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Role of Epidermal Growth Factor in Carcinogenesis

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Role of Epidermal Growth Factor in Carcinogenesis (CANCER RESEARCH 46, 1030-1037, March 1986] Role of Epidermal Growth Factor in Carcinogenesis Christa M. Stoscheck1 and Lloyd E. King, Jr.2 Veterans Administration Medical Center Research Service, Nashville 37203, and Department of Medicine, Division of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 Abstract rylates certain proteins on their tyrosine residues. Another mech anism may involve receptor clustering or a combination of clus For cell growth and division to occur, a large variety of meta tering and kinase activity which, in turn, produces an intracellular bolic processes must be carefully coordinated in the cell. Through signal, (b) Modulation of EGF-stimulated receptor activity (auto- evolutionary pressures, specific hormones and growth factors have acquired the ability to trigger a complex coordinated "pleio- regulation) occurs by at least three modes. First, binding and tropic growth response" in their target cells. This complex re kinase activities may be inhibited by phosphorylation of certain regulatory sites of the receptor. Second, receptor activity may sponse is mediated by specific cellular receptors and intracellular be reduced by receptor degradation following its interaction with messengers. Teleologically then, it makes sense that in onco- EGF. Third, sequestration of the EGF receptor in intracellular genesis this growth regulating network is utilized by the produc compartments may prevent EGF activation of this pool of recep tion of proteins which mimic growth factors, the activated form tors. of their receptors or, the messengers themselves. Several lines Several lines of evidence indicate that the EGF-stimulated cell of evidence indicate that the epidermal growth factor-stimulated regulatory system may play a role in carcinogenesis. This will be growth regulatory system is involved in cellular proliferation, both discussed in detail below. In brief, the first line of evidence normal and neoplastia Some of the effects of epidermal growth indicates that EGF directly elicits transformation-associated phe- factor in carcinogenesis are separable from its direct, growth notypes in certain target cells. Many of these effects are revers stimulatory effects. Thus, the role of epidermal growth factor in ible upon the removal of EGF, but in a small but highly significant carcinogenesis is more complex than is its role in stimulating number of already partially transformed cells, they are not re growth. versible; e.g., EGF has been observed to potentiate chemical transformation in vivo and viral transformation in vitro. The Introduction second line of evidence that EGF plays a role in carcinogenesis is that many cancer cells produce a peptide, termed «-TGF, EGF3 is a M, 6045 polypeptide which can stimulate or inhibit which is structurally related to EGF and activates the EGF proliferation or differentiation of a wide variety of cells (1-3). receptor. However, to date, it is not definitively determined While EGF is thought to play a role in almost every tissue in the whether a-TGF is essential for the transformed properties of its body both during development and in the adult, the exact nature parent cell. Another, albeit indirect, line of evidence is that EGF of this role is not clear. The inability to experimentally lower EGF depresses the immune system whose function is to destroy levels in mice by removing the salivary glands (4), the major site newly arising tumors (immune surveillance). The EGF-stimulated of EGF synthesis in the mouse (5), has hampered clarification of cell regulatory system could conceivably also be activated by a the role of EGF. This inability to alter EGF levels surgically is mutation of the receptor eliminating the requirement for elevated probably due to EGF being synthesized at several anatomical EGF (or TGF levels). This may be the mechanism by which sites in the body (6-9), where EGF functions more in a paracrine erythroblastosis or lymphoid leukosis viruses cause a variety of rather than an endocrine manner. Additionally, the use of anti cancers including erythroblastosis, sarcomas, and carcinomas. bodies against EGF are unlikely to lower EGF levels because of Also discussed are data which contradict the hypothesis that the the very fast turnover rate (half-life, 1.5 min) of EGF in vivo (10). EGF-stimulated cell regulatory system plays a role in carcinogen Since a specific receptor located at the cell surface is required esis. in order for EGF to interact with the cell, the availability of antisera against the EGF receptor which blocks EGF binding (11) offers a new approach in which to deplete cells of an EGF signal. EGFElicitsTransformation-associatedPhenotypesinNormal The EGF receptor is an integral membrane protein with many Cells complex functions which have recently been reviewed in detail elsewhere (12). Briefly, these functions fall into two categories; The addition of EGF to normal cells elicits certain responses signal transmission and autoregulation. (a) Signal transmission which are associated with neoplastic transformation. For exam may involve an intrinsic EGF-stimulated kinase which phospho- ple, EGF induces a partial loss of density dependent inhibition of growth and the dependency on serum for growth (2,13,14), an Received 5/28/85; revised 9/16/85; accepted 11/6/85. 1Recipient of a grant from the Veterans Administration Merit Review Board, increase in the level of phosphotyrosine in proteins (15-18), and American Cancer Society Institutional Research Grant IN-25X, and NIH Biomedicai an increase in cellular metabolism including sugar and amino Research Support Grant RR-05424. To whom requests for reprints should be acid transport, ATP turnover, and ornithine decarboxylase activ addressed. 2 Recipient of grants from the NIH (USPHS Grant AM 26518 and Biomedicai ity (19-20, 52, 53). EGF induces the expression the mRNA of c- Research Support Grant RR-05424), and funded by the Veterans Administration. fos and c-myc genes, cellular proto-oncogenes (22). Cellular 'The abbreviations used are: EGF, epidermal growth factor; TGF, transforming protooncogenes are the normal cellular homologs of viral onco- growth factor; PDGF, platelet-derived growth factor; TPA, 12-O-tetradecanoyl- phorbol-13-acetate; pp60, M, 60,000 phosphoprotein; p28, M, 28,000 protein; p21, genes. Oncogenic viruses are thought to have acquired the M, 21,000 phosphoprotein. oncogene from normal cellular RNA. Through uncontrolled CANCER RESEARCH VOL. 46 MARCH 1986 1030 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1986 American Association for Cancer Research. EGF AND CARCINOGENESIS expression (plus, in some cases, mutation as well) they induce transformed by the Kirsten murine sarcoma virus as is their EGF uncontrolled growth in the host cell (23). EGF also elicits certain receptor-positive parental cell line (70), indicating that a-TGF responses which are associated with cancer such as the loss of production may be a circumstantial consequence of cellular fibronectin, and an augmentation of the secretion of plasminogen transformation. activator (24-27). Growth of cells in soft agar, considered by The production of autostimulatory growth factors by cancer many (28-30) to be one of the best assays for showing the cells appears to be a general phenomenon. For example, simian tumorigenicity of a cell, is potentiated by EGF or EGF-like factors sarcoma virus-transformed cells, glioma, rhabdomyosarcoma, (31-33). This potentiation by EGF is even greater for partially and human osteosarcoma cells produce PDGF or PDGF-like transformed cells (34) and tumor cells (35, 36). Thus, EGF or proteins (71-73). Although PGDF alone does not cause cellular EGF-like proteins contribute toward the malignant phenotype of transformation, its homologue, the v-s/s-transforming protein, transformed cells in vivo. As discussed below, certain trans does (74-76). Other examples of autostimulatory growth factors formed cells produce EGF-like proteins which may feed back to are the production of nerve growth factor or an insulin-like growth the cell and elicit certain transformation-associated phenotypes. factor by melanoma cells, fibrosarcoma, and mammary tumor cells (77-81). High levels of tumor-produced growth factors can Interaction of Transforming Growth Factors with the EGF cause complications in tumor patients such as hypoglycemia and hypercalcemia (82-84). Receptor Several different "a-TGFs" were detected in human urine (29, Some, although not all, transformed cells produce EGF-like 30, 85). Two of these were present at significantly higher levels proteins, termed a-TGFs, which interact with the EGF receptor. in the urine of cancer patients than in normal humans. These These TGFs mimic most, if not all, of the actions of EGF. For patients had disseminated cancers such as small cell lung, renal, example, a-TGFs bind with high affinity to the EGF receptor, colon, and breast carcinomas, as well as melanomas and sar stimulate EGF receptor autophosphorylation, cause down regu comas. In vitro incubation in acid of the larger molecular weight, lation of the EGF receptor, stimulate cell growth, and promote cancer-associated TGF produced the smaller cancer associated precocious tooth eruption and eyelid opening (31, 32, 34, 37- TGF, indicating that both forms are derived from the same 42). Structural similarities have been shown between human and molecule. One of the other molecules exhibiting a-TGF activity rat a-TGF with human and mouse EGF (40 and 44% sequence was identified to be urogastrone, and the identity of the other homology, respectively (43-46). The DNA sequence encoding a- factors are not known but may be precursor forms of urogas TGF was observed in normal cells (46), indicating that it is an trone (86). These latter factors did not exhibit higher levels in the unmodified normal protein which is expressed in cancer cells in urine of cancer patients. Since it is currently not known how to abnormal quantities and/or at the wrong stage of the cells' differentiate TGF from EGF activities, immunological or sequenc development. a-TGF is not an EGF-like peptide from precursor ing data are necessary to identify these factors as EGF or TGF EGF (47, 48).
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