Susan Pfeifer-Ohlsson

Coexpression of the sis and myc proto-oncogenes in developing human placenta suggests autocrine control of trophoblast growth

First trimester human placentas actively express the sis proto-oncogene, the structural gene for the B chain of platelet-derived growth factor (PDGF). Using the in situ hybridization technique, the 4.2 kb c-sis transcript has been localized to the cytotrophoblastic component, especially the highly proliferative and invasive cytotrophoblastic shell, paralleling the distribution of c-myc transcripts in early placenta. Explants of first trimester placenta release significant levels of PDGF-like activity into the medium under apparent developmental control. Moreover, cultured trophoblasts display abundant high-affinity PDGF receptors and respond to exogenous authentic PDGF by an activation of the c-myc gene and DNA synthesis. The developing human placenta may therefore represent a case of autocrine growth regulation in a normal tissue, in which cells bearing receptors for a growth factor can also synthesize and respond to that factor.

Spatial and temporal pattern of cellular myc oncogene expression in developing human placenta: Implications for embryonic cell proliferation

We have analyzed staged human placentas by Northern, dot blot, and in situ hybridization to human c-myc probes. Placental RNA exhibits a stage-specific appearance of a 2.4 kb transcript of the c-myc gene. The frequency of this transcript varies 20 to 30 fold over the course of placental development, showing a peak at 4-5 weeks after conception, where the myc transcripts comprise about 0.05% by weight of the total placental mRNA. A clear decline in placental c-myc transcription is seen before the end of the first trimester of pregnancy. In situ hybridization to 125I-labeled myc probes demonstrates an unequal spatial distribution of myc transcripts in placental with particularly high expression in the cytotrophoblastic shell of early placenta. Labeling of placental explants with 3H-thymidine, the localization of myc transcripts to cytotrophoblasts, and the temporal pattern of myc expression all support a strong correlation between myc transcript abundance and cytotrophoblast proliferation. We argue for a role for the c-myc gene in the proliferation of normal cells in this tissue.

Temporal and spatial pattern of cellular myc oncogene expression during human placental development.

The human placental trophoblast component is of embryonic origin and is developmentally regulated; the tissue is highly proliferative and often described as pseudomalignant. Because cellular oncogenes have been implicated in normal cellular proliferation and differentiation processes, we have studied c-myc oncogene expression in relation to the progression of human placental development. The c-myc transcript shows a 20- to 30-fold variation over the course of placental development, with a peak at four to five weeks after conception. A clear decline in placental c-myc transcription is seen before the end of the first trimester of pregnancy. In situ hybridization to [125I]-labelled myc probes demonstrates an unequal distribution of myc transcripts in placenta, with particularly high expression in the cytotrophoblastic shell of the early placenta. The localization of myc transcripts to cytotrophoblast and the temporal pattern of myc expression support a strong correlation between myc transcript abundance and cytotrophoblastic proliferation. These findings are discussed in the light of a possible role for the c-myc gene in proliferation of normal cells.

Myc Expression in vivo During Human Embryogenesis

The postulated involvement of the myc oncogene in human neoplasia (Klein 1983, Adams 1985, Little 1984) lends considerable support from work on the retroviral myc oncogene. Thus, the v-myc oncogene promotes, directly or indirectly, immortalization of target cells, evasion from normal regulatory growth controls in addition to tumorigenic behaviour of transformed cells injected into syngeneic animals (Rapp 1985, Blasi 1985, Pfeifer-Ohlsson 1983).

THE MOLECULAR AND CELLULAR BIOLOGY OF GROWTH STIMULATORY PATHWAYS DURING HUMAN PLACENTAL DEVELOPMENT

The human placenta transiently expresses tumour-like properties, such as explosive cell proliferation, cell invasiveness and immune privilege. It is not clear whether or not all of these properties can be found coexpressed in single cytotrophoblastic cells, the main cell component of first trimester pregnancies (1–3). The attainment of the explosive, proliferative cell phenotype of cytotrophoblasts following blastocyst implantation is likely, however, to be a pivotal event in the generation of the “pseudomalignant” phenotype of the human placenta. At the end of the first trimester of pregnancy, the cytotrophoblasts permanently lose their proliferative potential and undergo accelerated rates of differentiation into the syncytiotrophoblasts (1–3). We have been interested, for a number of years, in understanding how the balance between trophoblast proliferation and differentiation is developmentally controlled. Given the “pseudomalignancy” of the early human placenta, the mechanisms underlying this process should be interesting not only for developmental biology, but also for tumor biology. This report presents an account of our research into these issues.

Regulation of c-myc mRNA and Protein Levels During Activation of Normal Human B Cells

The myc oncogene has been implicated in the control of cellular proliferation in both normal and neoplastic cells. Recently, several cell lines have been shown to express c-myc mRNA and protein throughout the cell cycle (Thompson et al 1985; Hann et al 1985; Rabbitts et al 1985). However, in several cell systems triggering of quiescent cells into G1 is accompanied by a marked burst of c-myc mRNA, peaking a few hours after stimulation (Kelly et al 1983; Goustin et al 1985; Smeland et al 1985a). This has focused on a possible function for the c-myc product during the induction of competence to respond to progression growth factors acting in G1. This theory finds support in studies on fibroblast cell lines, where experimental manipulation of c-myc levels was related to cell cycle progression (Armelin et al 1984; Kaczmarek et al 1985). In both cases the increased myc levels provoked an increased sensitivity to the action of progression factors.