostate epithelial cell growth. A number of chromosome alterations were observed including the loss of chromosomes 2p, 3p, 8p, 13, 14, 16, 17, 18, 21 and the gain of 7 and 20 in the tumor cell line (SCID5038D). These results demonstrate that this primary tumor-derived HPE cell line retained its neoplastic phenotypes and its prostate-specific markers and should allow studies to elucidate molecular and genetic alterations involved in prostate cancer. This is the first documented case of a malignant AR and PSA positive established human prostate cancer cell line from a primary tumor of a prostate cancer patient.
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PMID:A novel neoplastic primary tumor-derived human prostate epithelial cell line. 1273 99

A new cell line of human uterine endometrial undifferentiated carcinoma, designated as TMG-L, was established from the metastatic lymph node of 56-year-old patient TMG-L cells have been cultured with Ham's F-12 medium supplemented with 10% FCS and grew as a loosely adherent monolayer with polygonal or spindle-shaped cells exhibiting poor cell-cell contact and piled up against each other, showing a tendency to grow as floating cells. The doubling time of this cell line was about 48 hours, and chromosomal analysis revealed aneuploidy at passage 25. The cells formed tumors in SCID mouse, the histology of which was similar to that of undifferentiated carcinoma component of primary tumor. TMG-L cells showed the loss of expression and membranous localization of either E-cadherin or alpha-catenin, implied corresponding loss of their adhesive function. And this dysfunction implicated the biological aggressive behavior of uterine endometrial undifferentiated carcinoma. This cell line appears to provide a useful system for studying uterine undifferentiated carcinoma in vivo and in vitro.
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PMID:Establishment and characterization of a human uterine endometrial undifferentiated carcinoma cell line, TMG-L. 1297 23

The HSV-1 1716 mutant virus and similar oncolytic herpesviruses deficient in the gamma 34.5 neurovirulence gene are able to reduce the growth of tumors in mice. Here we demonstrate that HSV-1 1716 therapy moderately reduced the growth of tumors of the highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model. This moderate effect on 4T1 tumor growth was likely due to poor replication kinetics of HSV-1 1716 in 4T1 cells. Interestingly, HSV-1 therapy of the primary tumor increased the survival time of mice. Coincident with this increase was a reduction in metastases as determined by quantification of the number of metastatic cells in the lungs. HSV-1 therapy of the primary tumor was also able to reduce the establishment of a second challenge of 4T1 tumors. Moreover, infiltrates of both CD4(+) and CD8(+) T cells were detected in HSV-1 1716-treated tumors. An important role for the T cell infiltrates was confirmed when HSV-1 therapy did not reduce the growth of 4T1 tumors in SCID mice. Collectively, these results demonstrate that an HSV-dependent anti-tumor immune response is required for the reduction in primary 4T1 tumor growth and for the reduction in the establishment of metastases in this tumor model.
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PMID:HSV-1 therapy of primary tumors reduces the number of metastases in an immune-competent model of metastatic breast cancer. 1452 26

In our previous studies, we established a lymphogenous metastatic SCID mouse model using orthotopic implantation of human lung cancer cell lines. However, the lymphogenous metastatic potential of each cell line in our models does not reflect that of a primary tumor. In this study, we made orthotopic implanted models using primary cultured cells from surgically-resected lung cancer tissues. Tissues of 5 patients with non-small cell lung cancer (NSCLC) were applied to a primary culture method using a collagen gel coated flask. Suspensions of 2.0x10(4) cancer cells were injected into the left lung of SCID mice. We could maintain primary culture cells from 2 (FM205 and FT821 cells) of 5 lung cancers, and made orthotopically implanted SCID mouse models. The size of both tumors in implanted sites of the lung increased with time. The FM205 cells microscopically were metastasized to the mediastinum by 4 weeks after implantation and macroscopically metastasized by 16 weeks. The FT821 cells were microscopically metastasized to the mediastinum by 4 weeks after implantation and macroscopically metastasized by 6 weeks. The lymphogenous metastatic potential of these primary culture cells was similar to that of clinical tumors. As the lymphogenous metastatic potential of this model reflects that of the clinical tumor, it is useful for elucidating the mechanism of lymphogenous metastasis and selecting anticancer drugs suitable for an individual patients.
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PMID:Establishment of patient-like SCID mouse model by orthotopically implanting primary cultured cells from surgically-resected lung cancer tissues. 1453 83

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors and a crucial regulator of cellular differentiation. Differentiation-inducing and antiproliferative effects of PPAR-gamma suggest that PPAR-gamma agonists might be useful as effective anticancer agents. Few studies have examined the efficacy of these agonists in animal models of tumorigenesis, and their mechanism(s) of action are still not clear. Our studies indicate higher PPAR-gamma expression in primary tumors from non-small-cell lung cancer (NSCLC) patients when compared to normal surrounding tissue. The expression of PPAR-gamma was also observed in several NSCLC lines. The treatment of lung adenocarcinoma cells (A549) with troglitazone (Tro), a PPAR-gamma ligand, enhanced PPAR-gamma transcriptional activity and induced a dose-dependent inhibition of A549 cell growth. The observed growth arrest was predominantly due to the inhibition of cell proliferation without significant induction of apoptosis. Cell cycle analysis of Tro-treated cells revealed a cell cycle arrest at G(0)/G(1) with concomitant downregulation of G(0)/G(1) cyclins D and E. In addition, Tro treatment stimulated sustained Erk1/2 activation in A549 cells, suggesting the activation of a differentiation-inducing pathway. Furthermore, treatment of A549 tumor-bearing SCID mice with Tro or Pio inhibited primary tumor growth by 66.7% and significantly inhibited the number of spontaneous lung metastatic lesions. Collectively, our data demonstrate that activation of PPAR-gamma impedes lung tumor progression and suggest that PPAR-gamma ligands may serve as potential therapeutic agents for NSCLC.
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PMID:Peroxisome proliferator-activated receptor-gamma activation inhibits tumor progression in non-small-cell lung cancer. 1471 15

Down-regulation of the E-cadherin-mediated cell adhesion system is strongly related to cancer invasion and metastasis. Aberrant CpG hypermethylation in the promoter region of the E-cadherin gene has been shown to be responsible for reduction of E-cadherin expression. The present study was designed to test the hypothesis that the demethylating agent 5-aza-2'-deoxycytidine (AZA) can restore the E-cadherin system and reduce the potential for metastasis. AZA treatment modified the methylation status of the 5' CpG island in the E-cadherin promoter, and induced re-expression of E-cadherin in human cancer cells whose E-cadherin expression had been silenced. The re-expressed E-cadherin was correlated with increased in vitro aggregation and reduced motility. After inoculation of cancer cells (MDA-MB-435S) into the mammary fat pads of mice with severe combined immunodeficiency, the mice were treated for nine consecutive weeks with AZA three times per week i.p. The AZA treatment suppressed both growth of the primary tumor and lung metastasis in comparison with untreated controls, suggesting that the suppression of metastasis may be, at least partly, attributable to restoration of E-cadherin expression. Therefore, inhibition of DNA methylation may be useful for preventing cancer metastasis.
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PMID:5-aza-2'-deoxycytidine restores the E-cadherin system in E-cadherin-silenced cancer cells and reduces cancer metastasis. 1506 2

HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with malignant transformation and aggressive disease. Due to its overexpression in tumor cells and because it has been shown to be immunogenic, this protein represents an excellent target for T-cell immunotherapy. Peptide extracts derived from primary HLA-A*0201-positive (+) HER-2/neu+ human tumors by acid elution (acid cell extracts (ACEs)) were tested for their capacity to elicit in HLA-A*0201 transgenic mice, cytotoxic T lymphocytes (CTLs) lysing HLA-A*0201+ HER-2/neu+ tumor cells. Injections of ACE in transgenic mice induced CTLs capable of specifically lysing HER-2/neu+ tumor cell lines (also including the original HER-2/neu+ primary tumor cells from which the ACEs were derived) in an HLA-A*0201-restricted fashion. Adoptive transfer of ACE-induced CTLs was sufficient to significantly prolong survival of SCID mice inoculated with HLA-A*0201+ HER-2/ neu+ human tumor cell lines. Cytotoxicity of such ACE-induced CTL lines was directed, at least as detected herein, also against the HER-2/ neu peptides HER-2 (9(369)) and HER-2 (9(435)) demonstrating the immunodominance of these epitopes. HER-2 peptide-specific CTLs generated in the HLA-A*0201-transgenic mice, upon peptide immunization, lysed in vitro HER-2/neu+ human tumor cell lines in an HLA-A*0201-restricted manner and, when adoptively transferred, conferred sufficient protection in SCID mice inoculated with the same human tumor cell lines as above. However, CTLs induced by ACEs displayed enhanced efficacy in the therapy of xenografted SCID mice compared with the HER-2 peptide-specific CTLs (i.e., HER-2 [9(369)] or HER-2 [9(435)]). Even by administering mixtures of CTLs specific for each of these peptides, the prolongation of survival achieved was still inferior compared with that obtained with ACE-induced CTLs. This suggested that additional epitopes may contribute to the immunogenicity of such tumor-derived ACEs. Thus, immunization with ACEs from HER-2/neu+ primary tumor cells appears to be an effective approach to generate multiple and potent CTL-mediated immune responses against HER-2/neu+ tumors expressing the appropriate HLA allele(s). By screening ACE-induced CTL lines with synthetic peptides encompassing the HER-2/neu sequence, it is feasible to identify immunodominant epitopes which may be used in mixtures as vaccines with enhanced efficacy in both the prevention and therapy of HER-2/neu+ malignancies.
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PMID:Generation of human tumor-specific CTLs in HLA-A2.1-transgenic mice using unfractionated peptides from eluates of human primary breast and ovarian tumors. 1516 33

The expression of integrin alphaV subunit on 4 melanoma-derived cell lines (A2058, SK-mel-5, WM-115 and WM-266-4) was analyzed. WM-115 cells, which originate from a primary tumor, were negative, whereas all 3 metastasis-derived lines had high levels of alphaV. To study alphaV integrins in the survival of melanoma cells, we developed a novel strategy that is exempt from extracellular inhibitors of ligand binding, which can activate integrin signaling and have integrin-independent effects on apoptosis. A recombinant adenovirus was used to transfer cDNA coding for a single-chain intracellular anti-alphaV integrin antibody into the melanoma cells. Anti-alphaV integrin adenovirus effectively inhibited the cell surface expression of alphaV integrins. In cell culture experiments, the depletion of alphaV integrins detached cells from extracellular matrix and induced apoptosis. Moreover, it prevented WM-266-4 cells from forming tumors in severe combined immunodeficiency mice but it could not prevent the growth of tumors that were formed by alphaV-negative WM-115 cells. Our results indicate that in primary melanomas there are cells that survive without alphaV integrins, whereas during the progression of disease cells can develop a dependency on these receptors. Furthermore, the data oppose the possibility that in melanoma cells apoptosis could occur due to direct activation of caspases by ligand-free alphaV integrins on the cell surface.
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PMID:alphaV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma. 1530 76


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