Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study has investigated the impact of three specific dominant-negative p53 mutants (F134L, M237L, and R273H) on tumorigenesis by LNCaP prostate cancer cells. Mutant p53 proteins were associated with an increased subcutaneous "take rate" in NOD-SCID mice, and increased production of PSA. Tumors expressing F134L and R273H grew slower than controls, and were associated with decreased necrosis and apoptosis, but not hypoxia. Interestingly, hypoxia levels were increased in tumors expressing M237L. There was less proliferation in F134L-bearing tumors compared to control, but this was not statistically significant. Angiogenesis was decreased in tumors expressing F134L and R273H compared with M237L, or controls. Conditioned medium from F134L tumors inhibited growth of normal human umbilical-vein endothelial cells but not telomerase-immortalized bone marrow endothelial cells. F134L tumor supernatants showed lower levels of VEGF and endostatin compared with supernatants from tumors expressing other mutants. Our results support the possibility that decreased angiogenesis might account for reduced growth rate of tumor cells expressing the F134L p53 mutation.
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PMID:Over-expression of p53 mutants in LNCaP cells alters tumor growth and angiogenesis in vivo. 1672 21

Recent advances in stem cell biology enable us to identify cancer stem cells in solid tumors as well as putative stem cells in normal solid organs. In this study, we applied side population (SP) cell analysis and sorting to established hepatocellular carcinoma (HCC) cell lines to detect subpopulations that function as cancer stem cells and to elucidate their roles in tumorigenesis. Among four cell lines analyzed, SP cells were detected in Huh7 (0.25%) and PLC/PRF/5 cells (0.80%), but not in HepG2 and Huh6 cells. SP cells demonstrated high proliferative potential and anti-apoptotic properties compared with those of non-SP cells. Immunocytochemistry examination showed that SP fractions contain a large number of cells presenting characteristics of both hepatocyte and cholangiocyte lineages. Non-obese diabetic/severe combined immunodeficiency (NOD/SCID) xenograft transplant experiments showed that only 1 x 10(3) SP cells were sufficient for tumor formation, whereas an injection of 1 x 10(6) non-SP cells did not initiate tumors. Re-analysis of SP cell-derived tumors showed that SP cells generated both SP and non-SP cells and tumor-initiating potential was maintained only in SP cells in serial transplantation. Microarray analysis discriminated a differential gene expression profile between SP and non-SP cells, and several so-called "stemness genes" were upregulated in SP cells in HCC cells. In conclusion, we propose that a minority population, detected as SP cells in HCC cells, possess extreme tumorigenic potential and provide heterogeneity to the cancer stem cell system characterized by distinct hierarchy.
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PMID:Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. 1679 70

ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Galectins are a family of animal lectins that function both extracellularly (by interacting with cell surface and extracellular matrix glycoproteins and glycolipids) and intracellularly (by interacting with cytoplasmic and nuclear proteins) to modulate signaling pathways. We found that protease-resistant galectin-9 by modification of its linker peptide, hG9NC(null), prevented cell growth of HTLV-I-infected T-cell lines and primary ATL cells. The suppression of cell growth was inhibited by lactose, but not by sucrose, indicating that beta-galactoside binding is essential for hG9NC(null)-induced cell growth suppression. hG9NC(null) induced cell cycle arrest by reducing the expression of cyclin D1, cyclin D2, cyclin B1, Cdk1, Cdk4, Cdk6, Cdc25C and c-Myc, and apoptosis by reducing the expression of XIAP, c-IAP2 and survivin. Most of these genes are regulated by NF-kappaB, which plays a critical role in oncogenesis by HTLV-I. hG9NC(null) suppressed IkappaBalpha phosphorylation, resulting in suppression of NF-kappaB. Most importantly, treatment with hG9NC(null) (6.7 mg/kg injected intraperitoneally every day) reduced tumor formation from an HTLV-I-infected T-cell line when these cells were inoculated subcutaneously into SCID mice. Our results suggest that hG9NC(null) could be a suitable agent for the management of ATL.
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PMID:A modified version of galectin-9 suppresses cell growth and induces apoptosis of human T-cell leukemia virus type I-infected T-cell lines. 2196 Feb 63

Emerging reports are conclusively demonstrating the mutagenic risks involved in using retroviral vectors for gene therapy. Animal studies, as well as cases from a human clinical trial, have proven the potential of insertional leukemogenesis caused by a retroviral vector. Here, we report the observation of six T-lymphoblastic leukemia cases arising during the course of a gene therapy study for hemophilia B after transplantation of ex vivo transduced hematopoietic stem cells (HSCs) by a lentivirus vector. Three of these animals comprised secondary recipients of the same donor and LAM-PCR was performed to identify the vector integration loci. We located integrations in repeat elements of known genes, including a candidate brain-tumor locus, but none of these clones could be tracked in the leukemic blasts. Although transduced clones with an intact proviral cassette were detected in the spleen of the leukemic animals, they comprised a very small proportion, not correlating to the levels of leukemic blasts. After propagation of the latter in NOD/SCID mice, we could no longer detect the proviral cassette suggesting that the leukemic blasts were untransduced. We did, however, detect increased levels of reverse transcriptase activity in the leukemic blasts which may suggest activation of endogenous retroviruses. This study demonstrates that tumors arising in these type of gene therapy protocols are not necessarily due to vector insertional mutagenesis and highlights the importance of careful functional studies to delineate the nature of tumorigenesis.
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PMID:Murine leukemia following irradiation conditioning for transplantation of lentivirally-modified hematopoietic stem cells. 1737 92

Nonhomologous end joining (NHEJ) is a critical DNA repair pathway, with proposed tumor suppression functions in many tissues. Mutations in the NHEJ factor ARTEMIS cause radiation-sensitive severe combined immunodeficiency in humans and may increase susceptibility to lymphoma in some settings. We now report that deficiency for Artemis (encoded by Dclre1c/Art in mouse) accelerates tumorigenesis in several tissues in a Trp53 heterozygous setting, revealing tumor suppression roles for NHEJ in lymphoid and non-lymphoid cells. We also show that B-lineage lymphomas in these mice undergo loss of Trp53 heterozygosity by allele replacement, but arise by mechanisms distinct from those in Art Trp53 double null mice. These findings demonstrate a general tumor suppression function for NHEJ, and reveal that interplay between NHEJ and Trp53 loss of heterozygosity influences the sequence of multi-hit oncogenesis. We present a model where p53 status at the time of tumor initiation is a key determinant of subsequent oncogenic mechanisms. Because Art deficient mice represent a model for radiation-sensitive severe combined immunodeficiency, our findings suggest that these patients may be at risk for both lymphoid and non-lymphoid cancers.
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PMID:The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity. 1738 73

Retinoblastoma (RB) is the most common malignant tumor of the retina in human children. Although it has been hypothesized for a long time that RB derives from multipotent retinal stem cells (RSCs) or retinoblasts, the direct evidence that the presence of tumorigenic RSCs in RB tumors is still lacking. Some studies indicate that malignant tumors contain tumor stem cells similar to their normal tissue stem cell counterparts. With in vitro culture and differentiation method we demonstrate that tumorigenic retinal stem-like cells (RSLCs) indeed exist in RB lesions and that RB tumor-derived cultures encompass undifferentiated cells capable of extensive proliferation as clonal nonadherent neurospheres and can differentiate into different retinal cells in vitro. Interestingly, cultured cells expressed retinal development related genes including nestin, CD133, pax6, chx10 and Rx, and overexpressed Bmi-1, a gene required for self-renewal and proliferation of stem cells. Significantly, when these cultured cells were intraocularly transplanted into SCID mice, they gave rise to new tumors with histomorphological features and immunophenotypes similar to their parental primary RBs. The results show that RBs contain tumorigenic RSLCs that contribute to tumorigenesis. This study provides a new insight to investigate the histogenesis of RBs and establishes a model for other RB research.
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PMID:Identification of tumorigenic retinal stem-like cells in human solid retinoblastomas. 1756 41

PTEN mutations are among the most frequent genetic alterations found in human prostate cancers. Our previous works suggest that although precancerous lesions were found in Pten heterozygous mice, cancer progression and metastasis only happened when both alleles of Pten were deleted. To understand the molecular mechanisms underlying the role of PTEN in prostate cancer control, we generated two pairs of isogenic, androgen receptor (AR)-positive prostate epithelial lines from intact conditional Pten knock-out mice that are either heterozygous (PTEN-P2 and -P8) or homozygous (PTEN-CaP2 and PTEN-CaP8) for Pten deletion. Further characterization of these cells showed that loss of the second allele of Pten leads to increased anchorage-independent growth in vitro and tumorigenesis in vivo without obvious structural or numerical chromosome changes based on SKY karyotyping analysis. Despite no prior exposure to hormone ablation therapy, Pten null cells are tumorigenic in both male and female severe combined immunodeficiency mice. Furthermore, knocking down PTEN can convert the androgen-dependent Myc-CaP cell into androgen independence, suggesting that PTEN intrinsically controls androgen responsiveness, a critical step in the development of hormone refractory prostate cancer. Importantly, knocking down AR by shRNA in Pten null cells reverses androgen-independent growth in vitro and partially inhibited tumorigenesis in vivo, indicating that PTEN-controlled prostate tumorigenesis is AR dependent. These cell lines will serve as useful tools for understanding signaling pathways controlled by PTEN and elucidating the molecular mechanisms involved in hormone refractory prostate cancer formation.
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PMID:Murine cell lines derived from Pten null prostate cancer show the critical role of PTEN in hormone refractory prostate cancer development. 1761 63

Werner syndrome (WS) is a premature aging and cancer-prone disease caused by loss of the RecQ helicase WRN protein. Cultured WS fibroblasts display high genomic instability and senesce prematurely. Epigenetic inactivation of the WRN gene occurs in numerous tumor types, in which WRN demonstrates tumor suppressor-like activity (Agrelo et al., 2006). However, the role of WRN in tumors that express WRN protein is unknown. Here we report that the inhibition of WRN expression strongly impairs growth of 12 out of 15 cancer cell lines tested. For those cell lines in which WRN depletion induced high cell death, the majority of the surviving proliferative clones exhibited WRN expression. Growth arrest induced by WRN depletion was characterized by an accumulation of cells in the G2/M cell cycle phases and an increase in DNA damage. Importantly, WRN depletion inhibited tumor growth in vivo in SCID mouse xenograft models. Altogether, these findings support a dual role for WRN in tumorigenesis; tumor suppressor-like activity in tumors with WRN inactivation and the promotion of proliferation and survival in tumors that express WRN. These findings suggest a possible therapeutic role for WRN as an anti-cancer target, and highlight the importance of WRN protein status for tumorigenesis and clinical treatments of patients.
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PMID:Role for the Werner syndrome protein in the promotion of tumor cell growth. 1762 10

The reproductive hormone environment is an important influence upon spontaneous ovarian granulosa cell (GC) tumor development in genetically susceptible (SWR x SWXJ-9) F1 female mice: androgenic support during puberty stimulates tumorigenesis, while exposure to 17beta-estradiol (E(2)) suppresses tumor initiation. We sought to determine whether gonadotropic stimulation was sufficient to initiate GC tumors in a grafted model system, and to determine the potential for dietary isoflavones (genistein and daidzein) as alternatives to E(2) for tumor chemoprevention in vivo. Isolated ovaries from pre-pubertal (SWR x SWXJ-9) F1 females were transferred to the kidney capsule of host mice homozygous for the hypogonadal (hpg/hpg) and severe combined immunodeficiency (scid/scid) mutations. CB17; HPG-Prkdc(scid) Gnrh1(hpg)/Bm host mice received either follicle-stimulating hormone (FSH), or a functional analog for LH human chorionic gonadotropin for 2 consecutive weeks, at which time the ovary grafts were examined for evidence of tumor initiation. LH analog administration, but not FSH, initiated GC tumorigenesis in the graft system, suggesting that the LH surge at puberty initiates GC tumor development in genetically susceptible female mice. To assess the chemopreventive potential of phytoestrogens, GC tumor frequency was compared between (SWR x SWXJ-9) F1 females reared on an isoflavone-free diet versus a diet supplemented with 125 mug/g each of the isoflavones daidzein and genistein. It was observed that (SWR x SWXJ-9) F1 females reared on isoflavone-supplemented diet maintained significantly higher GC tumor frequency (22%) than females reared on isoflavone-free diet (11%), and that non-tumor-bearing siblings reared on the isoflavones had significantly increased ovarian weight, indicative of an overall stimulation of the reproductive hormone axis. The stimulation of GC tumorigenesis by isoflavones, which contrasts with the chemopreventive action of E(2) (2.5 mg/kg) administration during pubertal maturation, may result from general stimulation of ovarian growth, and the inability of the genistein and daidzein supplements to suppress LH secretion.
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PMID:LH analog and dietary isoflavones support ovarian granulosa cell tumor development in a spontaneous mouse model. 1763 51

The ability of CCL2 to influence prostate cancer tumorigenesis and metastasis may occur through two distinct mechanisms: 1) a direct effect on tumor cell growth and function, and 2) an indirect effect on the tumor microenvironment by the regulation of macrophage mobilization and infiltration into the tumor bed. We have previously demonstrated that CCL2 exerts a direct effect on prostate cancer epithelial cells by the regulation of their growth, invasion, and migration, resulting in enhanced tumorigenesis and metastasis. Here we describe an indirect effect of CCL2 on prostate cancer growth and metastasis by regulating monocyte/macrophage infiltration into the tumor microenvironment and by stimulating a phenotypic change within these immune cells to promote tumor growth (tumor-associated macrophages). VCaP prostate cancer cells were subcutaneously injected in male SCID mice and monitored for tumor volume, CD68(+) macrophage infiltration, and microvascular density. Systemic administration of anti-CCL2 neutralizing antibodies (CNTO888 and C1142) significantly retarded tumor growth and attenuated CD68(+) macrophage infiltration, which was accompanied by a significant decrease in microvascular density. These data suggest that CCL2 contributes to prostate cancer growth through the regulation of macrophage infiltration and enhanced angiogenesis within the tumor.
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PMID:CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. 1771 Jan 58


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