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

Bachmeier, Beatrice E.; Boukamp, Petra; Lichtinghagen, Ralf; Fusenig, Norbert E.; Fink, Edwin

doi:10.1515/bc.2000.064

Cited by 39 publications

(46 citation statements)

References 21 publications

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“…Elevated expression levels of MMP-9 are strongly correlated with malignant phenotype in SCC [34] and are characteristic of malignant transformation of cells [29]. In human keratinocyes constitutive production and secretion of MMP-9 correlate with the degree of tumorigenicity in malignantly transformed clones [33]. Thus, the dramatically increased secretion of MMP-9 observed in As-TM cells might be an important biomarker for arsenicinduced malignant transformation in human keratinocytes.…”

Section: Discussionmentioning

confidence: 97%

“…MMPs are a family of matrix-degrading enzymes that play a critical role in invasion and metastasis of malignant tumors and hypersecretion of MMPs is common in highly aggressive tumors [33]. MMP-9 specifically targets type IV collagen, a major component of basement membrane, and appears to play a crucial role in tumor invasion across the basement membrane [34].…”

Section: Discussionmentioning

confidence: 99%

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Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

162

147

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Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Diwan

Sun

et al. 2008

Free Radical Biology and Medicine

162

147

View full text Add to dashboard Cite

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“…When co-cultured with stromal fibroblasts malignant II-4 cells up-regulated MMP-1 and MMP-9 production while no up-regulation was found in benign A5 cells. In this study it was hypothesized that this reciprocal up-regulation of proteases between cancer cells and fibroblasts was likely to be mediated by soluble factors secreted by the cancer cells (Bachmeier et al, 2000). A more recent study showed that co-culture of non-malignant HaCaT cells with fibroblasts induced MMP-2 activation, an invasive phenotype and proteolysis of the ECM (Laeeq and Faust, 2007).…”

Section: Discussionmentioning

confidence: 97%

Nemosis of fibroblasts is inhibited by benign HaCaT keratinocytes but promoted by malignant HaCaT cells

et al. 2008

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Fibroblast Keratinocyte Growth factors A B S T R A C TCell-cell clustering of fibroblasts, called nemosis, leads to a massive growth factor, proteolytic and proinflammatory response. Culturing fibroblasts in conditioned medium collected from HaCaT keratinocyte cell panel representing different stages of skin carcinogenesis had a differential effect on fibroblast nemosis. Non-malignant keratinocytes had a nemosis-inhibiting effect on fibroblasts as seen by inhibition of COX-2 protein expression.Conditioned medium from malignant cells promoted fibroblast nemosis by inducing higher levels of COX-2, HGF/SF and VEGF. Even a small amount of malignant medium converted the inhibitory effect of benign medium, whereas non-malignant medium neutralized the nemosis-promoting effect of malignant medium. In collagen co-cultures benign keratinocytes caused a nemosis-inhibiting effect on fibroblast spheroids by inhibiting COX-2 induction, while with malignant keratinocytes myofibroblastic differentiation of fibroblasts was seen.

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“…12,13 The antibody has been already successfully used by other research groups. 15,16 It is produced continuously and will be provide for free to the scientific community upon request to Dr. Lichtinghagen. Thus, the antibody is well established and will be available to the research community in the future.…”

Section: Discussionmentioning

confidence: 99%

Prognostic impact of matrix metalloproteinase‐9 in operable non‐small cell lung cancer

Sienel¹,

Hellers²,

Morresi‐Hauf³

et al. 2002

Intl Journal of Cancer

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We assessed the clinical impact of MMP-9 expression on long-term survival in patients with operable non-small cell lung cancer (NSCLC). Primary tumors of 143 consecutive patients with NSCLC resected completely and without overt distant metastases (pT1-4, pN0-2, M0, R0) were examined for MMP-9 expression using immunohistochemistry with a polyclonal, affinity-purified rabbit antibody that recognizes both latent and active MMP-9. Immunohistochemical staining of tumor cells was evaluated in comparison to normal bronchiolar epithelium that served as an internal positive control. MMP-9 expression was categorized into negative, <5% tumor cells stained; heterogeneous, >5% and <95% tumor cells stained; and homogeneous, >95% The standard treatment for early stage NSCLC is surgery resulting in a 5-year survival rate of only 50 -60% in Stage I and II. 5,6 A better understanding of the molecular mechanisms of lung cancer progression might help to identify patients at risk for an unfavorable outcome with potential consequences for adjuvant therapy.Penetration of basement membranes and degradation of extracellular matrix are essential steps in the dissemination of tumor cells from primary tumors to distant organs. 7 One group of proteolytic enzymes that has been associated with these abilities is the matrix metalloproteinase family (MMP). Matrix metalloproteinase 9 (MMP-9) (92 kDa Type IV collagenase or gelatinase B) has the potency to degrade gelatin and Type IV collagen, 8 which is a major component of basement membranes. The clinical relevance of MMP 9 in NSCLC remains in discussion. First clinical trials investigating the efficacy of MMP-inhibitors in advanced cancer were rather disappointing. 9 Furthermore, previous studies examining the prognostic impact of immunohistochemical detection of MMP-9 in NSCLC 10,11 are discussed controversially because they did not demonstrate an independent prognostic impact of MMP-9 considering all standard prognostic factors included in the international system for staging lung cancer. 6 To clarify the prognostic impact of MMP 9 in operable NSCLC, we applied a new immunohistochemical evaluation system, focusing on homogeneous expression of MMP-9. The prognostic value was analyzed in relation to established prognostic factors of the TNM-system. Our study shows that the prognostic impact of homogeneous MMP-9 expression remains independent from possible prognostic joint effects of pT-status, pN-status, tumor histology and tumor grading. Because of this independence, MMP-9 may be considered as an interesting target for adjuvant anticancer therapy in operable NSCLC using selective MMP-inhibitors with high specificity for MMP-9. MATERIAL AND METHODS PatientsAfter approval by the ethical committee of the University of Munich and after written informed consent, tissue specimens of 147 consecutive patients with completely resected NSCLC were collected. The tumors were classified according to the international union against cancer (UICC) TNM-classification. 6 The preoperative staging of all patient...

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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

Cited by 39 publications

References 21 publications

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

Nemosis of fibroblasts is inhibited by benign HaCaT keratinocytes but promoted by malignant HaCaT cells

Prognostic impact of matrix metalloproteinase‐9 in operable non‐small cell lung cancer

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