Functional evidence for tumor-suppressor activity on chromosome 15 in human skin carcinoma cells and thrombospondin-1 as the potential suppressor

Boukamp, Petra; Bleuel, Kerstin; Popp, Susanne; Vormwald-Dogan, Vera; Fusenig, Norbert E.

doi:10.1002/(sici)1097-4652(199711)173:2<256::aid-jcp31>3.0.co;2-b

Cited by 19 publications

(10 citation statements)

References 7 publications

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“…TSP-1 was first discovered as a high molecular weight glycoprotein released by platelets in response to thrombin stimulation [60]. TSP-1 was subsequently mapped to chromosome 15 via translocation studies in squamous cell carcinoma (SCC) cell lines [61], and it has become recognized as a potent endogenous inhibitor of tumour angiogenesis in epithelial tissues including the skin [62][63][64]. As well, targeted overexpression of TSP-1 in the epidermis of transgenic mice prevents UVB-induced angiogenesis and cutaneous photo-damage [65].…”

Section: Discussionmentioning

confidence: 99%

Microarray analysis of UVB-regulated genes in keratinocytes: downregulation of angiogenesis inhibitor thrombospondin-1

Howell

Wang

Freed

et al. 2004

Journal of Dermatological Science

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Section: Discussionmentioning

confidence: 99%

Microarray analysis of UVB-regulated genes in keratinocytes: downregulation of angiogenesis inhibitor thrombospondin-1

Howell

Wang

Freed

et al. 2004

Journal of Dermatological Science

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“…TSP‐1 suppresses EC proliferation and migration, neovessel formation and tumour growth (Tolsma et al. 1993; Boukamp et al. 1997; Streit et al.…”

Section: Initial Steps In Psoriasis Pathogenesis: the Unsolved Riddlementioning

confidence: 99%

Angiogenesis drives psoriasis pathogenesis

Heidenreich

Röcken

Ghoreschi

2009

Int J Experimental Path

325

301

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Summary Psoriasis pathogenesis is closely associated with disease‐inducing Th1 and Th17 cells. Yet, several studies suggest that aberrant keratinocyte or endothelial cell signalling significantly contributes to disease manifestation. Histological hallmarks of psoriatic skin include the infiltration of multiple immune cells, keratinocyte proliferation and increased dermal vascularity. Formation of new blood vessels starts with early psoriatic changes and disappears with disease clearance. Several angiogenic mediators like vascular endothelial growth factor, hypoxia‐inducible factors, angiopoietins and pro‐angiogenic cytokines, such as tumour necrosis factor (TNF), interleukin (IL)‐8 and IL‐17, are up‐regulated in psoriasis development. Contact‐ and mediator‐dependent factors derived from keratinocytes, mast cells and immune cells may contribute to the strong blood vessel formation of psoriasis. New technologies and experimental models provide new insights into the role of angiogenesis in psoriasis pathogenesis. Interestingly, many therapies target not only immune cells, but also protein structures of endothelial cells. Here we summarize the role of pro‐angiogenic factors in psoriasis development and discuss angiogenesis as a potential target of novel therapies.

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“…Thus, we hypothesized that genes on this chromosome may have acted as tumor suppressors, because malignant conversion was obviously associated with loss of one or two copies of this chromosome. Consequently, reintroduction of a normal copy of chromosome 15 into a cell line isolated from a squamous cell skin carcinoma showing underrepresentation of chromosome 15 induced a significant delay in tumor growth [60] (Bleuel K, Popp S, Fusenig NE, Stanbridge EJ, Boukamp P, submitted for publication; see also below). These data clearly substantiate that mere expression of the ras oncogene in an immortalized human keratinocyte cell population was not sufficient to induce tumorigenic growth.…”

Section: Genetic Alterations In Tumorigenicmentioning

confidence: 99%

Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes

1998

Self Cite

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An in vitro carcinogenesis model of human skin keratinocytes has been developed based on the spontaneously immortalized keratinocyte cell line HaCaT. Immortalization, the initial stage in human carcinogenesis in vitro, was induced by ultraviolet-type mutations in the p53 gene followed by further genetic alterations leading to the loss of senescence genes, in particular on chromosome 3p. Despite multiple genetic changes, the HaCaT cell line sustained its genomic balance up to high passage levels and maintained a non-tumorigenic phenotype. Tumorigenic transformation was induced by ras oncogene transfection but also by culture stress and elevated temperature, resulting in benign and malignant tumorigenic clones. Malignant conversion was associated with the loss of a copy of chromosome 15, leading to a decrease in thrombospondin-1 (TSP-1) expression. Heat-induced malignant conversion was associated with a gain of material on chromosome 11, including the cyclin D1 gene. The microenvironment plays a major role in tumorigenic transformation and the control of malignant cells. Overexpression of platelet-derived growth factor in HaCaT cells caused mesenchyme activation and formation of benign tumors. Halting tumor angiogenesis completely prevented invasion of malignant cells and induced a benign tumor phenotype. Transfer of a normal chromosome 15 or TSP-1 transfection into a skin carcinoma line resulted in tumor suppression due to TSP-1-blocked tumor vascularization. Because of the reduced TSP-1 expression, blood vessels infiltrated the tumor, and it expanded. Progression to more aggressive tumor phenotypes required the in vivo environment and was caused by selection of a subpopulation and further genetic modifications. The improved autonomous growth of these cells was associated with new expression of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, which acted in an autocrine manner to stimulate proliferation and migration. With this in vitro skin carcinogenesis model we were able to demonstrate multiple stages in the transformation process that were associated with different genetic and phenotypic characteristics. In addition, we documented that modulation of the tumor stroma plays an important and decisive role in tumor development and progression. From this we hypothesize that the growth restraints of the microenvironment are increasingly lost with advancing stages of carcinogenesis but can be restored by modulation of the tumor stroma.

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Functional evidence for tumor-suppressor activity on chromosome 15 in human skin carcinoma cells and thrombospondin-1 as the potential suppressor

Cited by 19 publications

References 7 publications

Microarray analysis of UVB-regulated genes in keratinocytes: downregulation of angiogenesis inhibitor thrombospondin-1

Microarray analysis of UVB-regulated genes in keratinocytes: downregulation of angiogenesis inhibitor thrombospondin-1

Angiogenesis drives psoriasis pathogenesis

Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes

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