Mechanisms for the Initiation and Promotion of Carcinogenesis: A Review and a New Concept

Abstract

Carcinogenesis in humans is a multistage process, and the two major stages have been designated initiation and promotion. Although the biochemical basis for initiation and promotion remains to be established, recent research has provided important insights into potentially significant biologic mechanisms. These data are reviewed, and a new concept of carcinogenesis is presented. This concept suggests that the initiation of carcinogenesis may result from cellular immortalization and the development of defects in the integrated control of stem cell proliferation and differentiation and that the promotion of carcinogenesis may result when such initiated stem cells develop aberrant autoregulatory growth-control properties.

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

“…These include cells of the preleukemic diseases and cells of metaplastic and dysplastic lesions of epithelial tissues (7,8). These clinical observations and the results of our previous experimental studies (9)(10)(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.…”

“…Nutrient-dependent arrest (GN) resulting from isoleucine deprivation at low density was also induced as described (15), the only modification being that low density cultures were plated at 3 x 103 cells per cm2. Cell cycle analysis was done with a FACS IV flow microfluorimeter and cell cycle distributions were studied as described (9,15,28).…”

“…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).…”

Chemical carcinogenesis

“…At this stage, the initiated cells can remain latent for weeks, months or years, or they can grow in an autonomous and clonal fashion (Scott et al 1984, Dybing and Sanner 1999, Player et al 2004). This initiation process ensures that cellular division remains symmetrical by creating two new initiated cells (Trosko 2003).…”

“…It is a stage that can be moulded up by physiological factors and therefore limit the extent of experimental carcinogenesis. Some promoter agents are specific for a particular tissue, but others act simultaneously upon several tissues (Yuspa et al 1983, Scott et al 1984, Yuspa and Poirier 1988, Gutiérrez and Salsamendi 2001.…”