Showing papers by "Michael B. Sporn published in 1984"

Cellular Biology and Biochemistry of the Retinoids

Abstract: Publisher Summary This chapter discusses the cellular biology and biochemistry of the retinoids In isolated 9-day-old rat embryos, retinoic acid prevents the formation of the pharyngeal arches, which are derived from cephalic mesenchyme; these structures later form the maxilla and the mandible Another mesenchymal derivative, whose formation is markedly suppressed by retinoic acid in rat embryos, is the yolk sac circulation Retinoids can exert a powerful influence on cell differentiation in many different types of epithelia The effects of retinoids on differentiation of epithelia in organ culture result from a combination of complex cellular responses and interactions of different cell types in the explant One of the most illuminating examples of the ability of retinoids to promote differentiation is the effect of retinoids on mouse embryonal carcinoma cells These undifferentiated stem cells of teratocarcinomas are multipotential, that is, they can differentiate into a multiplicity of somatic cell types Another example of the ability of retinoic acid to promote terminal differentiation of neoplastic cells to nonneoplastic cell types is the effect of retinoic acid on human promyelocytic leukemia cells

Cellular transformation by coordinated action of three peptide growth factors from human platelets

Abstract: Platelet-derived growth factor (PDGF) is known to be involved in regulating the mitosis of connective tissue cells, and recent studies have also shown that it may function in mediating cellular transformation. The oncogene carried by simian sarcoma virus, sis, is homologous to one chain of PDGF, and treatment of non-neoplastic cells with this growth factor results in increased transcription of another oncogene, myc (ref. 9). PDGF also stimulates the synthesis of proteins that are characteristic of transformed cells. However, phenotypic transformation does not appear to result from the action of PDGF alone. For example, expression of myc does not transform cells in the absence of other oncogene expression. We have recently shown that platelets contain another peptide growth factor, transforming growth factor-beta (TGF-beta)12,13, in addition to PDGF. We report here that extracts of human platelets can induce anchorage-independent growth of nonneoplastic rat kidney (NRK) fibroblasts, but that purified PDGF alone does not elicit this effect. Rather, the transforming activity of the platelet extract is due to a concerted action of three distinct peptides: PDGF, TGF-ss and a newly identified analogue of epidermal growth factor (EGF).

Role of Retinoids in Differentiation and Carcinogenesis

Abstract: It has been known for more than 50 years that retinoids, the family of molecules comprising both the natural and synthetic analogues of retinol, are potent agents for control of both cellular differentiation and cellular proliferation (70). In their original clas sic paper describing the cellular effects of vitamin A deficiency in the rat, Wolbach and Howe clearly noted that there were distinct effects on both differentiation and proliferation of epithelial cells. During vitamin A deficiency, it was found that proper differentia tion of stem cells into mature epithelial cells failed to occur and that abnormal cellular differentiation, characterized in particular by excessive accumulation of keratin, was a frequent event. Furthermore, it was noted that there was excessive cellular proliferation in many of the deficient epithelia. Although the conclusion that an adequate level of retinoid was necessary for control of normal cellular differentiation and proliferation was clearly stated in the original paper by Wolbach and Howe, a satisfactory explanation of the molecular mechanisms underlying these effects on both differentiation and proliferation still eludes us more than 50 years later. It was inevitable that the basic role of retinoids in control of cell differentiation and proliferation would eventually find practical application in the cancer field, and there have been great ad vances in this area, particularly for prevention of cancer. Many studies have shown that retinoids can suppress the process of carcinogenesis in vivo in experimental animals (for reviews, see Refs. 7, 33, 51, 54, 56, and 57), and these results are now the basis of current attempts to use retinoids for cancer prevention in humans. Furthermore, there is now an extensive literature on the ability of retinoids to suppress the development of the malignant phenotype in vitro (for reviews, see Refs. 6, 8, 30, and 31 ), and these studies corroborate the use of retinoids for cancer prevention. Finally, most recently, it has been shown that reti noids can exert effects on certain fully transformed, invasive, neoplastic cells, leading in certain instances to a suppression of proliferation (30) and in other instances to terminal differentiation of these cells, resulting in a more benign, nonneoplastic pheno type (10,11,60,62). Even though there are many types of tumor cells for which this is not the case (33, 52) (indeed, at present there are only a limited number of instances in which such profound effects of retinoids on differentiation and proliferation of invasive tumor cells have been shown), this finding neverthe less has highly significant implications for the problem of cancer treatment. It emphasizes that in many respects cancer is fun damentally a disease of abnormal cell differentiation (36,44), and it raises the possibility that even invasive disease may eventually be controlled by agents which control cell differentiation rather than kill cells. Since carcinogenesis is essentially a disorder of cell differentiation, the overall scientific problem of the role of retinoids in either differentiation or carcinogenesis is essentially

Antagonistic Actions of Retinoic Acid and Dexamethasone on Anchorage-independent Growth and Epidermal Growth Factor Binding of Normal Rat Kidney Cells

Abstract: Type beta transforming growth factor (TGF-beta), in combination with epidermal growth factor (EGF) can induce nonneoplastic normal rat kidney cells to express a transformed phenotype and to form colonies in soft agar. Retinoic acid by itself has no effect on colony formation; but at concentrations of 10(-9) M or greater, it can greatly enhance the response of the cells to EGF and TGF-beta, as measured by colony growth in soft agar and expression of a transformed morphology in monolayer culture. Dexamethasone, at concentrations above 10(-9) M, has an opposite effect, inhibiting the TGF-beta-dependent formation of colonies in soft agar and restoring a more normal morphology to the cells. Added simultaneously, these two modulators act antagonistically; at equimolar concentrations, their opposite effects on colony formation are canceled. Retinoic acid and dexamethasone also have opposite and antagonistic effects on the binding of 125I-labeled EGF to normal rat kidney cells. Retinoic acid enhances the binding of EGF up to 6-fold, while dexamethasone reduces the binding to 50 to 60% of control levels. These effects on EGF binding show a dose dependence similar to the effects on colony formation in soft agar and on morphology in monolayer culture. Optimal effects on binding are observed 40 to 60 hr after treatment of the cells. It can be concluded that the abilities of retinoic acid and dexamethasone to alter expression of the transformed phenotype induced by treatment of normal rat kidney cells with TGF-beta and EGF are mediated at least in part through their effects on the EGF receptor.