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PubMed2001

Oncogenes, growth factors, receptor expression and proliferation markers in digestive neuroendocrine tumours. A critical reappraisal.

BACKGROUND: The main characteristic of the digestive neuroendocrine tumours (dNETs) is the low proliferating activity, even in the presence of malignant, metastatic behavior. PATIENTS AND METHODS: Considering that dNETs are rare diseases, relatively numerous studies, often including a conspicuous number of patients, have recently investigated the molecular mechanisms of neuroendocrine tumour genesis. RESULTS: In contrast to non-endocrine tumours of the digestive system such as carcinoma of the pancreas, colon and stomach, dNETs do not show alterations in oncogenes (ras, Myc, fos jun, Src) or in common tumor suppressor genes [p53, retinoblastoma suspectibility gene (Rb)]. MEN-1 gene alterations will likely be important in a proportion of sporadic dNETs. The role of various growth factors, novel oncogenes and tumour suppressor genes have also been investigated. However, results from these studies are non-conclusive and to date the molecular pathogenesis of these tumours has not been clarified. Studies on somatostatin receptor expression and synthetic analogues, as growth inhibitors in dNETs, although promising, have not reproduced in vivo all the antiproliferative effects showed in in vitro models. CONCLUSION: Although various functional genes and molecular mechanisms have been investigated in dNETs, to date the molecular pathogenesis of these tumours remains to be elucidated.

Biomarkers, Tumor↗
PubMed1992

Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes.

The type 1 glucose transporter (GLUT1) gene encodes an integral membrane glycoprotein responsible for facilitating transfer of glucose across plasma membrane and is rapidly activated by serum, growth factors, and by oncogenic transformation. To elucidate the molecular mechanisms of regulation of GLUT1 gene expression, we isolated and characterized the mouse GLUT1 gene. DNA elements regulating transcription of the gene were analyzed in transient expression assays after transfection of NIH/3T3 cells with a low background chloramphenicol acetyltransferase (CAT) vector system pSVOOCAT. We identified two enhancer elements; the first one is located 2.7 kilobases upstream of the cap site of the gene which contains the homologous sequences with two 12-O-tetradecanoylphorbol-13-acetate-responsive elements (TREs), a serum response element, a cyclic AMP-responsive element (CRE) and three GC boxes, and the second one is located in the second intron of the gene which contains the homologous sequences with two TREs and one CRE. With the promoter alone the transcription of the gene is activated by src, only slightly activated by ras and is not activated by serum and platelet-derived growth factor. When the gene is accompanied by one of these enhancers, the transcription is activated by all these stimuli.

3T3 Cells↗
PubMedDate not supplied

Proto-oncogenes, growth factor genes, receptor genes, differentiation genes and structural rearrangements in human cancer.

Information on chromosomal structural rearrangements in leukemia and solid tumors was retracted from a computerized databank and the literature. A binomial test procedure was used to determine the statistical significance of the observed numbers of breaks. Some 131 human cancer-specific chromosomal structural rearrangements were also taken from the literature. The results showed that breakage and deletion occurred preferentially in bands known to contain proto-oncogenes, growth factor genes, receptor genes and differentiation genes. Therefore, chromosomal structural rearrangements could be used to find and map new genes involved in the genesis and/or progression of neoplasia.

Cell Differentiation↗
PubMed2001

Functional cloning of the proto-oncogene brain factor-1 (BF-1) as a Smad-binding antagonist of transforming growth factor-beta signaling.

Using the plasminogen activator inhibitor (PAI) promoter to drive the expression of a reporter gene (mouse CD2), we devised a system to clone negative regulators of the transforming growth factor-beta (TGF-beta) signaling pathway. We infected a TGF-beta-responsive cell line (MvLu1) with a retroviral cDNA library, selecting by fluorescence-activated cell sorter single cells displaying low PAI promoter activity in response to TGF-beta. Using this strategy we cloned the proto-oncogene brain factor-1 (BF-1). BF-1 represses the PAI promoter in part by associating with both unphosphorylated Smad3 (in the cytoplasm) and phosphorylated Smad3 (in the nucleus), thus preventing its binding to DNA. BF-1 also associates with Smad1, -2, and -4; the Smad MH2 domain binds to BF-1, and the C-terminal segment of BF-1 is uniquely and solely required for binding to Smads. Further, BF-1 represses another TGF-beta-induced promoter (p15), it up-regulates a TGF-beta-repressed promoter (Cyclin A), and it reverses the growth arrest caused by TGF-beta. Our results suggest that BF-1 is a general inhibitor of TGF-beta signaling and as such may play a key role during brain development.

3T3 Cells↗
PubMed1986

[Interaction of growth factors and oncogenes in the tumorous transformation of cells].

Different aspects of the interaction of polypeptide growth factors with their receptors are reviewed. The problem of structural and functional interactions of the normal and transforming growth factors as well as the protein products of oncogenes during transmittance of a mitogenic signal and the proliferation regulation of normal and tumour cells is discussed.

Animals↗
PubMed1995

Growth factor requirement, oncogene expression and TP53 mutations of a tumorigenic and a non-tumorigenic subline of the human breast carcinoma cell line, HMT-3909.

From a human breast carcinoma cell line, HMT-3909, a tumorigenic and a non-tumorigenic subline have previously been described. Cells of both sublines have been characterised as carcinoma cells. In the present work we examined whether differences in growth factor requirements or oncogene expression may explain the difference in tumorigenicity. We found that exogenous growth factor dependence discriminated between the two sublines. No alterations in oncogenes or tumour suppressor genes were demonstrated that could explain the differences in tumorigenicity. The lower growth factor requirement and the higher growth rate of the tumorigenic subline indicates that, in these cells, growth potential may determine the outcome of the tumorigenicity assay.

Base Sequence↗
PubMed1989

The role of hematopoietic growth factors and oncogenes in leukemogenesis.

Understanding of the roles and molecular mechanisms of hematopoietic growth factors has increased greatly in recent years. This past decade has also brought us tantalizingly close to linking a group of genes normally involved in the regulation of growth and differentiation--the cellular proto-oncogenes--to the process of malignant transformation. In this article, we review the known actions of hematopoietic growth factors in normal hematopoiesis and in hematologic malignancies. We then discuss current concepts of the roles of proto-oncogenes in normal cells and their potential involvement in leukemogenic events. A merging of these concepts with classical hypotheses of multistage carcinogenesis is emphasized.

Growth Substances↗
PubMed1995

Convergent signalling in the action of integrins, neuropeptides, growth factors and oncogenes.

These findings have important implications for signal transduction and cell regulation. Most obviously, they suggest that tyrosine phosphorylation of a novel type of tyrosine kinase p125FAK is a point of convergence in the action of integrins, oncogenic forms of pp60src, mitogenic neuropeptides and growth factors (Fig. 3). One inference is that the signal transduction pathways initiated by these diverse groups of molecules have, at least in part, similar consequences for cellular function. The notion of convergence is reinforced by the striking similarity in the overall pattern of tyrosine phosphorylation produced through these different pathways. It is tempting to speculate that p125FAK, paxillin and p130 are components in a common programme of phosphorylation events stimulated by integrins, mitogenic neuropeptides and growth factors. The localization of p125FAK to focal adhesions is clearly consistent with a role for this protein as a junction point in the transduction of signals that regulate cell substrate adhesion and ultimately cell motility and cell shape, as suggested in Fig. 3. The existence of distinct pathways leading to p125FAK phosphorylation raises the possibility of synergistic interactions between integrins and G protein coupled receptors. In fact, integrin mediated p125FAK tyrosine phosphorylation appears to be mediated by a PKC dependent pathway (Vuori and Ruoslathi, 1993). By contrast, bombesin and LPA induce tyrosine phosphorylation of p125FAK and paxillin through a PKC independent pathway (Sinnett-Smith et al, 1993; Zachary et al, 1993; Seufferlein and Rozengurt, 1994). It is possible that tyrosine phosphorylation of p125FAK by bombesin, LPA and pp60v-src bypasses and perhaps mimics the phosphorylation caused by integrin activation. Further experimental work will be required to elucidate whether integrins and neuropeptides increase the autophosphorylation of Tyr-397 in p125FAK, as has been recently demonstrated in src-transformed cells (Schaller et al, 1994). Thus, molecular and cellular aspects of the role of p125FAK in signal transduction remain unclear. Specifically, the molecular steps by which different receptors (integrins, seven transmembrane domain receptors and tyrosine kinase receptors) can transduce signals leading to p125FAK tyrosine phosphorylation and the precise role of p125FAK in cell regulation are important areas for further research. Identification of the substrates of p125FAK, which given its localization are likely to reside in or be associated with focal adhesion, will be crucial for elucidating its role in cell regulation.

Animals↗
PubMed1988

Expression of selected growth factors and oncogenes in neurofibrosarcomas complicating von Recklinghausen disease.

One neurofibrosarcoma from each of three patients with von Recklinghausen neurofibromatosis (VRNF) was studied for the expression of selected growth factor genes and oncogenes. Comparative analyses were also performed on four neurofibromas and skin, nerve and muscle specimens from one of the patients with neurofibrosarcoma, an autopsy kidney specimen from a fifth VRNF patient, and normal liver and term placenta specimens from healthy control subjects. Northern blot hybridization techniques were used to analyze the amounts and sizes of mRNA resulting from the expression of eight genes. Insulin-like growth factor I showed a moderate level of expression in normal nerve and lower expression in two neurofibrosarcomas. Insulin-like growth factor II was moderately to heavily expressed in all specimens, and differential splicing patterns were seen. Platelet-derived growth factor showed low levels of expression in all three neurofibrosarcomas, skin, nerve, muscle and normal liver, low to moderate levels of expression in the neurofibromas, and high expression in normal control placenta. Beta-nerve growth factor was expressed at low levels in two neurofibrosarcomas and skin, but was not seen in other specimens. N-myc showed a low level of expression in one neurofibrosarcoma and a neurofibroma, and a higher level of expression in a second neurofibrosarcoma (and in this same subject's skin and nerve). Tissue-type plasminogen activator showed moderate levels of expression in two neurofibrosarcomas and one neurofibroma, but it was not seen in skin, nerve, kidney and normal term placenta specimens.

Blotting, Northern↗
PubMed1998

Activation of STAT transcription factors in oncogenic tyrosine kinase signaling.

Signal transducers and activators of transcription (STATs) are cytoplasmic transcription factors that translocate to the nucleus and regulate gene expression in response to cytokine and growth factor stimulation. Emerging evidence indicates that STAT signaling is also frequently activated by oncogenes and in tumor cells. Constitutive activation of STAT proteins has been reported in cell lines stably transformed by diverse oncoproteins that directly or indirectly activate specific tyrosine kinase signaling pathways. In addition, STAT activation has been detected in a variety of human tumors and tumor cell lines, many of which are known to harbor activated tyrosine kinases. Recent findings support a model in which activation of STAT signaling in the context of oncogenesis induces gene expression that participates in malignant transformation.

Animals↗
PubMed1993

Growth factors, mitogens, oncogenes and the regulation of glucose transport.

The erythrocyte (or HepG2/brain) type glucose transporter (GLUT 1) was the first of the family of facilitative glucose transporter proteins to be cloned [M. Mueckler et al., Science 229, 941-945, 1985]. GLUT 1 is expressed in most tissue types, all cell lines, transformed cells and tumour cells. It is thought to be responsible for "housekeeping" levels of glucose transport, i.e. the uptake of glucose required for oxidative phosphorylation. The rate of glucose transport via GLUT 1 can be regulated under conditions in which the metabolic rate must be adjusted such as cell division (mitosis and meiosis), differentiation, transformation and nutrient starvation. Here we review the recent literature on the control of glucose transport of mitogens, growth factors and oncogenes, and discuss some of the implications for the integration of cellular signalling pathways and cell growth.

Avian Sarcoma Viruses↗
PubMed1990

Growth factors and oncogenes in human gastrointestinal carcinomas.

Multi-autocrine loops of the epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), platelet-derived growth factor (PDGF) and TGF beta system are expressed in human gastrointestinal carcinomas. In esophageal and gastric carcinomas, they evidently play an important role in tumor progression. Gastrin, one of the major gut hormones, may also act as an autocrine growth factor for gastric and colonic carcinomas. The HST1 and INT-2 genes, belonging to the fibroblast growth factor gene family, are coamplified in approximately 50% of primary tumors and in all the metastatic tumors of esophageal carcinoma. TGF alpha and EGF are the ligands of the tumor cells that overexpress EGF receptor in esophageal carcinomas. The synchronous expression of EGF and its receptor, as well as TGF alpha and ras p21, is evidently correlated with the depth of tumor invasion, metastasis and prognosis of gastric carcinomas. Amplification of c-erbB-2 and EGF receptor genes has been observed in many metastatic sites of gastric carcinomas regardless of histological type. In addition to TGF alpha and EGF, TGF beta and PDGF A chain produced by tumor cells may stimulate collagen synthesis not only by fibroblasts but also by tumor cells themselves, resulting in extensive progression and diffuse fibrosis of scirrhous gastric carcinomas. Moreover, TGF alpha or EGF and estrogen may also play a cooperative role in the development of scirrhous gastric carcinoma. In colorectal carcinoma, it has been shown that the accumulation of several alterations in ras genes and p53 genes is most important for the conversion of adenoma to carcinoma. Critical genetic changes, including activation of oncogenes, mutation and deletion of tumor suppressor genes and disturbances in transcriptional regulatory sequences, may bring about aberrant expression of growth factors and their receptors in gastrointestinal carcinomas. The understanding of the significance of EGF-related growth factors in tumor progression provides a framework for a biological approach to the therapy of human gastrointestinal carcinomas. 8-Cl-cAMP, which inhibits expression of oncogenes and TGF alpha, may be useful not only for cancer therapy but also for the study of cell differentiation.

Carcinoma↗
PubMed1987

Hemopoietic growth factors and oncogenes in myeloid leukemia development.

Most primary myeloid leukemias are dependent for proliferative stimulation on the glycoprotein colony-stimulating factors. These agents are therefore mandatory co-factors in the development of myeloid leukemia. The CSFs also modify oncogene transcription, and in model leukemogenesis experiments GM-CSF has been shown to be a proto-oncogene. However, most evidence is against an autocrine hypothesis of myeloid leukemia based solely on CSF production by emerging leukemic cells. Because the CSFs also have differentiation commitment actions, they can induce differentiation in myeloid leukemic cells, and G-CSF in particular has an impressive capacity to suppress myeloid leukemic populations by this action. The antagonistic actions of the CSFs on myeloid leukemic cells make it difficult to predict whether they will prove to be useful agents in the management of myeloid leukemias.

Animals↗
PubMed2003

A novel orthotopic tumor model to study growth factors and oncogenes in hepatocarcinogenesis.

An orthotopic xenograft tumor model of hepatocellular carcinoma was created by injection of Hep 3B cells directly into the liver parenchyma of nude mice. Tumors were localized primarily in the injected lobe of the liver, beginning from the third week after tumor cell implantation. Thereafter, tumors grew rapidly, and animals usually died from hepatocellular carcinoma within 2 months. Insulin-like growth factor II, an embryonic growth factor and mitogen, is overexpressed in these tumors at both mRNA and protein levels. Oncogenes, such as c-myc, c-fos, and c-jun, are also up-regulated in this model. alpha-Fetal protein can be detected shortly after implantation and correlates with tumor growth, and measurement of serum alpha-fetal protein serves as an early biomarker to monitor the effect of antitumor therapy. Using this model, we have shown that inhibition of insulin-like growth factor II expression by a short methylated oligonucleotide prolongs survival. This in situ tumor model thus provides a fast, reliable, and reproducible means to study the therapeutic effect of inhibitors of growth factors and oncogenes in liver cancer.

Animals↗
PubMedDate not supplied

Role of Oncogenic Transcription Factor c-Myc in Cell Cycle Regulation, Apoptosis and Metabolism.

The myc gene was initially discovered as a prototypical retrovirally transduced oncogene. Over the decades, abundant evidence has emerged to support a causal role for the activated cellular gene, c-myc, in animal and human tumors. The gene encodes an oncogenic helix-loop-helix leucine zipper transcription factor that acts as a heterodimer with its partner protein, Max, to activate genes regulating the cell cycle machinery as well as critical metabolic enzymes. The additional ability of c-Myc to repress transcription of differentiation-related genes suggest that c-Myc is a central and key molecular integrator of cell proliferation, differentiation and metabolism.

Journal Article↗
PubMed1990

Growth factors and oncogenes in breast cancer.

The growth of normal breast epithelial cells is regulated by a complex interacting system of polypeptide factors and by steroid hormones. The cells respond to these factors through receptors which generate mitogenic and other intracellular signals. These second messengers provoke complex responses which may ultimately result in DNA replication and cell division. A comparison of normal cells and tumour cells, either in culture or from primary tumour biopsies, has revealed differences in growth factor and growth factor receptor expression. Such changes may represent aspects of the process of malignant transformation. In addition some evidence suggests that changes in second messenger systems may also occur. Finally several changes in nuclear oncogenes have been observed in breast cancers. It has been proposed that changes in the nuclear oncogenes, perhaps involving the loss of function of tumour suppressor genes, may allow cells to enter the cell cycle. Changes in growth factors, their receptors or intracellular second messenger systems may stimulate unregulated growth. The combination of these events provide a model for the process of carcinogenesis.

Breast Neoplasms↗