Natural History of Neoplastic Development: Initiation and Promotion

27 May

The nature of disease can be fully understood only in light of its pathogenesis or natural devel- opment within the organism. An understanding  of the pathogenesis  of disease is the basis for rational medical management  and therapy. The pathogenesis  of most infectious  diseases was elucidated prior to the discovery of antibiotics, thus permitting the use of these drugs in the ra- tional management and therapy of these diseases. Similarly, a better understanding of the patho- genesis of arteriosclerosis  has led to the rational use of diet in the control and management of this disease, which ultimately kills more individuals in our society than does cancer. Thus, it is reasonable to predict that enlarging our understanding of the pathogenesis of neoplastic disease will be equally useful.


One of the ubiquitous characteristics of the natural history of the development of a neoplasm in vivo is the extended period of time between the initial application of a carcinogen—be it physi- cal, chemical, or biological—and  the appearance of a neoplasm. This latency phenomenon  or tumor induction time, which can be demonstrated most readily following treatment with chemi- cal carcinogens,  has been shown to occur even when the carcinogen  is administered  continu- ously to an experimental animal. There is no obvious evidence of neoplastic growth or clinical neoplasia during the latency period. For example, when the carcinogen diethylstilbestrol  is ad- ministered to a pregnant animal, neoplasms appear only much later in the offspring. This latency phenomenon may also be seen after infection by some oncogenic viruses, ionizing radiation, or in the enigmatic production of sarcomas by the subcutaneous  implantation  of plastic or metal disks. Thus, the latency period of the carcinogenic process may be considered as a general fea- ture of the natural history of neoplasia. The period of latency varies with the type of agent, its dosage, and certain characteristics of the target cells as well as of the host.

Although morphological changes occurring during the early stages of neoplasia were de- scribed during the early decades of this century, it was in the 1940s that a better understanding of the biological changes that occur after exposure to a carcinogen was obtained. The beginnings of our understanding for the basis for the latency phenomenon in carcinogenesis was pioneered by Rous and Kidd (1941). Rous and his associates coined the term initiate in reference to the appli- cation of tar to the ear of a rabbit; subsequent wounding of the treated area promoted the appear- ance of neoplasms  growing  along the edge of the wound.  In 1944 Mottram  reported  that treatment  of mice with the irritant croton oil after a brief treatment  with a small amount of benz[a]pyrene resulted in a much higher incidence of skin tumors in the treated area than when the carcinogen was given alone. In 1947, Berenblum and Shubik’s extension of the work of Mot- tram clearly demonstrated that skin carcinogenesis in the mouse could be divided into a stage of initiation, which resulted from the direct administration  of a single dose of a known chemical carcinogen such as benz[a]pyrene or another carcinogenic polycyclic hydrocarbon, followed by a stage of promotion, which did not require the application of a carcinogenic agent but rather the repeated application of a second agent that by itself was incapable of inducing the neoplastic transformation.  These latter authors employed the irritant croton oil as the agent given repeat- edly, as had Mottram (1944), to complete the second stage, promotion.

The basic experimental protocol used by these investigators to demonstrate initiation and promotion in the development of skin cancer in the mouse, extended and refined by Boutwell (1964), is depicted in Figure 7.1. The experiment  was designed so that administration  of the “initiating agent” induced no tumors. When initiation was followed by chronic administration of croton oil, the promoting agent, in multiple doses, tumors developed whether the administration of croton oil was begun immediately  after initiation  or delayed for even as much as a year (Loehrke et al., 1983; Van Duuren et al., 1975), although the aging of the animal might decrease the efficiency of promotion (Chapter 8). Administration of croton oil prior to initiation or with-

Figure 7.1 Outline of the format of experiments  demonstrating  initiation  and promotion  as developed from studies of carcinogenesis  of mouse skin. Each line represents  an experimental  condition  in which there is either no application or a single application (x) of the initiating agent, usually a carcinogenic poly- cyclic hydrocarbon.  The multiple  vertical arrows represent  multiple  applications  of the promoting  agent (phorbol ester, phenobarbital,  or other known promoters for mouse skin). The time span may extend from 15 to more than 70 weeks, depending on the dosages of the initiator and promoter used, the mouse species and strain employed in the experiment, or the format of the experiment such as line 3, in which the delay between initiation and promotion may be more than a year. In line 6 the time intervals between applications of the promoting agent may be 4 weeks or more, whereas in the other experiments the promoting agent is administered twice weekly. The term tumors refers to papillomas or carcinomas, the latter occurring when the experiment is extended for a sufficiently long time.

out initiation resulted in no tumors. Interestingly,  when the frequency of administration  of the promoting agent was decreased to a tenth or less of the carcinogenic format, no tumors resulted (Boutwell, 1964). This last experiment suggested that the effects of the promoting agent were not very long lasting, in contrast to the effects of the initiating  agent (line 3). Boutwell  and others have maintained that the effects of promoting agents are reversible (see below).

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