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)

Matrix metalloproteinase-1 is induced by epidermal growth factor in human bladder tumour cell lines and is detectable in urine of patients with bladder tumours

“…This suggests that control of expression may not be just at the transcriptional level but that translational or post-translational mechanisms may come into play if protein synthesis is maximal and the message is still being increased. The higher dose of EGF used (50 ng ml') is a similar concentration to that in urine (Fisher and Lakshmanan, 1990) MMP1 in bladder tumour cells and urine 219 increase MMP expression and secretion, and thus contribute to tumour progression and metastasis. This is similar to the response of human oral squamous cell carcinoma (SCC) cell lines (Shibata et al, 1996) in which MMP9 was increased with doses of EGF greater than 10 ng ml-', which is ten-to 100-fold less than the EGF concentration in saliva.…”

“…Levels of epidermal growth factor (EGF) are known to be high in urine with a mean value of 80 ng ml-' (Fisher and Lakshmanan, 1990), but are lower in patients with bladder tumours and rise again after surgery (Fuse et al, 1992). Signal transduction pathways stimulated by EGF induce the activator protein-i (AP-1) transcriptional regulatory complex (Edwards et al, 1987), which is a known positive transcriptional regulator of MMP1 expression and stromelysin (MMP3) (McDonnell et al, 1990) in fibroblasts.…”

The Clinical Significance of Epidermal Growth Factor Receptor (EGF-R) in Human Breast Cancer: A Review on 5232 Patients*

“…E PIDERMAL growth factor (EGF) is a 53-aminoacid polypeptide (mol wt 6.045 K) that can influence proliferation and differentiation of a wide variety of cells (1)(2)(3)(4)(5)(6). EGF as well as transforming growth factor-a (TGF-a), both of which can activate EGF receptor (EGF-R), are probably produced locally in many tissues as local growth factors rather than as systemic hormones.…”

“…Receptors for EGF have been demonstrated on several breast cancer cell lines, especially on estrogen receptor (ER)-negative tumor cells, and in human primary tumors and metastases (4,13,14). At present there is no agreement on the clinical relationships and prognostic value of EGF-R in human breast cancer.…”

Effects of ozone and endotoxin coexposure on rat airway epithelium: potentiation of toxicant-induced alterations.

“…A common effector pathway of proteases and inflammatory mediators to induce metaplasia in airway epithelial cells may be the epidermal growth factor receptor (EGFR) system. EGF is an important growth factor for the development of neonatal lungs and is often expressed during repair processes in adult lung (77,78). Airway instillation of EGFR ligands into rat airways can lead to the development of mucous cell metaplasia, but only after EGFR expression is induced on airway epithelium by prior treatment with TNF-α (79).…”