Paracrine Factor and Cell-Cell Contact-Mediated Induction of Protease and c-ets Gene Expression in Malignant Keratinocyte/Dermal Fibroblast Cocultures

Ah, Borchers; Mb, Powell; Ne, Fusenig; Gt, Bowden

doi:10.1006/excr.1994.1183

Cited by 36 publications

(23 citation statements)

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“…As a whole, the results of Borchers et al (1994Borchers et al ( , 1997) and those presented in this study indicate that in the investigated model system MMP-9 is an example of a proteinase whose constitutive expression is increased in the higher tumorigenic cell line, but an additional increase, whether tumor or stroma cell-induced, is caused by interaction with the stroma. On the other hand, MMP-2 is a representative of those proteinases whose constitutive expression is enhanced in the tumorigenic cells, and tumor-stroma interaction does not result in further upregulation.…”

Section: Discussionsupporting

confidence: 60%

“…Recently, Borchers et al (1994) investigated II-4 cells (the corresponding II-4RT cells used in this study differ from II-4 in that they were re-established in culture after one in vivo passage of II-4 cells in athymic mice; Boukamp et al, 1990) for the induction of MMP-2 and MMP-9 expression when kept in monolayer coculture with human foreskin fibroblasts. They also studied HaCaT and II-4RT cells in an in vitro three-dimensional model, in which the keratinocytes were grown on a collagen gel embedded with human dermal fibroblasts (Borchers et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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Matrix Metalloproteinases-2, -3, -7, -9 and -10, But Not MMP-11, Are Differentially Expressed in Normal, Benign Tumorigenic and Malignant Human Keratinocyte Cell Lines

Bachmeier¹,

Boukamp²,

Lichtinghagen³

et al. 2000

Biological Chemistry

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In order to investigate the correlations between constitutive proteinase expression and the degree of tumorigenicity of cancer cells we have studied a model system of three keratinocyte cell lines. RT-PCR studies showed that the cell lines express the genes of matrix metalloproteinase-2, -3, -7, -9, -10 and -11, indicating that they are able to synthesize the corresponding enzymes. Actual MMP synthesis was proven by zymography and Western blotting. In conditioned media gelatinolytic activities or immunoreactive forms of MMP-2, -3, -7, -9, -10 and -11 were detected. The signal intensities showed that MMP secretion increases in the order HaCaT Ͻ A5 Յ II-4RT, whereas only MMP-11 is secreted by all cell lines in equal amounts. Intracellularly, enhanced levels of one or both of the tumorigenic variants were only found for MMP-3, -9 and -10, suggesting special functions of these intracellular MMP pools for the tumorigenic cell lines. For MMP-11 exclusive expression in stromal fibroblasts of tumor tissues is widely accepted; however, our results and three other recent reports demonstrate that this concept is not generally valid. In conclusion, the three keratinocyte cell lines investigated here represent an excellent model for studying constitutive expression and secretion of MMPs in correlation to the degree of in vivo tumorigenicity.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinases-2, -3, -7, -9 and -10, But Not MMP-11, Are Differentially Expressed in Normal, Benign Tumorigenic and Malignant Human Keratinocyte Cell Lines

Bachmeier¹,

Boukamp²,

Lichtinghagen³

et al. 2000

Biological Chemistry

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“…Recent in vivo studies have indicated that cancer cells are able to induce production of proteases by neighbouring stromal cells (Hewitt et al, 1991;Muller et al, 1991;Polette et al, 1991;Borchers et al, 1994). The inability to identify a specific MMP gene or genes common to all cancers supports the probability that progression may be affected by quantitative changes in levels of expression of one or more MMPs, differential expression of TIMP inhibitors, or qualitative changes in the specific genes expressed.…”

Section: Northern Blot Analysis Of Gelatinase a And B Transcriptsmentioning

confidence: 99%

Differential expression of matrix metalloproteinases in activated c-rasHa-transfected immortalized human keratinocytes

Meade-Tollin

Boukamp²,

Fusenig³

et al. 1998

Br J Cancer

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Summary Elevated expression of matrix metalloproteinases (MMPs), a family of secreted proteinases that degrade matrix components of basement membranes and connective tissues, is strongly correlated with malignant expression in various human epithelial cancers and epithelial cancer cell lines. We have tested whether elevated levels of MMP expression are also associated with malignant progression in human cutaneous squamous cell carcinoma. Constitutive levels of expression of steady-state mRNA and of secreted protein encoded by three MMP genes (matrilysin, gelatinases A and B) were compared in a unique in vitro model of human skin carcinogenesis. This model is composed of the parental immortalized non-tumorigenic human keratinocyte line (HaCaT), and three activated c-Harvey-ras-oncogene transfected variants (A-4, 1-7 and 11-4). Although clone A-4 is non-tumorigenic, clones 1-7 and 11-4 exhibit benign and malignant tumorigenic phenotypes, respectively, after subcutaneous injection into athymic nude mice. Northern blot, Western blot, and zymogram analyses revealed three MMP-specific patterns of expression. Constitutive matrilysin mRNA expression was markedly increased in the 1-7 cells compared with HaCaT, A-4 or 11-4 cells. Secreted promatrilysin was distinctly increased in the tumorigenic 1-7 and 11-4 cells compared with the nontumorigenic HaCaT and A-4 cells. Gelatinase A mRNA and secreted gelatinase A protein levels were increased in each transfectant compared with HaCaT. Both active and inactive forms of gelatinase A were detected. Gelatinase B transcripts were not detected, but an EDTA-inhibitable gelatinase activity comigrating with gelatinase B was moderately enhanced in both tumorigenic variants compared with the non-tumorigenic cells. Because promatrilysin and 92-kDa gelatinase secretion were increased in both benign and malignant tumorigenic cells, and not related to invasiveness in this model, it is concluded that enhanced constitutive expression of these two MMPs is associated with acquisition of the tumorigenic phenotype, before acquisition of the malignant phenotype.Keywords: matrilysin; gelatinase; matrix metalloproteinase; human; keratinocyte; HaCaT-ras; malignant progressionThe predominant cause of cancer morbidity and mortality is metastasis of malignant cells from the primary tumour to secondary sites. Therefore, a critical goal in cancer treatment is prevention of metastasis, a process that is considered to involve repeated proteinasemediated degradation and cancer cell invasion of basement membranes and underlying connective tissues. Members of the matrix metalloproteinase (MMP) family of zinc-containing endopeptidases may play a pivotal role in in vivo invasion and metastasis because they can degrade matrix components of the basement membrane. At least 15 different MMPs from human sources have been characterized (Pendas et al, 1997). MMPs are secreted as proenzymes, and are subsequently activated. Furthermore, modulation of MMP activity by endogenous tissue inhibitors of metalloproteinases (TIM...

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“…Furthermore, blocking the tumor promoterinduced AP-1 activity inhibited neoplastic transformation (Dong et al, 1994a, b;Huang et al, 1996c). In nude mice, the overexpression of a dominant negative mutant of Jun caused PDV carcinoma cells to lose their tumorigenicity Bowden et al, 1994;Borchers et al, 1994). Inhibition of AP-1 activity in transformed JB6 RT101 cells caused reversion of the tumor phenotype (Dong et al, 1995a, b;Lavrovsky et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Signal transduction through atypical PKCs, but not the EGF receptor, is necessary for UVC-induced AP-1 activation in immortal murine cells

Huang

Dong

1997

Oncogene

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The exposure of mammalian cells to ultraviolet (u.v.) irradiation leads to activation of transcription factors, such as AP-1 and NFkB. It is postulated that the EGF receptor but not protein kinase C (PKC) is the major membrane mediator in UVC-induced signal transduction. We demonstrate here that the antisense oligonucleotides of PKCz and the dominant negative mutant of PKCl/i as well as dominant negative PKCz markedly blocked UVC-induced AP-1 activity. In contrast, UVC-induced AP-1 activity in cells devoid of the EGF receptor (B82), is not signi®cantly di erent from that of the stable transfectants with a kinase-de®cient EGF receptor (B82M721), or wild-type EGF receptor (B82L). This was found at all UVC irradiation doses and time courses studied, while high levels of EGF-induced AP-1 activity were observed in B82L cells but not in B82 cells. This evidence strongly suggests that atypical PKCs, but not the EGF receptor, is necessary for UVC-induced AP-1 activation in JB6 and B82 cells.

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Paracrine Factor and Cell-Cell Contact-Mediated Induction of Protease and c-ets Gene Expression in Malignant Keratinocyte/Dermal Fibroblast Cocultures

Cited by 36 publications

References 0 publications

Matrix Metalloproteinases-2, -3, -7, -9 and -10, But Not MMP-11, Are Differentially Expressed in Normal, Benign Tumorigenic and Malignant Human Keratinocyte Cell Lines

Matrix Metalloproteinases-2, -3, -7, -9 and -10, But Not MMP-11, Are Differentially Expressed in Normal, Benign Tumorigenic and Malignant Human Keratinocyte Cell Lines

Differential expression of matrix metalloproteinases in activated c-rasHa-transfected immortalized human keratinocytes

Signal transduction through atypical PKCs, but not the EGF receptor, is necessary for UVC-induced AP-1 activation in immortal murine cells

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