Mechanisms for the Initiation and Promotion of Carcinogenesis: A Review and a New Concept  ROBERT E. SCOTT, M.D.  Mayo Clinic Proceedings  Volume 59, Issue 2, Pages 107-117 (February 1984) DOI: 10.1016/S0025-6196(12)60244-4 Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 1 Diagrammatic representation of initiation and promotion stages of carcinogenesis (top line) and the progression stage (bottom line). Initiation is depicted as a short interval during which a carcinogenic agent can induce a change in a cell which predisposes it to malignant transformation. In contrast, promotion is illustrated as a longer time interval during which repeated exposures to an active agent can induce the initiated cell to express the transformed phenotype (see text for additional description). Furthermore, progression is depicted as the time during which the transformed cell develops into a tumor. This process is influenced by immune responses, nutrient requirements, and vascularization of transformed cells. Large cluster of cells at lower left represents a tumor, and smaller cluster of cells below it represents cells that have detached and metastasized. Mayo Clinic Proceedings 1984 59, 107-117DOI: (10.1016/S0025-6196(12)60244-4) Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 2 Photomicrographs of human epithelium, showing normal organization (left) with proliferative cells adjacent to basement membrane (white arrow) and differentiated cells in suprabasal position (asterisk), especially on the epithelial surface. Maintenance of this architectural organization necessitates intact mechanisms for the integrated control of cell proliferation and differentiation. In contrast, the epithelium on the right represents “severe dysplasia/carcinoma in situ” and shows abrogation of the integrated control of cell proliferation and differentiation, as evidenced by presence of mitotic cells high in the epithelium (black and white arrows) and markedly aberrant differentiation. Mayo Clinic Proceedings 1984 59, 107-117DOI: (10.1016/S0025-6196(12)60244-4) Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 3 Phase microscopic appearance of undifferentiated 3T3 T proadipocytes (A) and differentiated 3T3 T adipocytes (B) that contain abundant refractive fat droplets. Many such cells have the appearance of so-called signet-ring cells. Mayo Clinic Proceedings 1984 59, 107-117DOI: (10.1016/S0025-6196(12)60244-4) Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 4 Schematic model of proadipocyte cell cycle, showing a series of different arrest states in G1. These are designated GD, GS, GC, and GN. The GD arrest state is the state at which cells must undergo growth arrest before nonterminal (GD,) or terminal differentiation (TD). GS and GC are related states that are regulated by growth factor requirements; GS is induced by culturing low-density cells in serum-deficient medium, and GC is induced by culturing cells at high density such that they deplete the medium of growth factors. GN is the G1 arrest state induced by nutrient deficiency—specifically, isoleucine deficiency in our studies. S, G2, and M denote other phases of the cell cycle. Mayo Clinic Proceedings 1984 59, 107-117DOI: (10.1016/S0025-6196(12)60244-4) Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 5 Schematic model for integrated control of cell proliferation and differentiation, showing that at least five steps are involved in this process. Cells first show growth arrest at the GD state (arrow 1). At GD, cells can remain quiescent, they can reinitiate proliferation (large arrow 5), or they can differentiate (arrows 2 and 3). If differentiation is induced, it is at least a two-step process. Cells first undergo nonterminal differentiation (arrow 2) and can maintain the nonterminally differentiated phenotype at the state designated GD,. The integrated control of cell proliferation and differentiation can be mediated at GD, as well as at GD. GD, cells can remain quiescent, they can undergo terminal differentiation (TD) (arrow 3), or they can reinitiate proliferation either while retaining the differentiated phenotype (small arrow 5) or after being induced to lose the differentiated phenotype (arrow 4 and then large arrow 5). Specific human plasma factors have been identified which regulate the process of GD arrest and differentiation, and specific vitamin, chemical, and growth factors have been identified which regulate proliferation with or without loss of the differentiated phenotype. Mayo Clinic Proceedings 1984 59, 107-117DOI: (10.1016/S0025-6196(12)60244-4) Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 6 New schematic model for initiation and promotion of carcinogenesis. This model suggests that initiation of carcinogenesis may result from defects in the integrated control of differentiation and proliferation (large stippled arrow) and that promotion may result when initiated cells are induced to proliferate aberrantly as a result of defective autoregulatory control processes that cause them to override growth-regulatory restriction points such as those at GD, GD, GS, and GC (large white arrow). Mayo Clinic Proceedings 1984 59, 107-117DOI: (10.1016/S0025-6196(12)60244-4) Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions

Fig. 7 Complex model, illustrating how specific defects in the integrated control of cell proliferation and differentiation can account for initiation and promotion of carcinogenesis that gives rise to tumors with a variety of different phenotypes (see text). Dotted lines indicate proposed sites of defects in the integrated control of cell proliferation and differentiation which may be associated with initiation of carcinogenesis. Heavy solid lines indicate proposed sites at which autoregulatory growth-control processes override growth-regulatory restriction points and thereby mediate the promotion of carcinogenesis. Asterisk (*) represents all three backup G1 growth-regulatory states (GC, GS, and GN). Mayo Clinic Proceedings 1984 59, 107-117DOI: (10.1016/S0025-6196(12)60244-4) Copyright © 1984 Mayo Foundation for Medical Education and Research Terms and Conditions