Targeting Vacuolar H+-ATPases as a New Strategy against Cancer

Fais, Stefano; Milito, Angelo De; You, Hyun Ju; Qin, Wenxin

doi:10.1158/0008-5472.can-07-1805

Cited by 244 publications

(263 citation statements)

References 26 publications

(42 reference statements)

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“…Many recent studies have revealed that 1) cancer cells produce numerous protons (H + ) by active glycolysis under hypoxia, or the Warburg effect [39][40]; 2) the protons are stored in lysosomes and other acidic vesicles by vacuolar-type H + -ATPase (V-ATPase), resulting in the lysosomes and other acidic vesicles becoming even more acidic in the cancer cells than in normal cells [41][42]; 3) the extracellular fluid around cancer cells is also more acidic due to the larger number of protons excluded from the cytosolic space by NHE (Na-H + exchanger), V-ATPase and MCT (monocarboxylate transporter) than that of normal cells, or the larger number of protons produced by carbonic anhydrase 9 [43]. Since AO accumulates in acidic environments, sarcoma cells with a large number of acidic vesicles, are not able to exclude AO easily, whereas normal cells with non-acidic environments and weak acidic lysosomes can quickly exclude AO.…”

Section: Mechanism Of Selective Ao Accumulation In Sarcomasmentioning

confidence: 99%

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

Kusuzaki¹,

Matsubara²,

Satonaka³

et al. 2014

Cureus

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We recently established the new limb salvage modality of acridine orange (AO) therapy (AOT), in an attempt to develop minimally invasive limb salvage surgery with minimal damage of normal tissues and a low risk of local recurrence. The treatment modality consists of intraoperative photodynamic surgery (iPDS) and photodynamic therapy (iPDT), followed by postoperative radiodynamic therapy (RDT) using AO for patients with high-grade malignant musculoskeletal sarcomas. Clinical results have shown that the treatment is associated with a low risk of local recurrence, the risk being almost the same as that following conventional wide resection, and yields superior limb function as compared to that obtained after wide resection.In this review, we present the detailed mechanism of selective accumulation of AO in sarcomas, which is related to the acidic environment and lysosomal acidity of the tumor cells induced by cancer-specific glycolysis not involving the define tricarboxylic acid (TCA) cycle (Warburg's effect). We also describe the clinical uses of AOT and the procedure for intraoperative photodynamic surgery (iPDS) using local administration of AO.

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Section: Mechanism Of Selective Ao Accumulation In Sarcomasmentioning

confidence: 99%

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

Kusuzaki¹,

Matsubara²,

Satonaka³

et al. 2014

Cureus

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“…It is conceivable that the tumor microenvironment conditions, including low pH (Fais et al , 2007 ;Fais , 2010 ), may be at least in part responsible for the increased exosome production and spillover in the bloodstream. These data make exosome detection in the human body fluids as one of the most important future clinical approach in the screening, diagnosis, and follow-up of tumor patients.…”

Section: Exosome-mediated Paracrine Propagation Within Tissues and Comentioning

confidence: 99%

Exosomes: the ideal nanovectors for biodelivery

Fais

Logozzi

Lugini

et al. 2012

Biological Chemistry

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Nanomedicine aims to exploit the improved and often novel physical, chemical, and biological properties of materials at the nanometric scale, possibly with the highest level of biomimetism, an approach that simulates what occurs in nature. Although extracellularly released vesicles include both microvesicles (MVs) and exosomes, only exosomes have the size that may be considered suitable for potential use in nanomedicine. In fact, recent reports have shown that exosomes are able to interact with target cells within an organ or at a distance using different mechanisms. Much is yet to be understood about exosomes, and currently, we are looking at the visible top of an iceberg, with most of what we have to understand on these nanovesicles still under the sea. In fact, we know that exosomes released by normal cells always trigger positive effects, whereas those released by cells in pathological condition, such as tumor or infected cells, may induce undesired, dangerous, and mostly unknown effects, but we cannot exclude the possibility that exosomes may also be detrimental for the body in normal conditions. However, whether we consider extracellular vesicles as a whole, thus including MVs, it appears that even in normal conditions, extracellular vesicles may lead to unwanted effects, depending on gender and age. This review aims to critically emphasize existing data in the literature that support the possible roles of exosomes in both diagnostic and therapeutic scopes.

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“…Such signaling is proposed to contribute to the action of acidification on neoplastic 10 transformation and tumor aggressiveness, where acidification is brought about by key transporters, such as the Vacuolar (H+)-ATPase. (63) A localized cell surface pH gradient has also been implicated in cancer cell migration. (3,64,65) Cell migration can be linked to acidification through cancer cell tolerance, initiation of matrix breakdown and neighboring cell death (65) .…”

Section: Ph In Vivomentioning

confidence: 99%

Windows to cell function and dysfunction: Signatures written in the boundary layers

Smith¹,

Collis²,

Messerli³

2010

BioEssays

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The medium surrounding cells either in culture or in tissues contains a chemical mix varying with cell state. As solutes move in and out of the cytoplasmic compartment they set up characteristic signatures in the cellular boundary layers. These layers are complex physical and chemical environments whose profiles both reflect cell physiology and provide conduits for intercellular messaging. Here we review some of the most relevant characteristics of the extracellular/intercellular space. Our initial focus is primarily with cultured cells but we extend our consideration to the far more complex environment of tissues and discuss how chemical signatures in the boundary layer can or may affect cell function. Critical to the entire essay are the methods used, or being developed, to monitor chemical profiles in the boundary layers. We review recent developments in ultramicro electrochemical sensors and tailored optical reporters suitable for the task 20 in hand. IntroductionThe advent of electron tomography with 3 dimensional image reconstruction has revealed a fundamental beauty and complexity behind the structure of the living cell. Notable contributions have come from several imaging laboratories but one of the most compelling can be found in Marsh et al.(1) From such reconstructions the complexity within a cell is quite staggering and in the 4 th dimension of time this entire structure is in motion. The question that becomes extremely interesting is how molecular and ionic signals are regulated and move within these matrices, where chemical diffusion will be significantly altered. (2) However, complexity, both structural and functional, does not stop at the plasma membrane but extends outwards 30 into the extracellular/intercellular space (EICS: Fig.1). The chemical dynamics within this space are hypothesized to play key roles in cancer, spreading depression, epilepsy and sleep disorders. (3)(4)(5)(6) The purpose of this essay is to consider what we can learn from this space and the methods for following the dynamics of chemical movement within the diffusive boundary layers that comprise an integral part of a cell. We will start by noting the physical and chemical features involved.

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Targeting Vacuolar H+-ATPases as a New Strategy against Cancer

Cited by 244 publications

References 26 publications

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

Intraoperative Photodynamic Surgery (iPDS) with Acridine Orange for Musculoskeletal Sarcomas

Exosomes: the ideal nanovectors for biodelivery

Windows to cell function and dysfunction: Signatures written in the boundary layers

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