cells thrive in a hypoxic microenvironment with an acidic extracellular pH. To survive in this harsh environment, tumor cells must exhibit a dynamic cytosolic pH regulatory system. We hypothesize that vacuolar H ϩ -ATPases (V-ATPases) that normally reside in acidic organelles are also located at the cell surface, thus regulating cytosolic pH and exacerbating the migratory ability of metastatic cells. Immunocytochemical data revealed for the first time that VATPase is located at the plasma membrane of human breast cancer cells: prominent in the highly metastatic and inconspicuous in the lowly metastatic cells. The V-ATPase activities in isolated plasma membranes were greater in highly than in lowly metastatic cells. The proton fluxes via V-ATPase evaluated by fluorescence spectroscopy in living cells were greater in highly than in lowly metastatic cells. Interestingly, lowly metastatic cells preferentially used the ubiquitous Na ϩ /H ϩ exchanger and HCO 3 Ϫ -based H ϩ -transporting mechanisms, whereas highly metastatic cells used plasma membrane V-ATPases. The highly metastatic cells were more invasive and migratory than the lowly metastatic cells. V-ATPase inhibitors decreased the invasion and migration in the highly metastatic cells. Altogether, these data indicate that V-ATPases located at the plasma membrane are involved in the acquisition of a more metastatic phenotype. metastasis; intracellular pH; migration; sodium ion/hydrogen ion exchanger; bicarbonate transport MAINTENANCE OF CYTOSOLIC pH (pH cyt ) is crucial to normal cell function because many cellular processes have a narrow pH optimum (38). Tumor cells possess high-glycolytic activity and produce acidic metabolites (39). Moreover, tumor cells often exist in a hypoxic microenvironment with a lower extracellular pH (pH ex ) than that of surrounding normal cells (10,15,40). Acidic pH ex and hypoxic environment are not permissive for cell growth and have been associated with apoptosis (14, 25). To minimize the potentially toxic reduction in pH cyt that would accompany growth in a chronically acidic environment, tumor cells must upregulate the proton extrusion mechanism(s) that maintains pH cyt . The ability to upregulate proton extrusion may be essential for tumor cell survival. The influence of pH cyt on many cellular functions has been studied with respect to cell growth (16), cell motility (27), tumorigenesis (36), metastasis (45), apoptosis (14), and drug resistance in cancer cells (28, 50).Four major types of pH cyt regulatory mechanisms have been identified in tumor cells: Na ϩ /H ϩ exchangers, bicarbonate (HCO 3 Ϫ ) transporters, proton-lactate symporters, and proton pumps (11,38,42). Recently, the vacuolar H ϩ -ATPase (VATPase) has emerged as a novel and important pH cyt regulatory system in some specialized cells, including tumor (25,26,28). This proton pump is ubiquitously expressed (33, 35), not only in vacuolar membranes but also in plasma membranes (26, 58) of eukaryotic cells. The V-ATPase is a multi-subunit enzyme complex composed of a me...

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INTRODUCTION: Achalasia has wide range presentations including gastrointestinal and respiratory symptoms. Septic shock is less common. CASE DESCRIPTION/METHODS: We report a case of a 59-year-old Caucasian woman who presented with 1-month history of dyspnea and cough worsening for one week. She reported intermittent vomiting, dysphagia and unintentional weight loss for the past 2 months. Upon admission, she was hypoxemic and developed septic shock. Computer tomography showed multifocal pneumonia and severe distension of the esophagus filled with debris (Figure 1) measuring 9.5 × 6 cm at the largest diameter. She was intubated and given board spectrum antibiotics and then transferred to the medical intensive care unit. Upper endoscopy demonstrated dilation in the entire esophagus filled with food and scattered whitish esophageal plaques, consistent with esophageal candidiasis. Four weeks of oral fluconazole was initiated to treat esophageal candidiasis. Propionibacterium species grew in one out of two blood cultures but the respiratory culture was negative. She required vasopressors for two days and then successfully extubated two days later. She underwent a barium esophagography showing dilated esophagus with distal narrowing “bird beak’s” appearance (Figure 2). Esophageal manometry confirmed type I achalasia demonstrating apersistalsis of the entire esophagus and hypertensive lower esophageal sphincter (Figure 3). She recovered from aspiration pneumonia and weaned off oxygen. She was scheduled to come back in 2 weeks for perioral endoscopic myotomy evaluation and was discharged home with oral fluconazole. DISCUSSION: Achalasia is an esophageal disease caused by loss of relaxation in the distal esophagus and lower esophageal sphincter. Most common presentations are dysphagia (90%), heartburn (75%) and regurgitation or vomiting (45%). Respiratory symptoms including cough or chronic aspiration account for 20-40%. However, septic shock as initial presentation is not common. Our patient had chronic aspiration to the lungs and developed aspiration pneumonia progressing to septic shock. Patients presenting with respiratory symptoms are reported to have a more dilated esophagus with an average mean diameter of 4.3 ± 2 cm. Our case has an esophagus double the average size. Perioral endoscopic myotomy has gained universal acceptance to treat achalasia and shows safety and efficacy.