Question: 

Does inhibition of the Na⁺/H⁺ exchanger (NHE1) lower metastasis of murine melanoma (B16V) cells?

Methodology: 

Adhesion, migration, invasion, and extracellular matrix (ECM) digestion were determined in vitro on two differently reconstituted matrices representing the dermis and the basement membrane. Moreover, two in vivo approaches were performed: A: For intravital observation of adhesive interactions between circulating tumor cells and the hepatic microcirculation, suspensions of CalceinAM fluorescent-labeled B16V cells with or without the specific NHE1-inhibitor cariporide were injected intraarterially into rats. A semi-quantitative analysis of tumor cell adhesion and extravasation was performed in mobilized left liver lobes of the laparotomized rats. B: Mice were fed on a cariporide containing diet. Three weeks after intradermal injection of a B16V cell suspension into the right flank, the primary tumor was removed and metastases were detected employing a small-animal PET/CT.

Result: 

B16V cells migrated on, however, did not invade the basement membrane-like matrix. By contrast, they slowed down drastically and became invasive on the dermis-like matrix. Cell adhesion was stronger on the basement membrane-like matrix, while matrix digestion more than doubled on the dermis-like matrix. Cariporide reduced adhesion and matrix digestion, slowed down migration and stopped invasion nearly completely regardless of the matrix composition used. In rats, cariporide reduced B16V cell migration/invasion into the liver parenchyma by about 50% while adhesion was only slightly lowered. In mice, cariporide directed metastases predominantly to the lungs.

Conclusion: 

The antimetastatic effect of NHE1-inhibition depends on the target organ's ECM composition. The strong presence of lung metastases in cariporide treated animals leads us to assume that the composition of the highly specialized pulmonary extracellular matrix and/or the local pCO₂/pO₂ ratio might impair the efficiency of cariporide.