An initiator of carcinogenesis selectively and stably inhibits stem cell differentiation: a concept that initiation of carcinogenesis involves multiple phases.

Abstract

A concept of carcinogenesis was recently de-vised in our laboratory that suggests the development of defects in the control of cell differentiation is associated with an early phase of carcinogenesis. To test this proposal directly, the effects of an initiator of carcinogenesis (i.e., UV irradiation) on proadipocyte stem cell differentiation and proliferation was assayed. (7,8). These clinical observations and the results of our previous experimental studies (9-11) and those of others (12)(13)(14) form the data base for our concept of carcinogenesis. This concept proposes that the development of defects in the control of differentiation represents an early phase of carcinogenesis, whereas the development of defects in the control of proliferation represents a later phase in the transformation process. In this regard, we have suggested that the development of defects in the control of differentiation and proliferation is mediated at distinct cell cycle states (Fig. 1). This suggestion is based on data that demonstrated that, in proadipocyte stem cells, cellular differentiation is mediated at a distinct complex G1 arrest state, designated GD/GD'/TD (15)(16)(17), and that cellular proliferation is further mediated at other G1 arrest states, such as those induced by growth factor deficiency, designated Gs/c, or by nutrient deficiency, designated GN (Fig. 1) (9, 10, 15, 18). To test the concept that an early phase of carcinogenesis is associated with the expression of defects in the control of differentiation, we performed the experiments reported in this paper. In these studies, we used incompletely initiated (19) and nontransformed proadipocyte stem cells (11). The results show that UV irradiation, an initiator of carcinogenesis (20, 21), selectively and stably inhibits proadipocyte stem cell differentiation without abrogating other mechanisms for the control of proliferation, such as those mediated at Gs/c and GN. The results also show that the development of defects in the control of differentiation occurs in a high percentage of UV-irradiated cells but that the vast majority of such cells are not transformed even though they do show an increased rate of spontaneous transformation.These observations have been synthesized with other data into an expanded concept that suggests that multiple phases are involved in the initiation of carcinogenesis. These include the development of (i) genetic instability and defects in the control of cellular commitment to differentiation, (ii) defects in the expression of the differentiated phenotype, and (iii) acquisition of responsiveness to tumor-promoting agents. METHODSCell Cultures and UV Irradiation. The proadipocyte stem cells used in this study are designated 3T3 T and were supplied by L. Diamond (22). These cells were cultured as described (15-17) and were repeatedly found to be free of mycoplasma contamination (23). They were passaged at 1-3 x 103 cells per cm2 and were allowed to grow in Dulbecco's modified Eagle's medium (DME medium)/10% fetal calf serum for 2...

Antidiabetic AD4743 enhances adipocyte differentiation of 3T3 T mesenchymal stem cells

“…The control of cellular differentiation and proliferation in normal cells is mediated in a complex fashion by a host of both positive and negative signals. Many studies indicate that the expression of defects in the coupling of cellular differentiation and proliferation are of etiological significance in various pathologic processes (Cherington et al, 1986(Cherington et al, ,1988Freytag, 1988;Scott and Maercklein, 1985;Sparks et al, 1986Sparks et al, , 1988. It is therefore of great importance to understand the mechanisms that regulate cellular proliferation and differentiation.…”

Stem Cell Technology–Emerging Framework for Hazard Assessment and Biosafety Considerations

“…Initiation of carcinogenesis involves a multi-stage process linked to defects in the control of stem cell differentiation (Scott & Maercklein, 1985). Increased spontaneous transformation of MSC in cell cultures exposed to a low dose of UV radiation is interpreted as part of the multi-stage process in carcinogenesis.…”

Suppression of tumorigenicity by the cell‐cycle‐dependent control of cellular differentiation and proliferation

“…In these studies we employed 3T3 T murine mesenchymal stem cells because they possess extremely well-characterized mechanisms to regulate both cellular differentiation and proliferation at distinct cell cycle states (Scott et al, 1982a(Scott et al, , 1985aScott and Maercklein, 1985). Non-mutagenic procedures were then employed to obtain 23 clonal variants of 3T3 T stem cells that expressed one of 4 distinct phenotypes for the regulation of cellular differentiation and proliferation.…”

“…In this regard, cancer cells typically show a reduced proclivity to differentiate and an increased proclivity to proliferate. Recent studies have, in fact, provided evidence that the expression of defects in the control of differentiation (Scott and Maercklein, 1985;Yuspa and Morgan, 1981) may be an early event in carcinogenesis and that expression of defects in the control of cellular proliferation associated with the expression of oncogenes may occur later in the process of carcinogenesis (Duesberg, 1983).…”

“…Since the control of both cellular differentiation and proliferation is regulated by cell-cycle-dependent mechanisms in many, if not all, cell types (Scott et al, 1982a;Wille and Scott, 1984;Pardee et al, 1978;Marks et al, 1982), we performed studies to determine if and how changes in such cell-cycle-dependent control processes can act to suppress carcinogenesis and the expression of tumorigenicity in vivo. In these studies we employed 3T3 T murine mesenchymal stem cells because they possess extremely well-characterized mechanisms to regulate both cellular differentiation and proliferation at distinct cell cycle states (Scott et al, 1982a(Scott et al, , 1984(Scott et al, , 1985aScott and Maercklein, 1985).…”