Expression and Prognostic Significance of Metalloproteinases and Their Tissue Inhibitors in Patients With Small-Cell Lung Cancer

Michael, M.; Babic, Bojana; Khokha, Rama; Tsao, Ming‐Sound; Ho, J. C.; Pintilie, Melania; Leco, Kevin J.; Chamberlain, Dean; Shepherd, Frances A.

doi:10.1200/jco.1999.17.6.1802

Cited by 149 publications

(85 citation statements)

References 22 publications

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“…DLKP and DLKP-CCNU cells secrete MMPs 2, 9 and 13 but are poorly invasive, suggesting that other mechanisms determine the drug-induced transition to the invasive phenotype. Despite the important role of MMP-2 in NSCLC, it is interesting to note that MMP-2 was not found in human SCLC, 42 which may indicate distinct strategies of invasion being used by these 2 types of lung cancer. Future studies investigating a potential role for the histone deacetylase metastasisassociated (MTA1) gene product, 43 as well as other metastasisassociated genes (e.g., mst1, nm23, KiSS1, MKK4, galectin-3, etc.)…”

Section: Discussionmentioning

confidence: 99%

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Liang

O’Driscoll

McDonnell

et al. 2004

Intl Journal of Cancer

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The human lung carcinoma cell line DLKP was exposed to sequential pulses of 10 commonly used chemotherapeutic drugs (VP-16, vincristine, taxotere, mitoxantrone, 5-fluorouracil, methotrexate, CCNU, BCNU, cisplatin and chlorambucil); resulting cell lines exhibited resistance to the selecting agents (ranging approx. 1.5-to 36-fold) and, in some cases, cross-resistance to methotrexate (approx. 1.4-to 22-fold), vincristine (1.6-to 262-fold), doxorubicin (Adriamycin, approx. 1.1-to 33-fold) and taxotere (approx. 1.1-to 36-fold). Several of the variants displayed collateral sensitivity to cisplatin. A marked increase in in vitro invasiveness and motility was observed with variants pulsed with mitoxantrone, 5-fluorouracil, methotrexate, BCNU, cisplatin and chlorambucil. There was no significant change in invasiveness of cells pulsed with VP-16, vincristine, taxotere or CCNU. All of the pulseselected variants showed elevated levels of MDR-1/P-gp protein by Western blot analysis, although mdr-1 mRNA levels were not increased (except for DLKP-taxotere). In DLKPtaxotere, MRP1 protein levels were also greatly elevated, but mrp1 mRNA levels remained unchanged. BCRP was upregulated in DLKP-mitoxantrone at both the mRNA and protein levels. Gelatin zymography, Western blot and RT-PCR showed that DLKP and its variants secreted MMPs 2, 9 and 13. MMP inhibition assays suggested that MMP-2 plays a more important role than MMPs 9 and 13 in cell invasion of these DLKP drug-resistant variants in vitro. Reducing intracellular drug levels, often associated with overexpression of P-gp, 3 members of the MRP family 4 and the BCRP/ MXR protein, 5 is an important and frequent mechanism of MDR.Invasion through basement membrane is believed to be a critical step in metastasis. There are 4 main classes of proteases involved in proteolytic degradation of the ECM: serine-, cysteine-and aspartyl-proteases as well as MMPs. 6 The MMPs are a family of more than 20 members produced by tumour cells, connective tissue cells and inflammatory cells. MMPs are secreted as latent proenzymes and activated by proteolytic removal of an aminoterminal domain. 7 A large body of evidence shows that MMPs play a crucial role in cancer invasion and metastasis. Based on sequence homology and substrate specificity, MMP-2 and MMP-9 are classified as type IV collagenases that degrade the major component (type IV collagen) of basement membrane; 8 MMP-13, also called "collagenase-3", belongs to a group known as interstitial collagenases, which degrade collagen types I, II, III, VII, VIII and X. 9 The possibility of a relationship between drug resistance and invasion/metastasis phenotypes has been raised by 2 types of observation: 10 firstly, some tumour cells selected for resistance to drugs are invasive/metastatic relative to nonresistant parental cells; secondly, in some cases, secondary (more metastatic) tumours are more resistant to chemotherapeutic drugs than their primary counterparts. In support of this, Osmak et al. 11 reported a study of drug-resistant cervical and ...

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Section: Discussionmentioning

confidence: 99%

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Liang

O’Driscoll

McDonnell

et al. 2004

Intl Journal of Cancer

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“…105 On the other hand, Vuoristo et al 106 found no prognostic value for serum total MMP-2 levels in patients with advanced cutaneous melanoma. Increased expression of MMP-3 in tumour cells of SCLC (107) and in serum of urothelial carcinoma patients 53 have shown only limited prognostic value. Increased MMP-7 expression levels in tumour cells of patients with oesophageal carcinoma 108 or pancreatic adenocarcinoma 109 may be associated with poor prognosis.…”

Section: Mmps As Prognostic Survival Markers In Cancermentioning

confidence: 99%

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Vihinen

Kähäri

2002

Intl Journal of Cancer

577

484

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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.

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“…38 In line with our observations, MMP-3 overexpression has been correlated with poor outcome in patients with esophageal and lung cancer. 21,39 The MMP/TIMP profile has been evaluated in other types of neuroendocrine cells and tumors, including thyroid C cells and medullary thyroid carcinomas, 40 normal pancreatic islet cells and islet cell tumors, 41 anterior pituitary cells and pituitary adenomas, 41 and carcinoids and small-cell lung cancers. 21,42 Interestingly, normal thyroid C cells were found strongly positive for MMP-2, MMP-9, TIMP-1, and TIMP-2, whereas medullary thyroid carcinomas were relatively more weakly stained.…”

Section: Table 4 Mmps and Timps Expression By Neoplastic Cells In 23mentioning

confidence: 99%

“…12 Some investigators have hypothesized that the disruption of the MMP/TIMP balance may be a factor in the progression of tumors to a more malignant phenotype and that certain MMPs may predict poor prognosis when expressed at high levels. 14 Indeed, the level of expression of some of these proteins has been correlated with tumor aggressiveness, as implied by increasing histologic grade; [15][16] advanced clinical stage; [17][18][19] poor patient survival 17,[20][21] in gastric, pancreatic, and lung cancer; and increased relapse rate in colorectal cancer. 22 Recently, the crucial role of MMPs in cancers has also generated considerable interest in the use of broad-spectrum synthetic MMP inhibitors as potential therapeutic agents for clinical use.…”

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confidence: 99%

Expression and prognostic significance of matrix metalloproteinases and their tissue inhibitors in primary neuroendocrine carcinoma of the skin

et al. 2003

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Primary neuroendocrine carcinoma (PNC) of the skin is the currently favored designation for the tumor originally described by Toker in 1972 as trabecular carcinoma, 1 and subsequently termed Merkel cell carcinoma on the basis of the electron microscopic findings of neurosecretory granules. 2 PNC is a rare, highly malignant neuroendocrine tumor that occurs most commonly in elderly Caucasian patients. Clinically, it usually appears as a rapidly growing nodule on sundamaged skin of the head and neck region and on the extremities, often being indistinguishable from other cutaneous neoplasms on clinical grounds alone. Affected patients have a high risk of disease progression: early local recurrences occur in about 33% of cases, and approximately 50% of patients will develop regional lymph node metastases with eventual death due to systemic dissemination in more than 33% of cases. [3][4] Because of its rarity, prognostic factors have not been fully established. However, cumulative data from small series have suggested that stage, size of the primary tumor, and gender may have an influence on survival, whereas the prognostic impact of anatomic location and age are more controversial. [5][6][7][8] Although various factors can determine the aggressiveness of PNCs, the capacity for invasion and metastasis of tumor cells, involving the degradation of components of basement membranes and the extracellular matrix, is certainly important. The matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes 9,10 involved in the degradation of different components of the extracellular matrix. At present, there is considerable evidence indicating that MMPs play important roles in local invasion and tumor spread. [10][11][12] The family of human MMPs comprises several members classified into 4 main classes according to their structure and in vitro substrate specificity: collagenases, gelatinases, stromelysins, and membrane-type MMPs [11][12] (Table 1).Tissue inhibitors of matrix metalloproteinases (TIMPs) are the major natural inhibitors of MMPs. To date, 4 types of TIMPs (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) have been recognized. The TIMPs are secreted proteins that complex MMPs and are involved in the inhibition of individual MMPs and regulation of their activity. 13 Indeed, it is thought that the balance between activated MMPs and TIMPs determines the

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Expression and Prognostic Significance of Metalloproteinases and Their Tissue Inhibitors in Patients With Small-Cell Lung Cancer

Abstract: MMPs and TIMPs are widely expressed in SCLC. Increased tumoral expression of MMP-3, -11, and -14 were independent negative prognostic factors for survival. The results support the evaluation of synthetic MMP inhibitors in patients with SCLC.

Cited by 149 publications

References 22 publications

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Expression and prognostic significance of matrix metalloproteinases and their tissue inhibitors in primary neuroendocrine carcinoma of the skin

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