Extracellular matrix composition and interstitial pH modulate NHE1-mediated melanoma cell motility
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Extracellular matrix composition and interstitial pH modulate NHE1-mediated melanoma cell motility. / Vahle, Anne-Kristin; Domikowsky, Britta; Schwöppe, Christian; Krähling, Hermann; Mally, Sabine; Schäfers, Michael; Hermann, Sven; Shahin, Victor; Haier, Jörg; Schwab, Albrecht; Stock, Christian.
In: INT J ONCOL, Vol. 44, No. 1, 01.2014, p. 78-90.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Extracellular matrix composition and interstitial pH modulate NHE1-mediated melanoma cell motility
AU - Vahle, Anne-Kristin
AU - Domikowsky, Britta
AU - Schwöppe, Christian
AU - Krähling, Hermann
AU - Mally, Sabine
AU - Schäfers, Michael
AU - Hermann, Sven
AU - Shahin, Victor
AU - Haier, Jörg
AU - Schwab, Albrecht
AU - Stock, Christian
PY - 2014/1
Y1 - 2014/1
N2 - The activity of the Na+/H+ exchanger NHE1 is required for human melanoma cell adhesion and migration. The goal of the present study was to suppress mouse melanoma (B16V) cell invasion in vivo by inhibiting NHE1. Intravital observations in mobilized left liver lobes of laparotomized male Sprague-Dawley rats disclosed that five minutes after intra-arterial administration of the B16V cell suspension, cells adhered to the endothelia of liver sinusoidal capillaries and started to migrate into the surrounding liver tissue. In the presence of the NHE1-specific inhibitor cariporide, migration/invasion was reduced by about 50% while adhesion was not lowered. Time-lapse video microscopy and adhesion/invasion assays revealed that in vitro, blockade of NHE1 by cariporide i) significantly decreased the migratory speed of the cells and ii) completely inhibited the invasive behavior of both an artificial, basement membrane-like and a dermis-like matrix. Cells were more motile on the basement membrane and more invasive on the dermis-like matrix. Small-animal PET (positron-emission tomography) analyses of B16V metastasis in female C57BL/6 mice showed that, although NHE1 inhibition hardly affected the percentage of animals developing metastases or relapses, metastases seem to get directed to the lungs in cariporide-treated animals while animals feeding on the standard diet show metastases spread all over the body. We conclude that i) B16V cells prefer to invade a dermis-like rather than a basement membrane-like matrix; ii) the extracellular matrix (ECM) composition strongly impacts on NHE1-dependent in vitro cell motility and invasion; and iii) the lungs are metastasis‑prone and impair the efficiency of cariporide due to their ECM composition and the pulmonary interstitial (extravascular) pH.
AB - The activity of the Na+/H+ exchanger NHE1 is required for human melanoma cell adhesion and migration. The goal of the present study was to suppress mouse melanoma (B16V) cell invasion in vivo by inhibiting NHE1. Intravital observations in mobilized left liver lobes of laparotomized male Sprague-Dawley rats disclosed that five minutes after intra-arterial administration of the B16V cell suspension, cells adhered to the endothelia of liver sinusoidal capillaries and started to migrate into the surrounding liver tissue. In the presence of the NHE1-specific inhibitor cariporide, migration/invasion was reduced by about 50% while adhesion was not lowered. Time-lapse video microscopy and adhesion/invasion assays revealed that in vitro, blockade of NHE1 by cariporide i) significantly decreased the migratory speed of the cells and ii) completely inhibited the invasive behavior of both an artificial, basement membrane-like and a dermis-like matrix. Cells were more motile on the basement membrane and more invasive on the dermis-like matrix. Small-animal PET (positron-emission tomography) analyses of B16V metastasis in female C57BL/6 mice showed that, although NHE1 inhibition hardly affected the percentage of animals developing metastases or relapses, metastases seem to get directed to the lungs in cariporide-treated animals while animals feeding on the standard diet show metastases spread all over the body. We conclude that i) B16V cells prefer to invade a dermis-like rather than a basement membrane-like matrix; ii) the extracellular matrix (ECM) composition strongly impacts on NHE1-dependent in vitro cell motility and invasion; and iii) the lungs are metastasis‑prone and impair the efficiency of cariporide due to their ECM composition and the pulmonary interstitial (extravascular) pH.
KW - Animals
KW - Cation Transport Proteins
KW - Cell Adhesion
KW - Cell Movement
KW - Extracellular Matrix
KW - Female
KW - Guanidines
KW - Humans
KW - Hydrogen-Ion Concentration
KW - Melanoma, Experimental
KW - Mice
KW - Neoplasm Invasiveness
KW - Rats
KW - Sodium-Hydrogen Antiporter
KW - Sulfones
U2 - 10.3892/ijo.2013.2158
DO - 10.3892/ijo.2013.2158
M3 - SCORING: Journal article
C2 - 24173371
VL - 44
SP - 78
EP - 90
JO - INT J ONCOL
JF - INT J ONCOL
SN - 1019-6439
IS - 1
ER -