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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human epidermal growth factor (EGF) receptor (HER) family of receptor tyrosine kinases has frequently been implicated in cancer. Apart from overexpression or mutation of these receptors, also the aberrant autocrine or paracrine activation of HERs by EGF-like ligands may be important in cancer progression. Neuregulins constitute a family of EGF-like ligands that bind to HER3 or HER4, preferably forming heterodimers with the orphan receptor HER2. Mesenchymal neuregulin typically serves as a pro-survival and pro-differentiation signal for adjacent epithelia. Disruption of the balance between proliferation and differentiation, because of autocrine production by the epithelial cells, increased sensitivity to paracrine signals or disruption of the spatial organization, may lead to constitutive receptor activation, in the absence of receptor overexpression. Consequently, the analysis of ligand expression and/or activated receptors in tumor samples may broaden the group of patients that can benefit from targeted therapies.
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PMID:Roles for neuregulins in human cancer. 1603 12

Lethal phenotypes of human prostate cancer are characterized by progression to androgen independence, although the mechanisms behind this progression remain unclear. Arsenic is a potential human prostate carcinogen that may affect tumor progression. In this study, we used a prostate cancer cell model in which an immortalized, nontumorigenic human prostate epithelial cell line (RWPE-1) had been malignantly transformed by chronic low-level arsenic to help determine whether arsenic affects prostate tumor progression. Control and CAsE-PE (chronic-arsenic-exposed human prostate epithelial) cells were continuously maintained in a complete medium [keratinocyte serum-free medium (K-SFM) with bovine pituitary extract and epidermal growth factor] or in a steroid-depleted medium (K-SFM alone). The arsenic-transformed cells showed a more rapid proliferation rate in complete medium than did control cells and also showed sustained proliferation in steroid-reduced medium. Although both control and CAsE-PE cells showed similar levels of androgen receptor (AR), androgens were less effective in stimulating cell proliferation and AR-related gene expression in CAsE-PE cells. For instance, dihydrotestosterone caused a 4.5-fold increase in prostate-specific antigen transcript in control cells but only a 1.5-fold increase in CAsE-PE cells. CAsE-PE cells also showed relatively low levels of growth stimulation by nonandrogen steroids, such as estradiol. Thus, arsenic-induced malignant transformation is associated with acquired androgen independence in human prostate cells. This acquired androgen independence was apparently not due to AR up-regulation, increased activity, or altered ligand specificity. The precise manner in which arsenic altered CAsE-PE growth and progression is undefined but may involve a bypass of AR involving direct stimulation of downstream signaling pathways.
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PMID:Acquisition of androgen independence by human prostate epithelial cells during arsenic-induced malignant transformation. 1614 Jun 17

Rapid repair of mucous epithelia is essential for preventing inflammation which is a critical component of cancer progression. 'Restitution' is an early repair process which can begin within minutes and is achieved via the migration of neighbouring cells into the wounded area. Mucosal restitution is a multistep process which requires continuous blood flow and includes at least (i) the reduction of cell-cell contacts and a shift in the cell shape towards a migratory phenotype (characteristics of the epithelial-mesenchymal transition), (ii) migration of cells, (iii) repolarization and formation of tight junctions (morphological restitution) and (iv) restoration of barrier function (transmucosal epithelial resistance, functional restitution). Secretory TFF (trefoil factor family) peptides TFF1, TFF2 and TFF3 are well known for their potent protective and healing effects after mucosal damage (function as 'luminal surveillance peptides'). Here, the contributions of the TFFs during the different steps of mucosal restitution are discussed, i. e. the modulation of cell-cell contacts, their motogenic activity and synergy with epidermal growth factor, their anti-apoptotic and pro-angiogenic effects. Special emphasis has been given to discussion of the various signal transduction networks triggered by TFFs. It is becoming increasingly clear that these pathways differ depending on the respective TFF.
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PMID:Trefoil factors TFF (trefoil factor family) peptide-triggered signals promoting mucosal restitution. 1637 81

Sphingosine 1-phosphate (S1P) the product of sphingosine kinase (SK) action plays an important role in various pathological conditions like inflammation and cancer. In this study, we show that in the human breast cancer cell line MCF7, epidermal growth factor (EGF) stimulates SK-1 activity in a biphasic manner with a first peak after 15 min and a second delayed activation occurring after 1 h up to 18 h and thereafter declining again. This delayed activation is accompanied by increased mRNA and protein expression of SK-1, but not SK-2. Mechanistically, the transcriptional upregulation is dependent on the classical mitogen-activated protein kinase, protein kinase C (PKC) and the phosphoinositide 3-kinase, since specific inhibitors of these enzymes all abolish the EGF-induced mRNA upregulation and activity of SK-1. Moreover, dexamethasone also suppressed EGF-induced SK-1 mRNA expression and activity which is reversed by the glucocorticoid receptor antagonist RU486. To see whether EGF-induced upregulation of SK-1 is of relevance for tumor progression, we investigated two hallmarks of carcinogenesis, i.e., cell proliferation and migration. Stimulation of cells with EGF leads to enhanced [(3)H]thymidine incorporation into DNA and also to stimulated migration in a modified Boyden chamber assay. When cells are depleted of SK-1, but not SK-2, by siRNA transfection or by dexamethasone treatment, EGF-induced proliferation and migration are drastically reduced. In summary, these data show that EGF causes an acute stimulation of SK-1 activity and, moreover, triggers a delayed SK activation which is due to increased gene transcription and de novo synthesis of SK-1, which in turn directs cells towards growth and increased motility. Thus, the sphingosine kinase-1 may represent a novel attractive target for cancer therapy.
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PMID:The epidermal growth factor stimulates sphingosine kinase-1 expression and activity in the human mammary carcinoma cell line MCF7. 1641 7

Neuropilins (NRP) are membranous receptors capable of binding two disparate ligands, class 3 semaphorins (SEMA) and vascular endothelial growth factors (VEGF), and regulating two diverse systems, neuronal guidance and angiogenesis. The neuropilin genes, NRP1 and NRP2, share similar protein structure, but differ in their expression patterns, regulation, and ligand-binding specificities. NRPs vary in their expression patterns; for example, endothelial cells express both NRP1 and NRP2, lymphatic endothelial cells predominantly express NRP2, and epidermal cells predominantly express NRP1. NRP expression can be differentially regulated by transcription factors, e.g. prox-1 induces NRP2 while suppressing NRP1, or by growth factors, e.g. epidermal growth factor (EGF) induces NRP1 but not NRP2. Nearly all tumor cells express NRP1, NRP2, or both. Carcinomas express NRP1, whereas neuronal tumors and melanomas predominantly express NRP2. SEMAs play a role in neoplasms as angiogenesis inhibitors. For example, SEMA3F, which binds specifically to NRP2, inhibits tumor angiogenesis and metastasis. Metastatic tumor cells lose SEMA3F expression during progression. Therefore, SEMA3F may have therapeutic potential. This article focuses on the role of NRPs and SEMAs in tumor progression and angiogenesis.
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PMID:Neuropilins in neoplasms: expression, regulation, and function. 1644 11

The matricellular protein SPARC (secreted protein acidic and rich in cysteine) has been implicated in development, differentiation, response to injury, and tumor biology by virtue of its regulation of extracellular matrix production/assembly and its antiadhesive and antiproliferative effects on different cell types. Despite numerous biological activities described for SPARC, cell surface receptors for this protein have not been identified. By phage display and in vitro-binding assays, we now show that SPARC interacts with stabilin-1, a scavenger receptor expressed by tissue macrophages and sinusoidal endothelial cells. The interaction is mediated by the extracellular epidermal growth factor-like region of stabilin-1 containing the sequence FHGTAC. Using FACS analysis and confocal microscopy, we demonstrate that stabilin-1 internalizes and targets SPARC to an endosomal pathway in Chinese hamster ovary cells stably transfected with this receptor. In human macrophages, stabilin-1 expression is required for receptor-mediated endocytosis of SPARC. SPARC was efficiently endocytosed by alternatively activated macrophages stimulated by IL-4 and dexamethasone, but not solely by Th1 or Th2 cytokines. A time course of ligand exposure to alternatively activated macrophages revealed that stabilin-1-mediated endocytosis of SPARC was followed by its targeting for degradation, similar to the targeting of acetylated low density lipoprotein, another stabilin-1 ligand. We propose that alternatively activated macrophages coordinate extracellular matrix remodeling, angiogenesis, and tumor progression via stabilin-1-mediated endocytosis of SPARC and thereby regulate its extracellular concentration.
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PMID:Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. 1667 Feb 88

Protein kinase C (PKC) zeta has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCzeta is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCzeta expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCzeta expression from normal to malignant tissue. PKCzeta activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCzeta using either kinase-dead PKCzeta mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCzeta inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCzeta is associated with SCCHN progression, (b) PKCzeta mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCzeta mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCzeta inhibitors function additively with other inhibitors that target similar or complementary signaling pathways.
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PMID:Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase. 1677 6

In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for tissue regeneration and cancer therapies. We describe new procedures for derivation and maturation of these stem cells into the tissue-specific cell progenitors. The localization of the adult stem cells and their niches, as well as their implication in the tissue repair after injuries and during cancer progression, are also described. The emphasis is on the interactions among certain developmental signaling factors, such as hormones, epidermal growth factor, hedgehog, Wnt/beta-catenin, and Notch. These factors and their pathways are involved in the stringent regulation of the self-renewal and/or differentiation of adult stem cells. Novel strategies for the treatment of both diverse degenerating disorders, by cell replacement, and some metastatic cancer types, by molecular targeting multiple tumorigenic signaling elements in cancer progenitor cells, are also illustrated.
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PMID:Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies. 1679 64

Prostaglandin E(2) (PGE(2)), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE(2) is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is down-regulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE(2) catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE(2) to inhibit cancer progression.
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PMID:Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression. 1681 38

In order to find a suppressor(s) of tumor progression in vivo for oral carcinoma (OC), we searched for molecules down-regulated in OC cells when the cells were treated with epidermal growth factor (EGF), whose receptor is frequently over-activated in OC. The expression of BRAK, which is also known as CXC chemokine ligand14 (CXCL14), was down-regulated significantly by the treatment of OC cells with EGF as observed by cDNA microarray analysis followed by reverse-transcriptase polymerase chain reaction analysis. The EGF effect was attenuated by the co-presence of a MEK inhibitor. The rate of tumor formation in vivo of BRAK-expressing vector-transfected tumor cells in athymic nude mice was significantly lower than that of mock vector-transfected ones. In addition tumors formed in vivo by the BRAK-expressing cells were significantly smaller than those of the mock-transfected ones. These results indicate that BRAK/CXCL14 is a chemokine, having suppressive activity toward tumor progression of OC in vivo.
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PMID:BRAK/CXCL14 expression suppresses tumor growth in vivo in human oral carcinoma cells. 1688 87


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