Centuries ago, an obscure report on an unusual skin cancer launched the modern era of cancer research. Ever since, skin research has made key contributions to our understanding of the biology and biochemistry of cancer pathogenesis. In 1775, Percival Pott published his essay entitled Chirurgical observations Relative to the Cataract, the Polypus of the Nose, the Cancer of the Scrotum, [etc.] describing the origin of the ‘‘soot-wart’’, a cancer of the inferior surface of the scrotum occurring with high frequency in English chimney sweeps (Brown and Thornton 1957). Pott attributed the cause of this tumor to ‘‘the lodgement of soot in the rugae of the scrotum’’, thus providing in one description the first recognition of environmental and occupational cancer, the first identification of a human carcinogen, the first opportunity for cancer prevention, and a protocol for surgical treatment. Included in that 797 word essay was a remarkably detailed description of the course of the disease from a local confined lesion to invasive and then disseminated lethal cancer. These insights were little noticed for almost 150 years until (Yamagiwa and Ichikawa, 1918) reported that the chronic topical application of coal tar on rabbit ears produced cutaneous squamous cell carcinomas, the first chemical carcinogenesis experiment. By describing the evolution Figure 1 of individual lesions, Yamagiwa and Ichikawa concluded that cancer developed through multiple phenotypic stages and progressed even after the carcinogen was removed. Over the ensuing 20 years, many biologists and chemists sought to identify the active carcinogen in coal tar, culminating in 1932 with the report by a group led by Ernest Kennaway that 3,4 benzpyrene was the potent polycyclic aromatic hydrocarbon in coal tar that produced cancers when topically applied to mouse skin. Incorporated into this project was the isolation or synthesis of multiple carcinogenic hydrocarbons, all recognized by their action as skin carcinogens (summarized in Kennaway, 1955). At the same time, the availability of synthetic carcinogens and a reliable squamous cancer model emboldened a group of pathologists and biologists to methodically explore the pathogenesis of the neoplastic skin lesions. For the next two decades, these investigators discovered concepts regarding skin cancer development that dominate our current understanding of cancer development in almost all epithelial tissues. In particular, the work of Cecil Mottram, Friedewald and Rous (Rous later won the Nobel Prize for his work on the viral etiology of skin cancer), and Berenblum and Shubik led to the following conclusions on the biology of cancer: cancer occurs through multiple stages with distinct operational mechanisms and required sequence; cancer is more frequent when proliferating tissues are exposed to carcinogens; the extent of exposure or potency of the carcinogen determines the latent period for tumor development; tumor development does not require continuous exposure to carcinogenic agents and the effect of a subtumorigenic carcinogen exposure is permanent; tumors will develop after a subtumorigenic carcinogen exposure if the target tissue is subjected to regenerative hyperplasia as caused by repeated wounding or application of an irritant (Berenblum and Shubik, 1947, 1949; Mottram, 1944a, b; Berenblum and Haran, 1955; Berenblum, 1957; Friedewald and Rous, 1944). It was Friedewald and Rous who coined the terms ‘‘initiation’’ and ‘‘promotion’’ to distinguish the irreversible action of a carcinogen and the non-carcinogenic reversible activity of an irritant, still a major part of the cancer lexicon today. One of the important additions to the skin cancer protocols provided by Berenblum was the use of topical croton oil, a non-carcinogenic skin irritant that induced the outgrowth of tumors from skin that had been treated with a subtumorigenic dose of carcinogen (initiated). Croton oil (Crotonis Oleum) is prepared from the seeds of Croton tiglium, a tree belonging to the natural order Euphorbiales and family Euphorbiaceae. Croton oil had been used for centuries as folk medicine and was known to induce inflammation and peeling of skin when applied topically and diarrhea when taken internally. Its potency to promote tumors on skin catalyzed interest among cancer biologists to identify the active compounds contained within the complex mixture. In a series of brilliant chemical purifications and analyses, Van Duuren and Hecker almost simultaneously identified phorbol myristate acetate (12-O-tetradecanoyl-phorbol-13-acetate), commonly
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Apr 4, 2017
Lin Jiang + 8
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