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J Surg Res. 2005 Apr;124(2):180-6.

Hypoxia augments gelatinase activity in a variety of adenocarcinomas in vitro.

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  • 1Department of Surgical Oncology and Technology, Imperial College, St. Mary's Hospital, London, United Kingdom. p.ridgway@ic.ac.uk

Abstract

BACKGROUND:

Hypoxia within solid adenocarcinomas and protease up-regulation has been independently implicated as poor prognostic indicators in a variety of tumor types. The authors hypothesize that Matrix Metalloproteases (MMP) are up-regulated in direct response to a hypoxic environment.

MATERIALS AND METHODS:

Colonic (SW1222), breast (MDA-MB231), and pancreatic (PSN-1) tumor cell lines were exposed to hypoxia (1% oxygen/94% nitrogen/5% carbon dioxide) for periods of up to 24 h. Reaction to a hypoxic environment was determined via invasion across a Matrigel-coated 8-microm Transwell filter. Activity of MMP 2 and 9 was assessed using gelatin zymography. Expression of tissue inhibitor of metalloproteases 1 (TIMP-1) was quantified using ELISA (Biotrak). Correlation between protease expression and invasive capacity was determined using a specific gelatinase inhibitor (MMPI; Calbiochem).

RESULTS:

All tumor lines demonstrated augmented invasion over 72 h (P < 0.01 all groups). Concomitant significant increase in MMP 2 and 9 activity was observed in the SW1222 and PSN-1 lines. MDA-MB231s showed increase in MMP 9 expression and in a unidentified 103-kDa gelatinase (P < 0.001). The hypoxia-augmented invasion was attenuated by the addition of a specific gelatinase inhibitor confirming interdependence.

CONCLUSIONS:

Hypoxia induces an increased invasive capacity via gelatinase up-regulation without loss of cell viability. This suggests a mechanism explaining the poorer prognosis seen in patients with protease-secreting solid adenocarcinomas.

PMID:
15820246
[PubMed - indexed for MEDLINE]
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