Die Pfortaderastligatur reduziert initial das Wachstum von Lebermetastasen durch Minderung der Mikroperfusion, bewirkt später jedoch eine gesteigerte Proliferation durch VEGF, HGF und TGF-α Expression

Abstract

Background: Whereas portal branch ligation (PBL) prior to resection may prevent liver failure after extended hepatic resection, clinical studies indicate that tumors within the ligated lobe develop accelerated growth. Therefore, we studied in a mouse model the time-dependent effect of PBL on angiogenesis and tumor growth of colorectal metastasis. Methods: According to an established liver metastasis model, CT-26 colon cancer cells were implanted in the left liver lobe of syngeneic BALB/c mice. Animals were randomized to PBL of the left liver lobe or control group. Microcirculatory responses and microvascular remodeling of the normal liver as well as angiogenesis, tumor cell proliferation, apoptosis and growth were studied 3d, 7d, 14d and 21d after PBL (n = 8 each) using intravital multifluorescence microscopy, laser Doppler fluxmetry, immunohistochemistry and biochemical techniques. Results: After 14 days tumor volume was significantly reduced by PBL (< 20 % of controls) when compared to controls. During the first 14d PBL induced a reduction of left hilar blood flow by ∼ 50 %, resulting in a delayed development of an angiogenic front of the tumors, a reduced density of draining tumor venules and reduced functional sinusoidal density in the normal liver. Sinusoidal dilation at the tumor border was associated by a significant increase of VEGF expression. PBL was associated with a higher leukocyte response in the tumor and normal liver. After a 14d period, immunohistological analyses demonstrated that PBL significantly induced tumor cell and hepatocyte proliferation as well as apoptosis. According to these findings, there was no significant difference on tumor volume after 21d. Conclusion: Microvascular remodeling within the ligated lobe and hepatocellular proliferation may explain the late accelerated tumor progression observed in patients after PBL.