The conversion stage of skin carcinogenesis

Marks, Friedrich; Fürstenberger, Gerhard

doi:10.1093/carcin/11.12.2085

Cited by 43 publications

(27 citation statements)

References 61 publications

(81 reference statements)

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“…For more details and an indepth discussion of mechanistic aspects of conversion, see Marks and Furstenberger (13).…”

Section: Hyperplastic Transformation and Tumor Promotionmentioning

confidence: 99%

“…Together with other skin cells (for instance the antigen-presenting Langerhans cells), the keratinocyte is not only the body's most advanced outpost, but it occupies a central position as a signaling interface between the surrounding environment and the body (15 (Fig. 3) called stroma reaction, which is a critical condition of tumor growth (2,13,24). One important aspect of the network appears to be the interaction between keratinocytes and T-lymphocytes (16,25).…”

Section: The Activated Keratinocytementioning

confidence: 99%

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Proliferative Responses of the Skin to External Stimuli

Marks¹,

Fürstenberger²

1993

Environmental Health Perspectives

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The skin, in particular the epidermis, offers unique opportunities to investigate the induction and control of cellular proliferation and tissue homeostasis both under in vivo and in vitro conditions. Moreover, it represents one of the most feasible model systems for experimental cancer research. As the primary border of the body, the skin has important protective and defensive functions. A general response to external injury consists of a thickening of the epithelial layer (epidermal hyperplasia) combined with an inflammatory reaction. This hyperplastic transformation of the skin is a critical condition of skin tumor development (i.e., conversion and promotion) and of the wound response. It is believed to be due to a transformation of keratinocytes into an activated state characterized by an increased rate of proliferation and the ability to release a series of growth factors and other cytokines that coordinate the defense reaction (e.g., hyperproliferation, recruitment of leukocytes, activation of the immune system) along autoand paracrine feedback loops. The initial and probably later phases of this response depend critically on a local release of eicosanoids such as prostaglandins and lipoxygenase-generated factors. A unique reaction seen upon phorbol ester treatment of mouse skin is a strong induction of the enzyme 8-lipoxygenase, which might be involved in skin tumor development by catalyzing the generation of clastogenic metabolites thought to play a role in the conversion stage.Hyperplasia may be considered to be the result of an imbalance between the rates of cell gain and cell loss. Therefore, hyperplastic transformation has to be distinguished from another response of skin to external stimuli where the homeostatic equilibrium is maintained (i.e., no hyperplasia develops in spite of strong hyperproliferation). This balanced hyperproliferation as induced by mild stimuli (pressure, phorbol ester 4-O-methyl-TPA) is neither accompanied by inflammatory reactions nor by the symptoms of keratinocyte activation. It may simply be due to an increased rate of cell-cycle traverse in the proliferative tissue compartment. In contrast, the prostaglandin-dependent activation of keratinocytes leading to hyperplastic transformation resembles in many aspects (such as, for instance, the activation of cell -cycle-related genes) the Go-S transition of cells in vitro. The control of proliferative homeostasis in normal epidermis is an unresolved problem. It is not known whether the rate of cell proliferation adapts automatically to the rate of terminal differentiation or whether this adaption is regulated by local factors such as the elusive chalones or other inhibitory signals like transforming growth factor [B.The same is true for stimulatory growth factors such as epidermal growth factor and transforming growth factor-a whose fimction may be that of wound hormones rather than of homeostatic regulators of normal tissue regeneration.

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“…For more details and an indepth discussion of mechanistic aspects of conversion, see Marks and Furstenberger (13).…”

Section: Hyperplastic Transformation and Tumor Promotionmentioning

confidence: 99%

Section: The Activated Keratinocytementioning

confidence: 99%

Proliferative Responses of the Skin to External Stimuli

Marks¹,

Fürstenberger²

1993

Environmental Health Perspectives

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“…The contrasting effects of the two phorbol esters TPA and retinoylphorbol acetate (RPA) on mouse skin tumorigenesis provide another example of the complex relationship between cell proliferation and carcinogenesis in mouse skin (74). Both TPA and RPA induce hyperplasia, but RPA is ineffective in promoting the early stages of malignant transformation in NMRI and CD-1 strains of mice.…”

Section: Proliferative Responses To Cytotoxic Damagementioning

confidence: 99%

Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Croy¹

1993

Environ Health Perspect

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There is much interest in incorporating knowledge of biological mechanisms of carcinogenesis into assessments of health risks to humans posed by chemicals in the environment. Debate over the soundness of using data from animal bioassays conducted at minimally toxic doses or fractions thereof for predicting cancer risks to humans exposed to much lower doses has stimulated interest in the question of whether genotoxic or mitotic effects predominate in chemical carcinogenesis. Cell division plays a key role at each stage in the evolution of cancer, and it is well documented that increased rates of cell proliferation can escalate the risk of malignancy. This article examines the current understanding of both mechanisms by which chemicals provoke cell proliferation and the contribution of various kinetic patterns of cell proliferation to carcinogenesis.

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“…One of the best-established in vivo models for multistage carcinogenesis is the chemically induced tumor model of mouse back skin, in which tumor initiation is achieved by the mutagen 7,12-dimethylbenz(a)anthracene and tumor promotion is driven by phorbol esters, such as 12-Otetradecanoylphorbol-13-acetate (TPA; refs. 3,4). Recently, we applied global gene expression analysis on samples derived from distinct tumor stages and could identify a comprehensive list of novel tumor-associated genes (5)(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Kallikrein 6 Induces E-Cadherin Shedding and Promotes Cell Proliferation, Migration, and Invasion

et al. 2007

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Recently, we described phorbol ester-induced expression of the brain and skin serine proteinase Bssp/kallikrein 6 (Klk6), the mouse orthologue of human KLK6, in mouse back skin and in advanced tumor stages of a well-established multistage tumor model. Here, we show KLK6 up-regulation in squamous skin tumors of human patients and in tumors of other epithelial tissues. Ectopic Klk6 expression in mouse keratinocyte cell lines induces a spindle-like morphology associated with accelerated proliferation, migration, and invasion capacity. We found reduced E-cadherin protein levels in the cell membrane and nuclear translocation of B-catenin in Klk6-expressing mouse keratinocytes and human HEK293 cells transfected with a KLK6 expression plasmid. Additionally, HEK293 cells exhibited induced T-cell factor-dependent transcription and impaired cell-cell adhesion in the presence of KLK6, which was accompanied by induced E-cadherin ectodomain shedding. Interestingly, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 interfere with KLK6-induced E-cadherin ectodomain shedding and rescue the cell-cell adhesion defect in vitro, suggesting the involvement of matrix metalloproteinase and/or a disintegrin and metalloproteinase (ADAM) proteolytic activity. In line with this assumption, we found increased levels of the mature 62-kDa ADAM10 proteinase in cells expressing ectopic KLK6 compared with mock controls. Finally, enhanced epidermal keratinocyte proliferation and migration in concert with decreased E-cadherin protein levels are confirmed in an in vivo Klk6 transgenic mouse model. [Cancer Res 2007; 67(17):8198-206]

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The conversion stage of skin carcinogenesis

Cited by 43 publications

References 61 publications

Proliferative Responses of the Skin to External Stimuli

Proliferative Responses of the Skin to External Stimuli

Role of chemically induced cell proliferation in carcinogenesis and its use in health risk assessment.

Kallikrein 6 Induces E-Cadherin Shedding and Promotes Cell Proliferation, Migration, and Invasion

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