Neoplastic cells, retinoid effects

Vitamin A (retinol) and its naturally occurring and synthetic derivatives, collectively referred to as retinoids (chemical structure), exert a wide variety of profound effects in apoptosis, embryogenesis, reproduction, vision, and regulation of inflammation, growth, and differentiation of normal and neoplastic cells in vertebrates. 

Lotan, R. (1980). Effects of Vitamin A and its Analogs (Retinoids) on Normal and Neoplastic Cells . Biochimica et Biophysica Acta, 605, 33-91. 

Loewus, F. (1965) Inositol Metabolism and Cell Wall Formation in Plants , Federation Proceedings of the Federation of American Societies for Experimental Biology, 24, 855-62 Lotan, R. (1980) Effects of Vitamin A and its Analogs (Retinoids) on Normal and Neoplastic Cells , Biochimica et Biophysica Acta, 605, 33-91 Lowden, J.A O Brien, J.S. (1979) Sialidosis a Review of Human Neurominidase Deficiency , American Journal of Human Genetics, 31, 1-18 Lucas, J.J., Waechter, C.J. Lennarz, W.J. (1975) The Participation of Lipid-linked Oligosaccharide in Synthesis of Membrane Glycoproteins , Journal of Biological Chemistry, 250,1992-2002... 

In this section we first discuss the effects of retinoids on nonneoplastic cells in culture and then the effects of retinoids on cultured neoplastic cells. As discussed earlier, the cell types affected are not limited to epithelial cells but include also cells of mesenchymal origin and cells derived from neural ectoderm. Since most of these cell culture systems require serum, they inherently include retinoids. However, it is not known whether all of these cell types have a requirement for retinoids. Therefore, one should always attempt to relate studies of retinoid action in vitro to the function of those particular cell types in vivo. 

In addition to the extensively studied models examined thus far, there are numerous other examples of the effects of retinoids on both growth and differentiation of neoplastic cells. Also, the important observation has been made that for certain neoplastic cells, anchorage-independent growth in semisolid medium is several orders of magnitude more sensitive to retinoid inhibition than is anchorage-dependent growth in monolayer. These examples are discussed below. 

To the extent that it is possible, we attempt to simplify the picture by discussing separately each of the cellular systems in which evidence exists for retinoid-mediated effects on protein kinases and protein phosphorylation. In studies of the biochemical effects of retinoids we are again faced with the central role occupied by their specific effects on neoplastic cells. The cellular systems employed for these studies have been either murine embryonal carcinoma cells (F9) or human promyelocytic leukemia cells (HL-60), each of which has been demonstrated to undergo terminal differentiation to nonneoplastic cell types following retinoid treatment (see Section IV,B,1 and 2), or murine melanoma cells in which retinoids have a marked antiproliferative effect (Section IV,B,3). 

Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393 386-389 Lotan R (1980) Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta 605 33-91... 

Mordan LJ, Mariner JE, Bertram JS (1983) Quantitative Neoplastic Transformation of C3H/10T1/2 Fibroblasts Dependence upon the Size of the Initiated Cell Colony at Confluence. Cancer Res 43 4062-4067 Loewenstein Rose B (1992) The cell-cell channel in the control of growth. Semin Cell Biol 3 59-79 Mordan LJ, Bertram JS (1983) Retinoid effects on cell-cell interactions and growth characteristics of normal and carcinogen-treated C3H/10T1/2 cells. Cancer Res 43 567-571... 

Whether the cells are derived from an established cell line or from primary cultures is another element that must be considered. While primary cultures most closely resemble the parent cell type in vivo, most cell culture experiments have been carried out using established cell lines, many of which are aneuploid. The ready availability of these established cell lines, many of which are neoplastic, and their reproducible response pattern have made them the subject of numerous investigations of retinoid action. However, their physiological relevance may be questionable therefore it is important, whenever possible, to relate the observed in vitro effects to similar effects of retinoids in vivo. 

Other in vitro experiments utilizing a wide variety of cell lines, both epithelial and fibroblastic, both nonneoplastic and neoplastic, have both supported and amplified these earlier observations. To simplify the presentation of the complex effects of retinoids on glycoprotein synthesis, various experimental systems have been listed in Table I, A. Only general features common to these investigations are discussed here. 

Indeed, it has even been shown that there are some fully neoplastic, transformed cells that can be induced to undergo terminal differentiation in response to treatment with retinoids, with loss of their neoplastic properties. The most striking examples of this phenomenon are the induction of terminal differentiation in murine F9 teratocarcinoma cells (Strickland and Mahdavi, 1978 Strickland, 1981) and human promyelocytic leukemia cells (Breitman et at., 1980, 1981, 1983). However, this does not appear to be a general effect of retinoids, and there are unfortunately only a limited number of instances in which such profound effects of retinoids on differentiation of invasive tumor cells have been shown. 

These studies have thus demonstrated that the actions of retinoids as inhibitors of neoplastic transformation are highly correlated with their abilities to increase connexin 43 expression, increase GJC, decrease saturation density and suppress proliferation in confluent cultures. However, it must be noted that these are only correlations and cannot prove a cause and effect relationship. More recent studies have utilized molecular methodology to over-express connexin 43 in a variety of cell types without the requirement for retinoid treatment. As will be discussed later in this chapter, these studies are also highly supportive of the role of junctional... 

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