Initiation-promotion versus complete skin carcinogenesis in mice: importance of dark basal keratinocytes (stem cells)

Our plain-English summary of Initiation-promotion versus complete skin carcinogenesis in mice: importance of dark basal keratinocytes (stem cells), by T.J. Slaga, A.J. Klein-Szanto (Cancer Investigation, 1983).

The study

• Authors: T.J. Slaga, A.J. Klein-Szanto
• Journal: Cancer Investigation
• Published: 1983;1(5):425-36
• Type of article: Review
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Tumor promotion research has accelerated at an explosive level during the past decade and continues to do so because of its importance to the understanding of the induction of human cancer. Furthermore, the promotion process, being mostly reversible allows one to find very effective ways to prevent cancer. The extensive data available as well as the multistage nature of tumor promotion suggests that this process, which is thought to occur in most tissues where cancer can be induced or occurs spontaneously, may involve the interaction of a number of environmental factors such as chemical, radiation, viruses and diet and nutrition, thus unifying all of the current areas of cancer research. In terms of human cancer, smoking, asbestos, radiation, alcohol and diet, and nutrition just to mention a few, are not thought to have more than a promotional influence in the carcinogenesis process. Here and in later papers we will discuss some important aspects of promotion as well as discuss the possible controversial nature of this process. In this review we present data which suggest that carcinogenesis can be operatively and mechanistically divided into various stages.

In plain English

This was a review of mouse skin experiments, not a study of people. The authors summarized experiments applying chemicals to mouse skin, mostly in SENCAR mice bred for sensitivity to skin tumors. Asbestos appeared only in the abstract's list of human cancer factors; no asbestos data were presented. SENCAR mice initiated with DMBA or BP, then given twice-weekly TPA from one week later, showed a dose-response to the initiating dose. With TPA, 100 nmol DMBA gave 22.0 papillomas per mouse at 15 weeks and carcinomas in 100% of mice at 50 weeks, against 0.5 and 5% at 0.1 nmol. Dark basal keratinocytes, which the authors suggested may be stem cells, fell from about 40% before birth to about 3% after. TPA showed a dose-response as a promoter after DMBA initiation; repeated TPA alone had weak tumor-causing activity without a dose-response. Promotion could be split into two stages, which inhibitor chemicals affected differently. The authors concluded skin carcinogenesis in mice can be divided into at least three stages. They stated it is not known whether human cancer goes through similar stages.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of experimental animal (mouse skin) carcinogenesis studies, drawing on the authors' laboratory work and other published studies
• Who was studied: Mice of several stocks and strains (SENCAR, CD-1, ICR/HA Swiss, BALB/c, C57BL/6, C3H, DBA/2), mainly SENCAR mice; numbers of animals not given in the text; no human subjects
• Exposure: Chemicals applied to mouse skin: tumor initiators DMBA and benzo(a)pyrene (BP); tumor promoters TPA, mezerein and others; inhibitors of promotion fluocinolone acetonide (FA), retinoic acid (RA), TPCK and DFMO. Asbestos was not studied.
• Main results:
  • SENCAR mice were initiated with DMBA or BP and then given twice-weekly TPA applications starting 1 week later. In these mice, tumors rose with initiator dose. DMBA 100 nmol gave 22.0 papillomas per mouse at 15 weeks, 100% of mice with papillomas and 100% with carcinomas at 50 weeks. The figures were 6.8, 100% and 40% at 10 nmol; 3.2, 93% and 22% at 1 nmol; and 0.5, 20% and 5% at 0.1 nmol. BP 200, 100 and 50 nmol gave 7.5, 3.2 and 1.4 papillomas per mouse, with 55%, 30% and 18% of mice with carcinomas.
  • SENCAR mice were between 10 and 20 times more sensitive to DMBA tumor initiation than CD-1 mice, and between three and five times more sensitive to BP tumor initiation.
  • C57BL/6 mice were very refractory to two-stage carcinogenesis by BP-TPA, but responded very well to complete carcinogenesis by BP.
  • In SENCAR mouse epidermis, the percentage of dark basal keratinocytes reached a maximum at the nineteenth day of gestation (ca. 40%) and fell abruptly after birth to ca. 3%. Old animals had 0.2%.
  • TPA promotion after DMBA initiation (10 nmol) showed a very good dose-response, measured both as papillomas per mouse at 15 weeks and as percent of mice with squamous cell carcinomas at 50 weeks.
  • TPA applied repeatedly by itself, without initiation, showed weak complete carcinogenic activity but no dose-response relationship.
  • Mezerein, a weak promoter on its own, acted as a potent second-stage (Stage II) promoter after limited TPA treatment. This was repeated in more than 15 separate experiments.
  • Inhibitors acted at different stages. RA was ineffective in Stage I but a potent inhibitor of Stage II. TPCK inhibited Stage I but not Stage II. DFMO was a potent specific inhibitor of Stage II. FA inhibited both stages, more so Stage I.
  • FA and TPCK counteracted the appearance of dark cells induced by TPA, whereas RA and DFMO had no effect.
  • Asbestos appears only in the abstract, in a list of human cancer factors the authors said are not thought to have more than a promotional influence. No asbestos data were reviewed or presented.
• The authors' conclusion: The authors concluded that skin carcinogenesis can be operationally and mechanistically divided into at least three stages: initiation, Stage I of promotion and Stage II of promotion. In their view, stimulation of dark basal keratinocytes is important in Stage I, and polyamines and cell proliferation are important in Stage II.
• Limitations the authors state:
  • The rankings of mouse strain sensitivity were a subjective analysis based only on BP and DMBA, because dose-response data were not available for many strains.
  • The data suggesting that initiation is similar across mouse strains were described as far from conclusive.
  • It is not known whether other experimental systems or human cancer go through stages similar to those in mouse skin.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, STEM.

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