Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiological role of insulin-like growth factor (IGF) II (IGF-II) in adult humans is poorly understood. Rather high levels of IGF-II persist in adult human serum, whereas, in rodents, IGF-II levels are very low. To investigate the physiological and carcinogenic effects of persistently elevated IGF-II in adults, we have produced two lines of transgenic mice in which high levels of IGF-II (20- or 30-fold increase above normal) are persistently maintained in the blood. The transgene is driven by the major urinary protein promoter, and it is highly expressed in the liver and perputial glands in both lines. The adult transgenic mice are smaller than controls, and their body composition is altered. Their lean body mass is reduced by 5-8%, whereas fat mass is reduced between 44 and 77%. The mice expressing the highest level of IGF-II (30x) develop hypoglycemia and hypoinsulinemia and IGF-I levels are normal. Mice in the lower expression line (20-fold elevated IGF-II) develop hypoglycemia progressively over their lifetime. Mice from both lines also develop a diverse spectrum of tumors at a higher frequency than controls after 18 months of age, and the most frequent types of tumors are hepatocellular carcinomas and lymphomas. Squamous cell carcinoma, sarcoma, and thyroid carcinomas also occurred in our test group. The long latent period before tumors arise and the wide spectrum of tumor types suggest that IGF-II may function primarily as a tumor progression factor in mice via autocrine and endocrine mechanisms of action.
 ...
PMID:Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice. 751 93

Since the presence of precursors (pro-forms) of the aspartyl endoprotease, cathepsin D, appears to be linked with tumor progression, their presence was examined in sera and tumor tissues of ovarian cancer patients. The role of cathepsin D pro-forms was further assessed in the dysregulated proliferation and chemoresistance observed in advanced ovarian cancer. Cathepsin D was isolated from sera of ovarian cancer patients (n = 20) and normal volunteers (n = 11), as well as from solubilized normal ovarian epithelium (n = 8) and ovarian epithelial tumor tissue (n = 12). The specific molecular forms of cathepsin D were analyzed in these samples by Western immunoblot. Multiple circulating molecular weight forms of cathepsin D were identified in ovarian cancer patients ranging from 24 to 60 kDa, while in normal controls, a major band was observed at 34 kDa in all samples and minor bands corresponding to 27 and 48 kDa were detected in approximately half of the controls. To assess its consequences on ovarian cancer, the 52-kDa protein was immunoprecipitated from culture medium of an exponentially growing ovarian tumor cell line and was further purified by reverse-phase high-pressure liquid chromatography. Its effect on proliferation was assayed by determining cell doubling times and their chemosensitivity was measured in a standard cytotoxicity assay using cisplatin. In addition, decapeptides corresponding to the pro-portion of cathepsin D were analyzed in parallel. Procathepsin D and one decapeptide, peptide 2, as well as IGF-II (as a known positive) increased cell proliferation, with doubling times of 28.4, 28.8, and 30.3 h, respectively, versus untreated UL-1 cells (36.4 h). Procathepsin D treatment of UL-1 tumor cells significantly increased the cisplatin LD(50) (74.9 microgram/ml) over untreated (33.9 microgram/ml) as well as IGF-II-treated (38.8 microgram/ml) cells. Peptide 2 also showed a significant increase in LD(50) (69.5 microgram/ml) compared to untreated and peptide 1-treated cells (37.1 microgram/ml). There are several unique forms of cathepsin D expressed and accumulated by ovarian tumors and these forms are detectable in the sera of those with ovarian cancer. The presence of these procathepsin D can increase the proliferation of these tumor cells, while decreasing their sensitivity to chemotherapeutic agents. While procathepsin D and IGF-II both enhance proliferation, only procathepsin D (and peptide 2) appears to modulate chemosensitivity, suggesting a separate receptor or pathway for this consequence.
 ...
PMID:Modulation of proliferation and chemosensitivity by procathepsin D and its peptides in ovarian cancer. 1041 29

In adrenocortical tumors, the malignant phenotype is associated with rearrangements (paternal isodisomy) at the 11p15 locus and IGF-II gene overexpression, strongly suggesting that the IGF system is a major determinant of adrenocortical tumor progression. The aim of this study was to validate an in vitro model for investigating the involvement of the IGF system in adrenocortical tumorigenesis. We analyzed the production of IGF mRNA and proteins, IGF-binding proteins (IGFBPs) and IGF receptors by the NCI H295R cell line, which is derived from a human adult adrenocortical carcinoma. H295R cells were shown to proliferate for a long period (26 days) in the absence of serum or any added growth factor. Northern blot analyses showed high IGF-II mRNA contents in H295R cells. The cells secreted large amounts of IGF-II protein (14 ng/10(6) cells per 48 h) although no IGF-I protein was detected. Western ligand blot analyses of conditioned media detected the presence of large amounts of a 34 kDa protein, which was identified as IGFBP-2 by immunoblotting. The presence of high-affinity binding sites for IGF-I and IGF-II on H295R cells was shown by binding experiments using radiolabeled IGFs and confirmed by reverse transcription PCR analyses showing type 1 and type 2 IGF receptors. Proliferation of H295R cells was inhibited by anti-IGF-II antibody (45%) and by anti-type 1 IGF receptor antibody (53%) indicating that IGF-II is an autocrine growth factor for these cells and that its effects are, at least in part, mediated by the type 1 IGF receptor. These findings confirm the involvement of the IGF system in adrenocortical tumors and suggest that the H295R cell line is a suitable in vitro model for studying the molecular mechanisms of adrenocortical tumor proliferation.
 ...
PMID:Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. 1042 44

The desmoplastic response to human breast carcinoma is a host myofibroblast-mediated collagenous response exhibiting synergistic effects on tumor progression. Although many paracrine interactions between breast carcinoma cells and myofibroblasts have been characterized, the event(s) which initiate desmoplasia have remained undefined. Our studies utilized c-rasH transfected MCF-7 cells which overexpress ras p2l and which are weakly tumorigenic in ovariectomized nude mice. The xenografts are desmoplastic and comprised of 30% myofibroblasts and 60 mg/g of interstitial collagen. In situ hybridization studies of these xenografts reveal a stromal gene expression pattern (stromelysin-3, IGF-II and TIMP-1) identical to that observed in human tumor desmoplasia. 17-beta estradiol increases c-rasH MCF-7 growth but abolishes desmoplasia. c-rasH MCF-7 in vitro constitutively produce myofibroblast mitogenic activity which competes with PDGF in a receptor binding assay. This myofibroblast mitogenic activity is unaltered by 17-beta estradiol/tamoxifen pretreatment in vitro. Transfection of c-rasH MCF-7 with a PDGF-A dominant negative mutant, 1308, produced by site-directed mutagenesis (serine-->cysteine129) reduces both homo- and heterodimer secretion of PDGF by as much as 90% but does not interfere with the secretion of other growth factors. Clones with low PDGF, though tumorigenic, are non-desmoplastic. Our results suggest that breast carcinoma-secreted PDGF is the major initiator of tumor desmoplasia.
 ...
PMID:Human breast carcinoma desmoplasia is PDGF initiated. 1098 Jun 9

Nonsteroidal anti-inflammatory drugs reduce the risk of colon cancer and this effect is mediated in part through inhibition of type 2 prostaglandin endoperoxide synthase/ cyclo-oxygenase (COX-2). In the present study, we demonstrate that COX-2 expression and PGE2 synthesis are up-regulated by an IGF-II/IGF-I receptor autocrine pathway in Caco-2 colon carcinoma cells. COX-2 mRNA and PGE2 levels are higher in proliferating cells compared with post-confluent differentiated cells and in cells that constitutively overexpress IGF-II. Up-regulation of COX-2 expression by IGF-II is mediated through activation of IGF-I receptor because: (i) treatment of Caco-2 cells with a blocking antibody to the IGF-I receptor inhibits COX-2 mRNA expression; (ii) transfection of Caco-2 cells with a dominant negative IGF-I receptor reduces COX-2 expression and activity. Also, the blockade of the PI3-kinase, that mediates the proliferative effect of IGF-I receptor in Caco-2 cells, inhibits IGF-II-dependent COX-2 up-regulation and PGE2 synthesis. Moreover, COX-2 expression and activity inversely correlate with the increase of apoptosis in parental, IGF-II and dominant-negative IGF-I receptor transfected cells. This study suggests that induction of proliferation and tumor progression of colon cancer cells by the IGF-II/IGF-I receptor pathway may depend on the activation of COX-2-related events.
 ...
PMID:IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PGE2 synthesis in Caco-2 human colon carcinoma cells. 1111 29

The epithelium to mesenchyme transition is thought to play a fundamental role during embryonic development and tumor progression. Loss of cell-cell adhesion and modification of both cell morphology and gene expression are the main events associated with this transition. There is a large amount of evidence suggesting that growth factors can initiate these events. Yet, the connection from growth factor induction to changes in cell adhesion and morphology is largely unknown. To elucidate this connection, we have investigated the action of IGF-II on E-cadherin/beta-catenin complex-mediated cell-cell adhesion and on beta-catenin/TCF-3 mediated gene expression. We can show that (1) IGF-II induces a rapid epithelium to mesenchymal transition; (2) IGF1R, the receptor for IGF-II, belongs to the same membrane complex as E-cadherin and beta-catenin; (3) IGF-II induces a redistribution of beta-catenin from the plasma membrane to the nucleus and an intracellular sequestration and degradation of E-cadherin; (4) IGF-II induces the transcription of beta-catenin/TCF-3 target genes. Based on the given case of IGF-II and E-cadherin/beta-catenin complex, this study reveals the backbone of a cascade connecting growth factor signaling with cell-cell adhesion during EMT.
 ...
PMID:IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition. 1152 79

Glypican-3 (GPC3), a proteoglycan bound to the cell membrane through a GPI anchor, is widely expressed in the embryo but down regulated in most adult tissues, with some exceptions as mammary cells. GPC3 is involved in the regulation of cell proliferation and survival in specific cell types. LM3, a murine mammary tumor cell line unable to express GPC3, was stably transfected with the rat GPC3 gene to analyze its role in tumor progression. Upon injection into syngeneic BALB/c mice LM3-GPC3 clones showed less local invasiveness and developed fewer spontaneous and experimental lung metastasis than controls. GPC3-expressing cells were more sensitive to apoptosis induced by serum depletion, exhibited a delay in the first steps of spreading and were less motile than controls. On the other hand, LM3-GPC3 cells were significantly more adherent to FN than control ones. We observed that GPC3 transfectants presented a higher expression of E-cadherin and beta-catenin, molecules whose down regulation has been associated with tumor progression. Exogenous TGF-beta increased MMP-9 activity in both control and GPC3-expressing cells, but did not modulate MMP-2. Contrarily, GPC3 expression prevented the increase of MMP-2 activity induced by IGF-II. Our results suggest that GPC3 has a protective role against mammary cancer progression.
 ...
PMID:Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model. 1290 26

Constitutive activation of Akt has been found in many types of human cancer, and is believed to promote proliferation and increased cell survival thereby contributing to cancer progression. In this study, we examined Akt phosphorylation on Ser473 and Thr308 in seven IGF-II-overexpressing rhabdomyosarcomas (RMS) cells. All the RMS cell lines tested had high levels of Akt phosphorylation on Thr308, whereas three cell lines (Rh5, Rh18, and CTR) had a much lower level of Akt phosphorylation on Ser473. To determine whether the difference in Akt phosphorylation on Ser473, but not on Thr308, observed among cell lines is a cell-specific phenomenon or due to other factors, which possibly downregulate Akt phosphorylation, we examined expression of PTEN protein, which acts as a negative regulator of the PI3K/Akt signaling pathway through its ability to dephosphorylate phosphatidylinositol 3,4,5-triphosphate (PIP3). The levels of PTEN expression inversely correlate with Akt phosphorylation on Ser473, but not on Thr308. Consistent with this finding, transfection of wild-type PTEN into RMS and mouse myoblast C2C12 cells resulted in reduced Akt phosphorylation on Ser473, but not on Thr308. Our data suggest that Ser473 may be a key target residue for PTEN to modulate the effects of IGF-II on activating the PI3K/Akt pathway in RMS cells. A better understanding of the pathway in RMS will likely contribute to insights into the biology of the RMS tumorigenesis and hopefully lead to novel therapeutic options.
 ...
PMID:Levels of PTEN protein modulate Akt phosphorylation on serine 473, but not on threonine 308, in IGF-II-overexpressing rhabdomyosarcomas cells. 1460 61

For more than a century, the role of wound healing in the growth of tumours has been implied based on observations in experimental and clinical studies. In the recent 10-15 years processes such as cell adhesion, angiogenesis, metastatic cascade and growth factors (fe: EGF, TGF-alpha, TGF-beta, IGF-1, IGF-II, PDGF) have been identified to play key roles in different stages of wound healing as well as in tumor progression. Experimental and clinical studies have established that wound healing creates a suitable environment favouring tumour growth and metastatic potential. Based on these observations, the clinical relevance of surgical procedures comes up, may playing a role in tumor recurrence after primary resection for cancer. This makes the opportunity of the development of completely new targeted approaches (antiangiogenic therapy, dormancy therapy) for the treatment of cancer. This review article is based on a case report of a 63-year-old female patient who had colonic adenocarcinoma metastasis of the hand after biting by a dog.
 ...
PMID:[The similarities between the mechanism of wound healing and tumor development--literature review on the occasion of a patient with colonic adenocarcinoma metastasis in a dog-bite wound]. 1569 41

The mammalian insulin-like growth factor (IGF)-II/cation-independent mannose 6-phosphate receptor (IGF2R) binds IGF-II with high affinity. By targeting IGF-II to lysosomal degradation, it plays a role in the maintenance of correct IGF-II levels in the circulation and in target tissues. Loss of IGF2R function is associated with tumor progression; therefore, the IGF2R is often referred to as a tumor suppressor. The interaction between IGF2R and IGF-II involves domains 11 and 13 of the 15 extracellular domains of the receptor. Recently, a hydrophobic binding region was identified on domain 11 of the IGF2R. In contrast, relatively little is known about the residues of IGF-II that are involved in IGF2R binding and the determinants of IGF2R specificity for IGF-II over the structurally related IGF-I. Using a series of novel IGF-II analogues and surface plasmon resonance assays, this study revealed a novel binding surface on IGF-II critical for IGF2R binding. The hydrophobic residues Phe(19) and Leu(53) are critical for IGF2R binding, as are residues Thr(16) and Asp(52). Furthermore, Thr(16) was identified as playing a major role in determining why IGF-II, but not IGF-I, binds with high affinity to the IGF2R.
 ...
PMID:A novel binding site for the human insulin-like growth factor-II (IGF-II)/mannose 6-phosphate receptor on IGF-II. 1747 26


1 2 3 Next >>