Pancreatic Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Pancreatic Cancer, including details on symptoms, causes, treatment, information. | ||||||||
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Hypoxia augments gelatinase activity in a variety of adenocarcinomas in vitro.Ridgway PF, Ziprin P, Alkhamesi N, Paraskeva PA, Peck DH, Darzi AW Department of Surgical Oncology and Technology, Imperial College, St. Mary's Hospital, London, United Kingdom. p.ridgway@ic.ac.uk 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. Published 11 April 2005 in J Surg Res, 124(2): 180-6.
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