Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment

Zucker, Stanley; Cao, Jian; Chen, Wen-Tien

doi:10.1038/sj.onc.1204097

Cited by 498 publications

(371 citation statements)

References 67 publications

Supporting

Mentioning

358

Contrasting

Unclassified

Order By: Relevance

“…For such studies it is recommended to measure the targeted MMP in tumor tissue to identify patients who are more likely to respond to MMP inhibitor therapy. 9 Our data suggest that for immunohistochemical examination of MMP-9 expression in tumor specimens, an evaluation system that focuses on homogeneous expression is recommended. The present study may provide a basis for studies that examine the value of homogeneous MMP-9 expression for the preselection of patients to be included in trials investigating specific protease inhibitor therapy after surgical resection of NSCLC.…”

Section: Discussionmentioning

confidence: 93%

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Sienel¹,

Hellers²,

Morresi‐Hauf³

et al. 2002

Intl Journal of Cancer

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 93%

mentioning

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

View full text Add to dashboard Cite

show abstract

“…In addition, the best effects can perhaps be gained in adjuvant therapy or in early stages of cancer, when tumour burden is minimal. 151 In situations with large tumour mass or rapid cancer progression, there can also be extensive ECM remodelling and thus a long-term or a high-dose administration of an MMPI would be needed to gain high enough local concentration for proper inhibition of tumour spread. The expression and activity of MMPs are especially abundant in the peritumoural area, where tumour angiogenesis also takes place.…”

Section: Future Considerationsmentioning

confidence: 99%

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Vihinen

Kähäri

2002

Intl Journal of Cancer

582

484

View full text Add to dashboard Cite

Degradation of extracellular matrix is crucial for malignant tumour growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumour tissue or serum of patients with advanced cancer and their role as prognostic indicators in cancer is studied. In addition, therapeutic intervention of tumour growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors are in clinical trials in cancer. In this review, we discuss the current view on the feasibility of MMPs as prognostic markers and as targets for therapeutic intervention in cancer.

show abstract

“…[67][68][69][70] Matrix metallopeptidases appear integral to tumorigenesis and have been targeted by inhibitors; however, clinical trials of advanced lung, prostate, pancreas, brain, and GI tract malignancies have shown little efficacy to date. 64,71 More data may be needed before a successful clinical trial is completed. 64 One surprising finding was that more differentially expressed genes were identified when comparing actinic keratosis with normal skin (423 genes) than comparing squamous cell carcinoma with normal skin (390 genes).…”

Section: P53 Signalingmentioning

confidence: 99%

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Hui

Binder

2011

Modern Pathology

View full text Add to dashboard Cite

Actinic keratosis is widely believed to be a neoplastic lesion and a precursor to invasive squamous cell carcinoma. However, there has been some debate as to whether actinic keratosis is in fact actually squamous cell carcinoma and should be treated as such. As the clinical management and prognosis of patients is widely held to be different for each of these lesions, our goal was to identify unique gene signatures using DNA microarrays to discriminate among normal skin, actinic keratosis, and squamous cell carcinoma, and examine the molecular pathways of carcinogenesis involved in the progression from normal skin to squamous cell carcinoma. Formalin-fixed and paraffin-embedded blocks of skin: five normal skins (pooled), six actinic keratoses, and six squamous cell carcinomas were retrieved. The RNA was extracted and amplified. The labeled targets were hybridized to the Affymetrix human U133plus2.0 array and the acquisition and initial quantification of array images were performed using the GCOS (Affymetrix). The subsequent data analyses were performed using DNA-Chip Analyzer and Partek Genomic Suite 6.4. Significant differential gene expression (42 fold change, Po0.05) was seen with 382 differentially expressed genes between squamous cell carcinoma and normal skin, 423 differentially expressed genes between actinic keratosis and normal skin, and 9 differentially expressed genes between actinic keratosis and squamous cell carcinoma. The differentially expressed genes offer the possibility of using DNA microarrays as a molecular diagnostic tool to distinguish between normal skin, actinic keratosis, and squamous cell carcinoma. In addition, the differentially expressed genes and their molecular pathways could be potentially used as prognostic markers or targets for future therapeutic innovations.

show abstract

Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment

Cited by 498 publications

References 67 publications

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

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

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

Contact Info

Product

Resources

About