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

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?

[1]  C. V. van Noorden,et al.  The role of gelatinases in colorectal cancer progression and metastasis. , 2004, Biochimica et biophysica acta.

[2]  Bonnie F. Sloane,et al.  Unraveling the role of proteases in cancer. , 2000, Clinica chimica acta; international journal of clinical chemistry.

[3]  A. Paradiso,et al.  Phosphoinositide 3-Kinase Is Involved in the Tumor-specific Activation of Human Breast Cancer Cell Na+/H+Exchange, Motility, and Invasion Induced by Serum Deprivation* , 2000, The Journal of Biological Chemistry.

[4]  Erik Sahai,et al.  Mechanisms of cancer cell invasion. , 2005, Current opinion in genetics & development.

[5]  S. Caldeira,et al.  Na+/H+ exchanger‐dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation‐associated phenotypes , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[6]  K P Dingemans,et al.  Mechanisms of metastasis. , 1979, Biochimica et biophysica acta.

[7]  D. Barber,et al.  p160ROCK mediates RhoA activation of Na–H exchange , 1998, The EMBO journal.

[8]  R. Stern,et al.  CD44 Interaction with Na+-H+ Exchanger (NHE1) Creates Acidic Microenvironments Leading to Hyaluronidase-2 and Cathepsin B Activation and Breast Tumor Cell Invasion* , 2004, Journal of Biological Chemistry.

[9]  R. Gillies,et al.  Why do cancers have high aerobic glycolysis? , 2004, Nature Reviews Cancer.

[10]  M. Björklund,et al.  Gelatinase-mediated migration and invasion of cancer cells. , 2005, Biochimica et biophysica acta.

[11]  A. Szpaderska,et al.  An intracellular form of cathepsin B contributes to invasiveness in cancer. , 2001, Cancer research.

[12]  L. Bourguignon,et al.  Hyaluronan-mediated CD44 Interaction with RhoGEF and Rho Kinase Promotes Grb2-associated Binder-1 Phosphorylation and Phosphatidylinositol 3-Kinase Signaling Leading to Cytokine (Macrophage-Colony Stimulating Factor) Production and Breast Tumor Progression* , 2003, Journal of Biological Chemistry.

[13]  S. Grinstein,et al.  Cytosolic Alkalinization Increases Stress-activated Protein Kinase/c-Jun NH2-terminal Kinase (SAPK/JNK) Activity and p38 Mitogen-activated Protein Kinase Activity by a Calcium-independent Mechanism* , 1997, The Journal of Biological Chemistry.

[14]  M. Lamfers,et al.  Potentiation of anti-cancer drug activity at low intratumoral pH induced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) and its analogue benzylguanidine (BG) , 1999, British Journal of Cancer.

[15]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[16]  S. Alper,et al.  Polarization of Na+/H+ and Cl−/Hco 3 − Exchangers in Migrating Renal Epithelial Cells , 2000, The Journal of general physiology.

[17]  R. Gillies,et al.  The physiological environment in cancer vascularization, invasion and metastasis. , 2001, Novartis Foundation symposium.

[18]  I. Macdonald,et al.  Metastasis: Dissemination and growth of cancer cells in metastatic sites , 2002, Nature Reviews Cancer.

[19]  I. Tannock,et al.  The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase. , 1998, British Journal of Cancer.

[20]  T. Kislinger,et al.  Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases , 2000, Nature.

[21]  I. Madshus,et al.  Regulation of intracellular pH in eukaryotic cells. , 1988, The Biochemical journal.

[22]  M. Karmazyn Role of sodium-hydrogen exchange in cardiac hypertrophy and heart failure: a novel and promising therapeutic target , 2001, Basic Research in Cardiology.

[23]  Erik Sahai,et al.  Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis , 2003, Nature Cell Biology.

[24]  S. Grinstein,et al.  Role of Intracellular pH in Proliferation, Transformation, and Apoptosis , 1997, Journal of bioenergetics and biomembranes.

[25]  Roberto Buccione,et al.  Foot and mouth: podosomes, invadopodia and circular dorsal ruffles , 2004, Nature Reviews Molecular Cell Biology.

[26]  P. Friedl Prespecification and plasticity: shifting mechanisms of cell migration. , 2004, Current opinion in cell biology.

[27]  M. Zaccolo,et al.  Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. , 2005, Molecular biology of the cell.

[28]  A. Pardee,et al.  Intracellular pH is increased after transformation of Chinese hamster embryo fibroblasts. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Karl Brand,et al.  Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species 1 , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  M. Stratford,et al.  The relationship between extracellular lactate and tumour pH in a murine tumour model of ischaemia-reperfusion. , 1997, British Journal of Cancer.

[31]  D. Barber,et al.  Na(+)/H(+) exchanger NHE1 as plasma membrane scaffold in the assembly of signaling complexes. , 2004, American journal of physiology. Cell physiology.

[32]  C. Juel Lactate-proton cotransport in skeletal muscle. , 1997, Physiological reviews.

[33]  S. Aaronson,et al.  Microinjection of ras p21 induces a rapid rise in intracellular pH , 1987, Molecular and cellular biology.

[34]  M. Tatsuta,et al.  Involvement of phosphorylation of tyr‐31 and tyr‐118 of paxillin in MM1 cancer cell migration , 2002, International journal of cancer.

[35]  E. T. Gawlinski,et al.  The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. , 2002, Cancer research.

[36]  J. Segall,et al.  Intravital imaging of cell movement in tumours , 2003, Nature Reviews Cancer.

[37]  B. Groner,et al.  Effect of Ha-ras on phosphatidylinositol metabolism, Na+/H+-antiporter and mobilization of intracellular calcium. , 1988, Advances in enzyme regulation.

[38]  L. Gerweck,et al.  Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. , 1996, Cancer research.

[39]  J. Foidart,et al.  Acidic Extracellular pH Induces Matrix Metalloproteinase-9 Expression in Mouse Metastatic Melanoma Cells through the Phospholipase D-Mitogen-activated Protein Kinase Signaling* , 2005, Journal of Biological Chemistry.

[40]  U. Rodeck,et al.  Regulation of intracellular pH in human melanoma: potential therapeutic implications. , 2002, Molecular cancer therapeutics.

[41]  A. Paradiso,et al.  The Na+–H+ exchanger-1 induces cytoskeletal changes involving reciprocal RhoA and Rac1 signaling, resulting in motility and invasion in MDA-MB-435 cells , 2004, Breast Cancer Research.

[42]  M. Rechsteiner,et al.  Regulation of enzyme levels by proteolysis: the role of pest regions. , 1988, Advances in enzyme regulation.

[43]  D. Barber,et al.  A developmentally regulated Na-H exchanger in Dictyostelium discoideum is necessary for cell polarity during chemotaxis , 2005, The Journal of cell biology.

[44]  Gregory S Karczmar,et al.  MRI of the tumor microenvironment , 2002, Journal of magnetic resonance imaging : JMRI.

[45]  G. Giannelli,et al.  Human Hepatocellular Carcinoma (HCC) Cells Require Both α3β1 Integrin and Matrix Metalloproteinases Activity for Migration and Invasion , 2001, Laboratory Investigation.

[46]  M. Solaiyappan,et al.  Extracellular acidification alters lysosomal trafficking in human breast cancer cells. , 2003, Neoplasia.

[47]  L. Ng,et al.  Activity and density of the Na+/H+ antiporter in normal and transformed human lymphocytes and fibroblasts. , 1994, The American journal of physiology.

[48]  I. Silver,et al.  Breast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanism , 1997, Clinical & Experimental Metastasis.

[49]  O. Pappo,et al.  Mammalian heparanase: Gene cloning, expression and function in tumor progression and metastasis , 1999, Nature Medicine.

[50]  Peter Friedl,et al.  Compensation mechanism in tumor cell migration , 2003, The Journal of cell biology.

[51]  R. Cardiff,et al.  CD44v3,8–10 is involved in cytoskeleton‐mediated tumor cell migration and matrix metalloproteinase (MMP‐9) association in metastatic breast cancer cells , 1998 .

[52]  K. Hunter Ezrin, a key component in tumor metastasis. , 2004, Trends in molecular medicine.

[53]  D. Barber,et al.  Expression profile of genes regulated by activity of the Na-H exchanger NHE1 , 2004, BMC Genomics.

[54]  J. Pedraz,et al.  Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis , 2003, British Journal of Cancer.

[55]  H. Petty,et al.  Pericellular proteolysis by leukocytes and tumor cells on substrates: focal activation and the role of urokinase-type plasminogen activator , 2004, Histochemistry and Cell Biology.

[56]  Sergio Grinstein,et al.  Diversity of the mammalian sodium/proton exchanger SLC9 gene family , 2004, Pflügers Archiv.

[57]  J. Pouysségur,et al.  pHi, aerobic glycolysis and vascular endothelial growth factor in tumour growth. , 2001, Novartis Foundation symposium.

[58]  L. Bourguignon,et al.  CD44 Interaction with Tiam1 Promotes Rac1 Signaling and Hyaluronic Acid-mediated Breast Tumor Cell Migration* , 2000, The Journal of Biological Chemistry.

[59]  D. Leibfritz,et al.  Na+/H+ exchange subtype 1 inhibition during extracellular acidification and hypoxia in glioma cells , 2002, Journal of neurochemistry.

[60]  W. Boron,et al.  Long-term expression of c-H-ras stimulates Na-H and Na(+)-dependent Cl-HCO3 exchange in NIH-3T3 fibroblasts. , 1994, The Journal of biological chemistry.

[61]  E. T. Gawlinski,et al.  A reaction-diffusion model of cancer invasion. , 1996, Cancer research.

[62]  E. Bruyneel,et al.  Tenascin‐C and SF/HGF produced by myofibroblasts in vitro provide convergent proinvasive signals to human colon cancer cells through RhoA and Rac , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[63]  D. Barber,et al.  The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. , 2002, Annual review of pharmacology and toxicology.

[64]  I. Nabi,et al.  Autocrine Activation of the Hepatocyte Growth Factor Receptor/Met Tyrosine Kinase Induces Tumor Cell Motility by Regulating Pseudopodial Protrusion* 210 , 2002, The Journal of Biological Chemistry.

[65]  J L Pedraz,et al.  Hydrogen ion-dependent oncogenesis and parallel new avenues to cancer prevention and treatment using a H(+)-mediated unifying approach: pH-related and pH-unrelated mechanisms. , 1995, Critical reviews in oncogenesis.

[66]  E. Butcher,et al.  Elevation of Intracellular cAMP Inhibits RhoA Activation and Integrin-dependent Leukocyte Adhesion Induced by Chemoattractants* , 1997, The Journal of Biological Chemistry.

[67]  R. Gillies,et al.  Nm23‐transfected MDA‐mB‐435 human breast carcinoma cells form tumors with altered phospholipid metabolism and pH: A 31P nuclear magnetic resonance study in vivo and in vitro , 1999, Magnetic resonance in medicine.

[68]  H. Fukushima,et al.  Calcitonin inhibits proton extrusion in resorbing rat osteoclasts via protein kinase A , 2003, Pflügers Archiv.

[69]  R. Kerbel Tumor angiogenesis: past, present and the near future. , 2000, Carcinogenesis.

[70]  M. Mareel,et al.  Clinical, cellular, and molecular aspects of cancer invasion. , 2003, Physiological reviews.

[71]  B. Groner,et al.  Induction of v-mos and activated Ha-ras oncogene expression in quiescent NIH 3T3 cells causes intracellular alkalinisation and cell-cycle progression. , 1987, Gene.

[72]  Bonnie F. Sloane,et al.  Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. , 1994, Cancer research.

[73]  P. Dieterich,et al.  Migration of human melanoma cells depends on extracellular pH and Na+/H+ exchange , 2005, The Journal of physiology.

[74]  I. Nabi,et al.  Regulation of the formation of tumor cell pseudopodia by the Na(+)/H(+) exchanger NHE1. , 2000, Journal of cell science.

[75]  A. Paradiso,et al.  Release of the aspartyl protease cathepsin D is associated with and facilitates human breast cancer cell invasion , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[76]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[77]  H. Uramoto,et al.  Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. , 2003, Cancer treatment reviews.

[78]  D. Barber,et al.  Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1 , 2002, The Journal of cell biology.