Showing papers on "Growth factor receptor inhibitor published in 1990"

Ligand-induced transformation by a noninternalizing epidermal growth factor receptor

Abstract: Identification of a mutant epidermal growth factor (EGF) receptor that does not undergo downregulation has provided a genetic probe to investigate the role of internalization in ligand-induced mitogenesis. Contact-inhibited cells expressing this internalization-defective receptor exhibited a normal mitogenic response at significantly lower ligand concentrations than did cells expressing wild-type receptors. A transformed phenotype and anchorage-independent growth were observed at ligand concentrations that failed to elicit these responses in cells expressing wild-type receptors. These findings imply that activation of the protein tyrosine kinase activity at the cell membrane is sufficient for the growth-enhancing effects of EGF. Thus, downregulation can serve as an attenuation mechanism, without which transformation ensues.

Overexpression of the human insulinlike growth factor I receptor promotes ligand-dependent neoplastic transformation.

Abstract: The human insulinlike growth factor I receptor was overexpressed in NIH 3T3 cells as well as human and rat primary fibroblast strains. The NIH 3T3 cells displayed a ligand-dependent, highly transformed phenotype. When exposed to insulinlike growth factor I or supraphysiologic levels of insulin, NIH 3T3 cells that expressed high levels of receptors formed aggregates in tissue culture dishes, colonies in soft agar, and tumors in nude mice. Expression of 1 million receptors per cell, a 40-fold increase above the base-line level, was required for anchorage-independent growth. Primary fibroblasts that expressed high levels of receptors displayed a ligand-dependent change in morphology and an increase in saturation density but did not acquire a fully transformed phenotype. The results demonstrate that when amplified, this ubiquitous growth factor receptor behaves like an oncogenic protein and is capable of promoting neoplastic growth in vivo.

The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity.

Abstract: We have isolated the gene for a novel growth regulator, amphiregulin (AR), that is evolutionarily related to epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). AR is a bifunctional growth modulator: it interacts with the EGF/TGF-alpha receptor to promote the growth of normal epithelial cells and inhibits the growth of certain aggressive carcinoma cell lines. The 84-amino-acid mature protein is embedded within a 252-amino-acid transmembrane precursor, an organization similar to that of the TGF-alpha precursor. Human placenta and ovaries were found to express significant amounts of the 1.4-kilobase AR transcript, implicating AR in the regulation of normal cell growth. In addition, the AR gene was localized to chromosomal region 4q13-4q21, a common breakpoint for acute lymphoblastic leukemia.

Metabolism and effects of epidermal growth factor and related growth factors in mammals.

Abstract: The initial observations of Stanley Cohen in the 1960s established that EGF induced in vivo effects such as precocious eyelid opening and tooth eruption. Subsequently the actions of EGF have been extensively explored in cell culture systems. The receptor for EGF was characterized as a prototype model for other growth factors and the now extensive in vitro data indicate multiple functions for EGF. Moreover, EGF and EGF receptors have been characterized in many tissues, and EGF has been identified in most body fluids of several mammalian species. Interestingly, neither EGF antibody administration to newborn animals nor passive immunization of pregnant rodents against EGF has caused major deleterious effects (except the delay in epidermal maturation events), as might be expected from the in vitro studies. This is in contrast to the effects of nerve growth factor antiserum in developing rodents. Also, to date, no pathological EGF deficiency disorder has been characterized. However, the EGF family of growth factors appears to be important in mammalian development and function, although the precise roles and significance are not yet clear. Members of the family may have a role in embryogenesis and fetal growth since receptors have been identified in fetal tissues. Available evidence suggests that TGF alpha subserves the growth factor family roles in fetal development. In the developing postnatal animal pro-EGF mRNA, immunoreactive EGF, immunoreactive TGF alpha, and EGF receptors are present in many tissues. EGF also is produced and secreted by the maternal mammary gland, and mammary derived EGF appears to be important in gut development in the neonatal rodent. There is now extensive data to indicate important hormone-EGF interactions. In the postnatal period, thyroid and steroid hormones including retinoic acid have been shown to modulate EGF and/or EGF receptors in several tissues. GH increases EGF binding in liver and increases urine EGF concentrations. Moreover, EGF stimulates secretion of several hypothalamic and pituitary hormones, increases placental production of hCG and human chorionic somatomammotropin, increases adrenal cortisol production, and inhibits testicular, ovarian, and thyroid hormone secretions. As summarized in this review EGF has been implicated in a number of developmental events including palate and skin differentiation, growth of hair follicles, eye opening and tooth eruption, lung maturation, gut and liver growth, and differentiation of neurons. These EGF actions probably are mediated via autocrine, paracrine, and endocrine routes. A role for salivary and urine EGF in the maintenance of adult stomal, gut, and urinary epithelial surface integrity seems likely, although not yet proven.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell-cell adhesion mediated by binding of membrane-anchored transforming growth factor alpha to epidermal growth factor receptors promotes cell proliferation.

Abstract: The precursor for transforming growth factor alpha, pro-TGF-alpha, is a cell surface glycoprotein that can establish contact with epidermal growth factor (EGF) receptors on adjacent cells. To examine whether the pro-TGF-alpha/EGF receptor pair can simultaneously mediate cell adhesion and promote cell proliferation, we have expressed pro-TGF-alpha in a bone marrow stromal cell line. Expression of pro-TGF-alpha allows these cells to support long-term attachment of an EGF/interleukin-3-dependent hematopoietic progenitor cell line that expresses EGF receptors but is unable to adhere to normal stroma. This interaction is inhibited by soluble EGF receptor ligands. Further, the hematopoietic progenitor cells replicate their DNA while they are attached to the stromal cell layer and become foci of sustained cell proliferation. Thus, pro-TGF-alpha and the EGF receptor can function as mediators of intercellular adhesion and this interaction may promote a mitogenic response. We propose the term "juxtacrine" to designate this form of stimulation between adjacent cells.

Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors.

Abstract: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and appears to arise from developing striated muscle-forming cells. Since insulin-like growth factor II (IGF-II) is involved in normal muscle growth and maturation and elevated IGF-II mRNA levels have previously been reported in rhabdomyosarcomas, we have been studying the possible role of IGF-II in the unregulated growth and invasive potential of these embryonal tumors. In this study, we demonstrate that 13 of 14 rhabdomyosarcoma tumors express high levels of IGF-II mRNA relative to normal adult muscle and also express mRNA for the type I IGF receptors on their cell surface, the receptor thought to mediate the effects of IGF-II on muscle cells. We have established several rhabdomyosarcoma cell lines in mitogen-free media and demonstrate that these cells express type I IGF receptors on their cell surface and secrete IGF-II into the media. Exogenous IGF-II is able to stimulate cellular motility in these cell lines as assayed in a modified Boyden chamber. Finally, alpha IR-3, a type I receptor antagonist, inhibits the growth of these cell lines in serum-free media but does not inhibit IGF-II-induced motility of these cells. These data suggest that endogenously produced IGF-II functions as an autocrine growth and motility factor in many rhabdomyosarcoma tumors. The mitogenic actions of IGF-II are mediated through a domain of the type I IGF receptor that is blocked by alpha IR-3. IGF-II-induced motility may be mediated through an alternative signaling pathway.

Accumulation of p21ras.GTP in response to stimulation with epidermal growth factor and oncogene products with tyrosine kinase activity.

Abstract: The ras gene product (p21) is a GTP-binding protein and has been thought to transduce signals regulating proliferation or differentiation of cells. Like other GTP-binding proteins, p21.GTP is an active conformation, which can transduce the signals downstream, whereas p21.GDP is an inactive one. Recently, we have shown that p21.GTP levels increased in cells treated with fetal bovine serum or platelet-derived growth factor to initiate DNA synthesis. In this paper, we report that epidermal growth factor can also increase the amounts of p21.GTP in the cells. Effects of epidermal growth factor and platelet-derived growth factor are not additive. In contrast, mutant [Val12]p21, which has transforming activity, responded neither to platelet-derived growth factor nor to epidermal growth factor. We also found that the ratio of p21.GTP to p21.GDP increased 3- to 4-fold in transformants carrying activated erbB-2/neu or v-src oncogenes. These results strongly suggest an important role of p21 in transduction of signals for both normal proliferation and malignant transformation through growth factor receptors with tyrosine kinase activity or related oncogene products.

Transforming growth factor beta is a potent inhibitor of interleukin 1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action.

Abstract: Transforming growth factor beta (TGF-beta) acts as a potent inhibitor of the growth and functions of lymphoid and hemopoietic progenitor cells. Cell proliferation depends not only on the presence of growth factors, but also on the development of specific receptor-signal transducing complexes. We therefore investigated whether the inhibitory actions of TGF-beta could be mediated by inhibition of growth factor receptors. TGF-beta inhibited the constitutive level of interleukin 1 receptor (IL-1R) expression on several murine lymphoid and myeloid progenitor cell lines, as well as IL-1R expression induced by interleukin 3 (IL-3) on normal murine and human bone marrow cells. Furthermore, treatment of bone marrow progenitor cells with TGF-beta concomitantly inhibited the ability of IL-1 to promote high proliferative potential (HPP) colony formation as well as blocked IL-1-induced IL-2 production by EL-4 6.1 cells. These findings provide the first evidence that the inhibitory action of TGF-beta on the growth and functional activities of hematopoietic and T cells is associated with a reduction in the cell surface receptor expression for IL-1.

Interleukin 1 is an autocrine regulator of human endothelial cell growth.

Abstract: Proliferation of endothelial cells is regulated through the autocrine production of growth factors and the expression of cognate surface receptors. In this study, we demonstrate that interleukin 1 (IL-1) is an inhibitor of endothelial growth in vitro and in vivo. IL-1 arrested growing, cultured endothelial cells in G1 phase; inhibition of proliferation was dose dependent and occurred in parallel with occupancy of endothelial surface IL-1 receptors. In an angiogenesis model, IL-1 could inhibit fibroblast growth factor-induced vessel formation. The autocrine nature of the IL-1 effect on endothelial proliferation was demonstrated by the observation that occupancy of cell-surface receptors by endogenous IL-1 depressed cell growth. The potential significance of this finding was emphasized by the detection of IL-1 in the native endothelium of human umbilical veins. A mechanism by which IL-1 may exert its inhibitory effect on endothelial cell growth was suggested by studies showing that IL-1 decreased the expression of high-affinity fibroblast growth factor binding sites on endothelium. These results point to a potentially important role of IL-1 in regulating blood vessel growth and suggest that autocrine production of inhibitory factors may be a mechanism controlling proliferation of normal cells.

Structure, expression and function of a schwannoma-derived growth factor.

Abstract: DURING the development of the nervous system, cells require growth factors that regulate their division and survival. To identify new growth factors, serum-free growth-conditioned media from many clonal cell lines1 were screened for the presence of mitogens for central nervous system glial cells. A cell line secreting a potent glial mitogen was established from a tumour (or 'schwannoma') derived from the sheath of the sciatic nerve. The cells of the tumour, named JS1 cells, were adapted to clonal culture and identified as Schwann cells. Schwann cells secrete an autocrine mitogen2 and human schwannoma extracts have mitogenic activity on glial cells3. Until now, neither mitogen has been purified. Here we report the purification and characterization of a mitogenic molecule, designated schwannoma-derived growth factor (SDGF), from the growth-conditioned medium of the JS1 Schwann cell line. SDGF belongs to the epidermal growth factor family, and is an autocrine growth factor as well as a mitogen for astrocytes, Schwann cells and fibroblasts.

Fibroblast growth factor and its involvement in developmental processes.

Abstract: Publisher Summary This chapter focuses on the role of fibroblast growth factor (FGF) in early development and its putative role in the developmental and functional aspects of various organs that have been shown to contain predominantly basic fibroblast growth factor (bFGF). The bioactivity of both bFGF and acidic fibroblast growth factor (aFGF) can be positively or negatively regulated by TGF- β , depending on the cell type. Therefore, the ability of various tissues to synthesize FGFs, or TGF- β , and the relative concentrations of these growth factors in the microenvironment would determine whether cell proliferation and differentiation were selectively enhanced or repressed by FGF. A number of growth factors have recently been isolated and characterized, their roles in vivo, as well as their physiological relevance, are still largely conjectural. In most cases identification of their biological roles rests on the correlation between their mRNA expression in various tissues at various stages of development, rather than on a direct causality between growth factor expression and morphogenetic events.

4. The role of the epidermal growth factor receptor and the c‐erbB‐2 protein in breast cancer

Abstract: Breast cancer cells are derived from epithelial cells lining the ducts of the breast One of the fundamental characteristics that distinguish tumour cells from normal cells is that cancer cells grow in an apparently unregulated way Understanding the mechanisms that regulate the growth and differentiation of normal breast epithelial cells and the differences between these systems in cancer cells is one of the central goals of research into the cell biology of breast cancer

Growth-regulatory factors for normal, premalignant, and malignant human cells in vitro.

Abstract: Normal human cells, cells from nonmalignant proliferative lesions, and primary and metastatic tumor cells can be maintained in vitro and analyzed for requirements for growth in chemically defined media. The human melanocytic cell system with normal melanocytes, precursor nevus cells, and primary and metastatic melanoma cells has been extensively studied for the phenotypic properties of the cells, including their requirements for exogenous growth factors and other mitogens. In high calcium-containing W489 medium, normal melanocytes require four supplements: IGF-I (or insulin); bFGF, TPA, and alpha-MSH. Nevus cells are largely independent of bFGF. Depletion of TPA from medium is not as detrimental to nevus cells as it is to melanocytes, but the phorbol ester is still essential for maintenance of the typical nevic phenotype. Primary melanoma cells require at least one growth factor, IGF-I (or insulin), for continuous proliferation. On the other hand, metastatic cells of melanoma as well as of carcinomas of colon and rectum, bladder, ovary, and cervix are able to proliferate after a short adaptation period in medium depleted of any growth factors and other proteins. Doubling times of metastatic tumor cells in protein-free medium are only 30-60% longer than in FCS-containing medium. The growth autonomy of human tumor cells is apparently due to the endogenous production of growth factors. Likely candidates for autocrine growth stimulation of human tumor cells are TGF-alpha, TGF-beta, and PDGF. Melanoma and colorectal carcinoma cells express functional EGF/TGF-alpha receptors, and produce TGF-alpha, indicating that this growth factor is produced for autocrine stimulation. In addition to the use of anti-growth factor antibodies, other strategies for the inhibition of autocrine growth stimulation include mAbs to growth factor receptors, soluble receptors, receptor-mimicking antiidiotype antibodies, and active immunization against growth factors. Whether any of these therapeutic approaches is clinically feasible will need to be determined in extensive preclinical investigations.

Autocrine and paracrine growth regulation of breast cancer: clinical implications.

Abstract: Research using experimental models of human breast cancer has broadened our understanding of the possible biochemical pathways regulating breast cancer growth. Breast cancer cells express receptors for and respond to a variety of steroid and polypeptide hormones and growth factors. Specific oncogenes are also expressed in breast cancer cells, and levels of expression may relate to tumor growth and aggressiveness. Recent studies have shown that breast cancer cells can even synthesize and secrete various growth factors that could stimulate tumor growth through autocrine and/or paracrine mechanisms. Secretion of some of these growth factors is regulated by estrogen, providing a possible mechanism for estrogen induced growth. Knowledge of these growth regulatory pathways has potentially important clinical implications. Blockade of these pathways offers new possible treatment strategies, much as antiestrogens have been used to inhibit tumor growth. Quantification of the expression of certain oncogenes, growth factor receptors, or the growth factors themselves, may provide prognostic information for the individual patient. Finally, it is plausible that measurement of these tumor products in body fluids might provide tumor markers that are useful in the diagnosis and treatment of breast cancer.

Epidermal growth factor and transforming growth factor-alpha in the development of epithelial-mesenchymal organs of the mouse.

Abstract: Publisher Summary This chapter focuses on the role of epidermal growth factor (EGF) and transforming growth factor type α (TGF-α) in organogenesis in mouse. It discusses EGF and the related growth factor, transforming growth factor type α (TGF-α) and also discusses specific morphogenetic events in which EGF/TGF-α may participate and that involve epithelial-mesenchymal interactions. There is a substantial amount of evidence that EGF-like growth factors have a physiological role in organ development and that the action of EGF or TGF-α in the development of epithelial-mesenchymal organs is associated with tissue interactions that guide morphogenesis and differentiation. EGF and TGF-α act as paracrine mediators of tissue interactions during organ development, as has been suggested for TGF-α, which, together with fibroblast growth factor, acts as a morphogen to induce differentiation of embryonic tissue that is normally induced by tissue interactions.

Receptors for epidermal growth factor and insulin-like growth factor-I on preimplantation trophoderm of the pig

Abstract: 125I-labelled epidermal growth factor (125I-EGF) and 125I-labelled insulin-like growth factor-I (125I-IGF-I) bound to trophoderm cells from pig blastocysts obtained on days 15–19 of pregnancy. Specific binding was detected on freshly isolated cell suspensions and on cells cultured for several days. The binding of 125I-EGF was inhibited by increasing concentrations of EGF, but not by various other growth factors and hormones. Chemical cross-linking of 125I-EGF to its receptors using disuccinimidyl suberate (DSS) revealed a radiolabelled band of relative molecular mass 160,000, similar to that identified as the EGF receptor in other cell types. The binding of 125I-IGF-I was inhibited by both IGF-I and insulin, indicating that the receptors were either type I IGF receptors or insulin receptors. Cross-linking of 125I-IGF-I to serum-free supernatants from trophoderm cultures showed that the cells secreted an IGF-binding protein, giving a complex of relative molecular mass about 45,000. The presence of receptors for EGF and IGF/insulin suggests that these factors could be involved in regulating the growth and development of the early blastocyst.

The Role of Growth Factors in the Control of Neurogenesis

Abstract: The development of the vertebrate nervous system is controlled by neuron production and neuron death. Neurogenesis proceeds in two stages, proliferation of neuronal precursor cells in germinal zones or peripheral ganglia and differentiation of cycling precursor cells to postmitotic neurons. The number of neurons generated during the initial phases of proliferation and differentiation are fairly constant and specific for different nuclei in the central nervous system (CNS) (Cowan and Wenger, 1967; Roger and Cowan, 1973; Oppenheim, 1981) or defined ganglia of the peripheral nervous system (PNS) (Landmesser and Pilar, 1974; Oppenheim, 1981; Hofer and Barde, 1988). The final number of neurons is obtained during the process of selective neuronal death which results in a substantial reduction of the numbers of neurons that are produced initially (Oppenheim, 1981; Cowan ef al. , 1984). The extent of neuronal death has been demonstrated to depend on the embryonic environment and the size of the innervated target (Hamburger and Levi-Montalcini, 1949). In the case of the sympathetic and sensory neurons of the PNS it was shown that selective survival is controlled by nerve growth factor (NGF). The role of NGF in the process of neuronal cell death has been clarified by the demonstration that the addition of NGF prevents neuron death, that interfering with the biological action of NGF results in complete neuron death, and by demonstrating the presence of limiting amounts of NGF in target regions of sensory and sympathetic neurons (Thoenen and Barde, 1980; Levi-Montalcini, 1987; Barde, 1989). There is also evidence that besides NGF there are additional neurotrophic factors which are structurally related to NGF, but which act on a different spectrum of neurons (Barde et al., 1982; Leibrock et al., 1989; Barde, 1989; Hohn et al., 1990; Maisonpierre et al . , 1990). In contrast to the process of neuron death, the phase of neuron production is not controlled by an interaction of the cells with a peripheral or central target (Levi-Montalcini, 1949; Landmesser and Pilar, 1974; Kelly and Cowan, 1977; Oppenheim, 1981; Tanaka and Landmesser, 1986). There is evidence from studies using chimeric mice that the number of particular neurons in the CNS is intrinsically controlled by cell-autonomous mechanisms (Williams and Herrup. 1988). It seems, however, that the evidence for cell-autonomous neuron generation cannot be generalized for the control of neurogenesis in other parts of the nervous system, as there are examples of local, extrinsic control of neuron production both in the CNS and PNS which will be discussed in this review. The need to understand more about the control of neuronal proliferation has been emphasized by the recent demonstration of regional differences in the numbers of motorneurons in the chick spinal cord before the onset of motorneuron death (Oppenheim et af., 1989). Differences between the numbers of dividing cells in brachial and non-brachial dorsal root ganglia have also been reported previously (Hamburger and Levi-Montalcini, 1949). A segmental pattern of neuroepithelial proliferation has been described in the chick hind brain which may eventually lead to the formation of rhombomeres (Lumsden, 1990). These data indicate that the final neuron number in these cases is not only influenced by target interactions but by a region-specific pattern of neuronal proliferation. It should also be kept in mind that neuron death, although found throughout the nervous system, has been observed preferentially in projecting neurons, whereas, for instance, the cell number of interneurons in the retina (Rager and Rager, 1978; Sengelaub and Finlay, 1982; Spira et al., 1984) and the neuron number in some other cases (Oppenheim, 1981) is much less reduced. The cell number in these cases may be intrinsically controlled or determined by local control of proliferation and differentiation. In this paper, in vivo evidence for epigenetic influences on neuronal proliferation is reviewed, experiments designed to analyse proliferation in vitro are then described, and finally the possible role of growth factors identified in vitro in the control of proliferation is discussed. For a more general review on the control of neuronal cell number, the reader is referred to the recent review by Williams and Herrup (1988).

The Epidermal Growth Factor

Abstract: The article is a review of recent knowledge of the structural relationships of epidermal growth factor (EGF) with other biological products occurring in a wide range of animal species and some viruses. The place of EGF and related products in the physiology of the whole organism is discussed against this background. Special attention is given to the role of EGF as a tissue growth factor and to the participation of related products in cancer.