Showing papers by "Randall J. Ruch published in 1999"

Gap junctional intercellular communication and connexin43 expression in human ovarian surface epithelial cells and ovarian carcinomas in vivo and in vitro.

Abstract: Gap junctional intercellular communication (GJIC) and the expression of gap junction proteins (connexins) are frequently decreased in neoplastic cells and have been increased by cAMP and retinoids. GJIC and connexin expression were investigated in early passage normal human ovarian surface epithelial (HOSE) cells, human ovarian adenocarcinoma cell lines (CaOV-3, NIH:OVCAR-3, SK-OV-3 and SW626) and surgical specimens of human serous cystadenocarcinomas. We hypothesized that GJIC and connexin expression would be decreased in neoplastic cells and would be increased by cAMP and retinoic acid. Cultured HOSE cells exhibited extensive fluorescent dye-coupling and connexin43 (Cx43) expression; other connexins were not detected. The ovarian adenocarcinoma cell lines had little dye-coupling or connexin expression. Deletions and rearrangements of the Cx43 gene were not detected by Southern blotting in the carcinoma lines. N6, 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate and all-trans-retinoic acid inhibited cell proliferation, but did not enhance GJIC or Cx43 expression. Surface epithelial cells of benign ovaries expressed Cx43, but this expression was barely detectable in ovarian serous cystadenocarcinomas. Thus, normal HOSE cells had extensive GJIC and Cx43 expression whereas ovarian carcinoma cells had less and cAMP and retinoic acid did not change these, although both agents inhibited cell growth.

The role of oval cells and gap junctional intercellular communication in hepatocarcinogenesis.

Abstract: The role of oval cells, and Gap Junctional Intercellular Communication (GJIC) in hepatic differentiation and neoplasia is controversial. Oval cells accumulate in great number when hepatocyte regeneration is blocked following massive hepatotoxicity or after treatment with some hepatocarcinogens. This suggests oval cells are facultative stem cells or close progeny of liver stem cells that are activated only under specific conditions. Studies with oval cell lines clearly indicate that they can differentiate into hepatocytes and that neoplastic derivatives of oval cells can produce hepatocellular and biliary neoplasms. Because hepatocytes express Cx32 and biliary cells express Cx43, the differentiation of oval cells into hepatocytes or In addition, because Cx32 hemichannels and Cx43 hemichannels cannot form heterotypic patent channels, the type of connexin expressed by the differentiating oval cell will determine whether it communicates with hepatocytes or biliary epithelial cells, respectively. This communication may be necessary for the further differentiation and regulated growth of the differentiating oval cells and impairment of this GJIC may contribute to the formation of hepatocellular and cholangiocellular neoplasms. The type of connexin expressed may also determine the susceptibility of the differentiating oval cells to the various types of rodent liver tumor promoters. Thus, three major points have been developed here. First, Cx32 or Cx43 expression and GJIC with hepatocytes or biliary epithelial cells, respectively, may determine the final differentiated fate of oval cells. Secondly, blocked GJIC may determine whether oval cells progress to hepatocellular or cholangiocellular carcinoma. Lastly, the ability of tumor promoters to block Cx32 or Cx43-mediated GJIC in differentiating oval cells may determine whether these agents promote the formation of hepatocellular or cholangiocellular carcinomas. Thus, GJIC may be the key factor in the differentiation of oval cells and blocked GJIC may promote their neoplastic transformation in a lineage-specific manner. In this chapter, we have outlined several new hypotheses on the role of oval cells and GJIC in hepatocarcinogenesis. We hope that other investigators will consider our ideas, but realize these views will be contentious to many. Our intent, however, was to stimulate discussion and debate, even argument, because truth often arises amidst controversy and may be found in the most peculiar places.

Chapter 24: Role of Gap Junctions in Cellular Growth Control and Neoplasia: Evidence and Mechanisms

Abstract: Publisher Summary This chapter focuses on the role of gap junctional intercellular communication (GJIC) in cellular growth control and neoplasia and considers the large body of evidence concerning this role. It also presents a model of how GJIC might contribute to cellular growth regulation. More than three decades ago, Loewenstein and Kanno were the first to hypothesize a role for GJIC in the control of cellular growth and defective GJIC in cancer. This hypothesis was proposed before the first ultrastructural description of a gap junction or the availability of molecular tools to study gap junctions and their protein subunits, the connexins. The hypothesis is a marvel of scientific insights. More recently, the laboratories of Yamasaki, Trosko, Mehta, Naus, Lau, and others have made major contributions to the field. They have been leaders in the validation of the Loewenstein and Kanno hypothesis and the development of this rapidly expanding area of gap junction research.