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The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis

Key Points

  • The gradient from the extracellular pH (pHe) to the intracellular pH (pHi) is reversed in tumours. That is, tumours become more acidic extracellularly and more alkaline intracellularly.

  • This reversed pH gradient arises early in transformation and is driven primarily by oncogene-dependent stimulation of the Na+/H+ exchanger NHE1, which results in cellular alkalinization and subsequent aerobic glycolysis and H+/lactate symport.

  • Cellular alkalinization induces cell proliferation that is independent of serum and substrate anchorage, which results in dense disorganized cell masses that are poorly vascularized.

  • Poor vascularization, together with the increased proton-extrusion ability of the tumour cell, produces the tumour-specific metabolic microenvironment. Owing to positive-feedback interactions between the tumour cell and this microenvironment, an ever higher reversed pH gradient is achieved as the disease progresses.

  • Both the acidic pHe and the constitutive activity of NHE1 have roles in driving protease-mediated digestion and remodelling of the extracellular matrix. They also stimulate the invasive phenotypes of the cell — actin remodelling for increased motility and the formation of invasive structures such as leading-edge pseudopodia and invadopodia.

  • Little is known about the signal-transduction systems that regulate NHE1 activity and that are associated with invasion.

  • The formation of a tumour-microenvironment model of invasion and metastasis that integrates the interaction of cell structure with the biochemistry, physiology and regulation of NHE1 will lead to a better understanding of the dynamics of the invasive response of the tumour cell to the microenvironment.

Abstract

Recent research has highlighted the fundamental role of the tumour's extracellular metabolic microenvironment in malignant invasion. This microenvironment is acidified primarily by the tumour-cell Na+/H+ exchanger NHE1 and the H+/lactate cotransporter, which are activated in cancer cells. NHE1 also regulates formation of invadopodia — cell structures that mediate tumour cell migration and invasion. How do these alterations of the metabolic microenvironment and cell invasiveness contribute to tumour formation and progression?

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Figure 1: NHE1 in transformation and pHi homeostasis.
Figure 2: The development of the tumour metabolic microenvironment.
Figure 3: The location of NHE1 in invasive cells and role of NHE1 in pseudopod maintenance.
Figure 4: The effect of low pHe on lysosome transport in MDA-MB-435 breast cancer cells.
Figure 5: A proposed multistep invasion scenario.
Figure 6: Signal transduction mediating NHE1-dependent invasion.

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Acknowledgements

Work in the S.J.R. laboratory is supported by PSO CNR-MIUR (Progetti Strategici 'ONCOLOGIA' Consiglio Nazionale delle Ricerche Ministero dell'Istruzione, dell'Università e della Ricerca), FIRB (Fondo per gli Investimenti della Ricerca di Base) and CEGBA (Centro di Eccellenza di Genomica in Campo Biomedico ed Agrario). We would like to thank A. Bellizzi and G. Busco for help in designing the figures and the movie.

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Supplementary information S1 (movie)

S1 (movie) | Role of NHE1 on morphology of MDA-MB-435 human metastatic breast cells. The cell was treated with the benzoylguanidine derivative, cariporide (HOE642, 5 µM) at the start of the film and images were aquired every 30 seconds for approximately 60 minutes in transmitted light at 1000X. Inhibition of NHE1 by addition of HOE642/cariporide produces a rapid retraction of the long leading-edge pseudopodia of the cell towards the main cell body. This is followed by a retraction of the trailing edge and then a rounding of the cell. Notice also the long leading-edge pseudopodia from a neighboring cell extending into the screen from above which also retracts towards the top of the screen after treatment. Videomicroscopy was performed using a Nikon ECLIPSE TE 2000 S microscope equipped with a MSMI-DV-FC (Princeton Instruments) CCD camera. Images were collected and analysed using the Metafluor 4.6 software (Universal Imaging Corp., Molecular Devices). (MPG 290 kb)

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DATABASES

Entrez Gene

E7

HRAS

NM23

Swiss-Prot

β1-integrin

cathepsin B

CD44

HGF receptor

MAPK14

MMP9

NHE1

PI3K

PKA

RHOA

ROCK1

TNC

VIL2

National Cancer Institute

breast cancer

colon cancer

kidney cancer

FURTHER INFORMATION

Stephen J. Reshkin's homepage

Glossary

SET POINT

The intracellular pH value below which the Na+/H+ exchanger NHE1 becomes activated.

METABOLIC MICROENVIRONMENT

The in vivo microenvironment within tumours is significantly different from that within normal tissues. It is characterized by the presence of closely linked, dynamic extracellular areas of low pH, low serum levels and hypoxia, and is known as the tumour-specific physiological or metabolic microenvironment. It arises as a consequence of the dysregulation of proliferation, apoptosis and growth-factor signalling and causes a pathological and disorganized increase in cell number and density and a decrease in access to circulation.

STROMAL MICROENVIRONMENT

Tumours have an extensive adjacent stromal compartment that provides the framework for the tumour. It is composed of connective tissue that contains fibroblasts, immune and inflammatory cells, and cells that are derived from blood vessels, nerves and the extracellular matrices. Cancer cells communicate with and alter the adjacent stroma to form a permissive and supportive environment for tumour progression — the 'reactive' tumour stroma microenvironment.

HYALURONAN

A large, negatively charged specialized glycoprotein with polysaccharide side chains that participates in defining the properties of pericellular matrices and in transducing signals in proliferating and migrating cells. Hyaluronan is the main ligand for CD44, a cell-surface glycoprotein receptor, and is overproduced in many types of human tumour.

INTRAVASATION

The passage of tumour cells from the tumour and its surrounding tissue into blood vessels (haematogenous dissemination) or lymph vessels (lymphatic dissemination).

REACTION-DIFFUSION MODELLING

A model that combines mathematical analyses, experimental data and clinical observations to describe the interaction of tumour and normal (host) tissue in determining the spatiotemporal diffusive distribution of proton concentration and its role in directing invasion of the host tissue by the tumour.

AMOEBOID MORPHOTYPE

Amoeboid invasion is characterized by an amorphous cell morphology and rapid changes in direction that are made possible by rapid remodelling of the cell-cortical actin cytoskeleton. It is thought that amoeboid movement involves very weak cell–extracellular matrix (ECM) interactions and is protease-independent, because cells move through gaps that already exist in the ECM.

MESENCHYMAL MORPHOTYPE

Mesenchymal invasion is characterized by an elongated polarized cell shape and is dependent on secreted proteases to digest the extracellular matrix. The initiating event for mesenchymal invasion is usually activation of tyrosine-kinase receptors or adhesion receptors, or exposure to the metabolic microenvironment. These events lead to the formation of a complex, tubulin- and actin-rich pseudopodial protrusion, the tip of which is rich in small integrin-dependent focal contacts where the secretion of proteases occurs.

OSTEOCLASTS

Specialized multinucleated bone-resorbing cells that are responsible for the degradation of bone.

VACUOLAR H+-TRANSPORTING ATPASE

A complex enzyme composed of numerous subunits that is ubiquitously expressed in eukaryotic cells, where it is located in intracellular acidic organelles. In some specialized acid-extruding cells, such as osteoclasts, an increase in V-ATPase-dependent proton secretion correlates with an increase in V-ATPase plasma-membrane expression owing to a rapid recycling between intracellular vesicles and the plasma membrane.

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Cardone, R., Casavola, V. & Reshkin, S. The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis. Nat Rev Cancer 5, 786–795 (2005). https://doi.org/10.1038/nrc1713

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