(1973). The Function and Mechanism of Promoters of Carcinogenesis. CRC Critical Reviews in Toxicology: Vol. 2, No. 4, pp. 419-444.

The Function and Mechanism of Promoters of Carcinogenesis

Publisher Summary This chapter reviews the studies on the mechanism of tumor promotion in mouse skin by croton oil and phorbol diesters and on the effects of these compounds on cell cultures of various types. The chapter discusses the findings in the field of tumor promoters during mid- 1979 and provides sources in the literature that are useful as background. For an historical perspective of the concept of two-stage carcinogenesis and tumor promotion are described. The demonstration of two distinct stages in experimentally induced cancer in animals suggests that there are two stages in environmentally induced cancer in humans. Tumor induction can be divided into two distinct treatment stages, initiation and promotion, and that the promotion stage is reversible. Compounds with tumor-promoting activity are a class of cocarcinogens that are not themselves mutagenic or carcinogenic but that cause the formation of tumors when applied repeatedly after an irreversible event has been "initiated" by a carcinogen. Prevention of human cancer requires the identification and, wherever possible, the elimination of these agents. Because promotion is a reversible process that requires repeated exposure over a period of time, in contrast to the rapid, irreversible process of initiation by carcinogens, manipulation of promotion would seem to be the best method of cancer prevention. The identification of promoters in the environment, and the elucidation of their mechanisms of action, could lead to prophylactic measures such as the development of drugs specifically designed to interfere with the promotion mechanism and prevent tumor formation.

Tumor promoters and the mechanism of tumor promotion.

At a level which was effective as a skin tumor promoter, croton oil increased the rate of incorporation of tritiated precursors into mouse skin macromolecules. After a single application of croton oil, the early 2- to 3-fold stimulation of RNA and protein synthesis and the 60% inhibition of DNA synthesis was followed by a 3-fold stimulation of DNA synthesis at 18 hr. The rates of macromolecular synthesis returned to normal levels within 7 days. A single application of cantharidin, a weak tumor promoter, stimulated both DNA and RNA synthesis in mouse skin. Treatment with either croton oil or cantharidin stimulated the synthesis of rapidly labeled RNA when measured 2 hr after treatment; stimulation of RNA synthesis may be important in the process of promotion. When an incision was made in initiated skin, tumors developed along the line of wound healing. Because croton oil, cantharidin, and other promoters cause hyperplasia and because wound healing causes a local stimulation of mitosis, a stimulation of cell division may be involved in promotion. A possible molecular mechanism of skin carcinogenesis is discussed.

https://cancerres.aacrjournals.org/content/canres/30/2/312.full.pdf

Studies on the mechanism of skin tumor promotion.

https://backend.orbit.dtu.dk/ws/files/152316057/Accepted_article.pdf

Toxicity of silver ions, metallic silver, and silver nanoparticle materials after in vivo dermal and mucosal surface exposure: A review

The first indication that experimental carcinogenesis could be augmented by the addition of noncarcinogenic stimuli resulted from scarification of mouse skin combined with, or following, tar painting (Deelman, 1924; Deelman and van Erp, 1926), and later, from combined applications of carcinogenic hydrocarbons with (noncarcinogenic) creosote oil (Sall et al., 1940). But the establishment of sequential stages in carcinogenesis arose by the convergence of two subsequent lines of inquiry.

Sequential Aspects of Chemical Carcinogenesis: Skin

The correlation of promotion of tumour growth and of induction of hyperplasia in epidermal two-stage carcinogenesis

The correlation of promotion of tumour growth and of induction of hyperplasia in epidermal two-stage carcinogenesis.

Human papillomavirus (HPV), most commonly HPV16, causes a growing subset of head and neck squamous cell carcinomas (HNSCCs), including the overwhelming majority of oropharynx squamous cell carcinomas in many developed countries. Circulating biomarkers for HPV‐positive HNSCC may allow for earlier diagnosis, with potential to decrease morbidity and mortality. This case‐control study evaluated whether circulating tumor HPV DNA (ctHPVDNA) is detectable in prediagnostic plasma from individuals later diagnosed with HPV‐positive HNSCC. Cases were participants in a hospital‐based research biobank with archived plasma collected ≥6 months before HNSCC diagnosis, and available archival tumor tissue for HPV testing. Controls were biobank participants without cancer or HPV‐related diagnoses, matched 10:1 to cases by sex, race, age and year of plasma collection. HPV DNA was detected in plasma and tumor tissue using a previously validated digital droplet PCR‐based assay that quantifies tumor‐tissue‐modified viral (TTMV) HPV DNA. Twelve HNSCC patients with median age of 68.5 years (range, 51‐87 years) were included. Ten (83.3%) had HPV16 DNA‐positive tumors. ctHPV16DNA was detected in prediagnostic plasma from 3 of 10 (30%) patients with HPV16‐positive tumors, including 3 of 7 (43%) patients with HPV16‐positive oropharynx tumors. The timing of the plasma collection was 19, 34 and 43 months before cancer diagnosis. None of the 100 matched controls had detectable ctHPV16DNA. This is the first report that ctHPV16 DNA is detectable at least several years before diagnosis of HPV16‐positive HNSCC for a subset of patients. Further investigation of ctHPV16DNA as a biomarker for early diagnosis of HPV16‐positive HNSCC is warranted.

P Stephens

Papers

The correlation of promotion of tumour growth and of induction of hyperplasia in epidermal two-stage carcinogenesis.

Detection of circulating tumor human papillomavirus DNA before diagnosis of HPV‐positive head and neck cancer