Possible Significance of Abnormal Dermal Collagen and of Epidermal Regeneration in the Pathogenesis of Skin Cancers

Gillman, Theodore; Penn, Jack; Bronks, Doris; Roux, Marie

doi:10.1038/bjc.1955.24

Cited by 39 publications

(5 citation statements)

References 7 publications

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“…There is nothing in the present observations which is incompatible with the suggestion already mentioned of Gillman et al (1955) regarding the possible histogenesis of tumours, or with that of Wolbach (1951) if it is qualified to admit the possibility of regeneration or attempted regeneration of hair follicles from the superficial epidermis. In Wolbach's view, carcinomas arise in papillomas, and papillomas arise from hair follicles which have lost their papilla rest cells, necessary for the organisation of the mature follicle.…”

Section: Discussioncontrasting

confidence: 91%

The Early Effects of 9: 10-Dimethyl-1:2-Benzanthracene on Mouse Skin, and their Significance in Relation to the Mechanism of Chemical Carcinogenesis

Orr¹

1955

Br J Cancer

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R{eceivedl for publication October 1 9, 1 955.IT is known that most skin carcinogens, applied to the body surface, are elimllinated froma the body in the course of a week or two. The resultant tumours take several months to appear. This would seemn to point to some sort of irlreversible action on one or mnore of the " permanent " structures (e.g., dermis, v-ascular or nerve ,supply, etc.) or on the treated field as a whole, rather than on inldividual epidermal cells which are subject to loss by attrition and otherwise.AWhen it was generally believed that carcinogens were only effective if applied at intervals over a long period, it was possible to accept the hypothesis of a direct attack on the cell, though even then it was difficult to understand why t;he later attacks were so mnuch more effective than the early ones. But when it was established by Berenbluni and Shubik (1947) that a single application of a potent carcinogen was adequate if followed up by a co-carcinogen (croton oil) which does not itself produce many tuinours, it became necessary to postulate a two-stage action if the direct cellular hypothesis was to survive.Experiments from this department (Billingham, Orr and Woodhouse, 1951 Mlarchant and Orr, 19i53, 19f55) have shown that if the actual carcinogen-treated epidermis is transplanted to an untreated site on the other side of the body, it (loes not develop tumours even if subsequently treated with croton oil. The same applies to thin Thiersch grafts; in order to transplant the carcinogenetic field it is necessary to use thick Thiersch or whole-skin grafts. On the other hanid, if the carcinogen-treated area is deprived of its original epidermis, and resuirfaced with untreated epidermis, tumours appear in the usual incidence.,Such findings strongly support the view that the essential action of the carcinogen is not on the epithelial cell itself, but there remained the possibility that the effective epithelium was contained in the deeper parts of the hair follicles. If so, it is strange that skin tumours induced in the ordinary way only rarely show trichoepithelionmatous structure (though the skin tumours of mice treated over a wider body field with methylcholanthrene in oil not infrequently show follicular or sebaceous differentiation). Though many workers have already investigated the role of hair follicles in experimental carcinogenesis, it was thought worth while to see what happens to the follicles after a single treatment with 9: 10-dimethyl-1: 2-benzanthracene, which was not one of the carcinogens included in a previous histological survey (Orr, 1938). The results, which form the subject of the present communication, were more dramatic than was anti-

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Section: Discussioncontrasting

confidence: 91%

The Early Effects of 9: 10-Dimethyl-1:2-Benzanthracene on Mouse Skin, and their Significance in Relation to the Mechanism of Chemical Carcinogenesis

Orr¹

1955

Br J Cancer

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“…Accumulating evidence currently points toward the impact of fibroblast‐secreted factors on keratinocyte repair and proliferation during NMSC development . Ultimately, this may have implications in the enhancement of protective and therapeutic strategies against UV‐induced malignancies.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Investigations on the Effect of Dermal Fibroblasts on Keratinocyte Responses to Ultraviolet B Radiation

Fernandez

Lonkhuyzen

Dawson

et al. 2014

Photochem & Photobiology

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Exposure to ultraviolet radiation is closely linked to the development of skin cancers in humans. The ultraviolet B (UVB) radiation wavelength (280-320 nm), in particular, causes DNA damage in epidermal keratinocytes, which are linked to the generation of signature premalignant mutations. Interactions between dermal fibroblasts and keratinocytes play a role in epidermal repair and regeneration after UVB-induced damage. To investigate these processes, established two and three-dimensional culture models were utilized to study the impact of fibroblast-keratinocyte crosstalk during the acute UVB response. Using a coculture system it was observed that fibroblasts enhanced keratinocyte survival and the repair of cyclobutane pyrimidine dimers (CPDs) after UVB radiation exposure. These findings were also mirrored in irradiated human skin coculture models employed in this study. Fibroblast coculture was shown to play a role in the expression and activation of members of the apoptotic cascade, including caspase-3 and Bad. Interestingly, the expression and phosphorylation of p53, a key player in the regulation of keratinocyte cell fate postirradiation, was also shown to be influenced by fibroblast-produced factors. This study highlights the importance of synergistic interactions between fibroblasts and keratinocytes in maintaining a functional epidermis while promoting repair and regeneration following UVB radiation-induced damage.

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“…Evidence is accumulating to indicate that tumours may arise when the ability of the hair follicle to differentiate is impaired because of loss of the dermal papilla rests or some other factor (cf. Wolbach, 1951;Gillman et al, 1955).…”

Section: Discussionmentioning

confidence: 99%

The effects of a single dose of 7,12-dimethylbenz(a)-anthracene on the epidermis and hair follicles of mice, with notes on concurrent changes in the ovaries and adrenals.

Bond¹,

Orr²

1969

Br J Cancer

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IN spite of the fact that skin was the first tissue in which chemical carcinogenesis was demonstrated, and that it is possible to study all stages of the carcinogenic process by inspection, there is still much controversy over the mechanism. One factor that has given rise to much debate is the part played by the hair follicles.In a previous paper (Orr, 1955), results were described which appeared to show that with a potent carcinogen the original hair follicles were completely destroyed, and replaced by differentiation from the regenerating epidermis, and that neither the original nor the neogenetic hair follicles gave rise to tumours.The earlier experiment was done with outbred albino mice. The present paper seeks to confirm and expand the results using pure-strain mice. During necropsies on the animals, changes were observed in the ovaries and adrenals, and brief notes on the nature of such changes have been appended to the main object of this communication. MATERIAL AND METHODSThree pure-line strains of mice were used: BALB/cf/Sp, March (MAf/Sp), and C3H/Sp. All mice were female; this was originally because of availability, but when during the experiment changes were observed in the ovaries, it was decided to continue with this sex. Twenty-eight mice of each strain were used. They were housed in metal boxes, up to three in a box, and fed on Purina Laboratory Chow, with water ad libiturn.They received one application (circa 0.15 ml.) of a 0.5% solution in acetone of 7,12-dimethylbenz(a)anthracene (DMBA), on the interscapular skin. Half of them received this on the first day of the experiment, the remainder 4 days later, to obviate the necessity for killing animals at the week-ends. One animal of each strain was killed with ether 4, 5, 6, 7, 9, 11, 13, 15, 17, 19, 21 and 28 days after DMBA. The remainder of the BALB/cf and MAf were then treated twice weekly with croton oil, 0.500 in acetone, to determine that the dose of DMBA was effectively carcinogenic. The painted area of skin, with a margin of unpainted skin, was removed, stuck on filter paper to keep it flat, fixed in Bouin's solution, embedded in paraffin wax, cut in the sagittal plane so as to get the hair follicles longitudinally, and stained with haematoxylin and eosin, and with toluidine blue (0.1%). When changes were noted at an early stage in the adrenals and ovaries, these organs were similarly processed for histology. Other organs were examined

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Possible Significance of Abnormal Dermal Collagen and of Epidermal Regeneration in the Pathogenesis of Skin Cancers

Abstract: Images Figs. 1-6 Figs. 7-12

Cited by 39 publications

References 7 publications

The Early Effects of 9: 10-Dimethyl-1:2-Benzanthracene on Mouse Skin, and their Significance in Relation to the Mechanism of Chemical Carcinogenesis

The Early Effects of 9: 10-Dimethyl-1:2-Benzanthracene on Mouse Skin, and their Significance in Relation to the Mechanism of Chemical Carcinogenesis

In Vitro Investigations on the Effect of Dermal Fibroblasts on Keratinocyte Responses to Ultraviolet B Radiation

The effects of a single dose of 7,12-dimethylbenz(a)-anthracene on the epidermis and hair follicles of mice, with notes on concurrent changes in the ovaries and adrenals.

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