• Bispecific antibodies
• KCNH2
• Kv 11.1
• cancer signaling
• cancer treatment
• ion channels
• metastasis
• therapeutic antibodies

• Humans
• Animals
• Neoplasms/drug therapy
• Neoplasms/pathology
• Integrin beta1/metabolism
• Molecular Targeted Therapy
• Antineoplastic Agents/pharmacology
• Biomarkers, Tumor/metabolism
• Ether-A-Go-Go Potassium Channels/antagonists & inhibitors
• Ether-A-Go-Go Potassium Channels/metabolism

• calcicoptosis
• cuproptosis
• drug resistance
• ferroptosis
• gastric cancer
• metal ion

• National Natural Science Foundation of China

• Cancer
• Chemoresistance
• Ion channels
• Molecular mechanism

• Humans
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Ion Channels/metabolism
• Apoptosis

• diagnosis & prognosis
• gastric cancer (gc)
• herg1
• ion channel
• molecular biomarker
• monoclonal antibody
• personalised medicine
• predictive medicine
• targeted therapy

• hERG1 channel
• ileum
• neuroendocrine tumours
• pancreas
• prognosis

• Animals
• Antibodies, Monoclonal/metabolism
• ERG1 Potassium Channel
• Ether-A-Go-Go Potassium Channels/genetics
• Ether-A-Go-Go Potassium Channels/metabolism
• Humans
• Ileum/metabolism
• Integrin beta1/metabolism
• Neuroendocrine Tumors
• Pancreas/metabolism
• Prognosis
• Rats

• 1662 Italian Association for Cancer Research
• 15627 Italian Association for Cancer Research
• 21510 Italian Association for Cancer Research
• N/A University of Florence
• 20174TB8KW Ministry of Education, Universities and Research
• 813834 European Union

Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemoresistance development.

Gastric cancer (GC) is still a relevant health issue worldwide. The identification of prognostic factors for progression of gastric dysplasia (GD), the main pre-cancerous lesion of the intestinal-type GC, is hence mandatory.

A cohort of 83 GD endoscopic samples belonging to Italian subjects was collected. hERG1 expression was evaluated by immunohistochemistry and scored 0–3, depending on the percentage of stained cells. Expression data were analysed in conjunction with clinico-pathological and survival data.

hERG1 turned out to be expressed in 67.47% (56 out of 83) of the GD samples. hERG1 expression was higher in high-grade GD compared to low-grade GD (29 out of 39, 74.36% vs 27 out of 44, 61.36%), although the statistical significance was not reached (P=0.246). No association emerged between hERG1 expression and clinical features of the patients (age, gender, localization, H. pylori infection, gastritis and intestinal metaplasia). In a subset of cases for which sequential samples of gastric lesions (from GD to Early Gastric Cancer and Advanced Gastric Cancer) were available, hERG1 expression was maintained in all the steps of gastric carcinogenesis from GD onwards. A general trend to increased expression in advanced lesions was observed. hERG1 score had a statistically significant impact on both Progression-Free Survival (P=0.018) and Overall Survival (P=0.031). In particular, patients displaying a high hERG1 score have a shorter survival.

hERG1 is aberrantly expressed in human GD samples and has an impact on both PFS and OS, hence representing a novel prognostic marker for progression of GD towards GC of the intestinal histotype. Once properly validated, hERG1 detection could be included in the clinical practice, during endoscopic surveillance protocols, for the management of GD at higher risk of progression, as already proposed for Barrett’s oesophagus.

• Kv11.1
• endoscopic surveillance in gastric dysplasia
• immunohistochemistry
• intestinal type gastric adenocarcinoma
• prognosis

• Clinical targets
• Colorectal cancer
• Esophageal cancer
• Gastric cancer
• Gastrointestinal cancer
• Hepatocellular carcinoma
• Ion channels
• Novel therapies
• Pancreatic cancer
• Prognostic biomarker

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Carcinogenesis/drug effects
• Carcinogenesis/pathology
• Disease Models, Animal
• Disease Progression
• Disease-Free Survival
• Down-Regulation
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/mortality
• Gastrointestinal Neoplasms/pathology
• Humans
• Ion Channels/antagonists & inhibitors
• Ion Channels/metabolism
• Up-Regulation

• R15 CA195061 NCI NIH HHS

The antibody era has greatly impacted cancer management in recent decades. Indeed, antibodies are currently applied for both cancer diagnosis and therapy. For example, monoclonal antibodies are the main constituents of several in vitro diagnostics, which are applied at many levels of cancer diagnosis. Moreover, the great improvement provided by in vivo imaging, especially for early-stage cancer diagnosis, has traced the path for the development of a complete new class of antibodies, i.e., engineered antibody fragments. The latter embody the optimal characteristics (e.g., low renal retention, rapid clearance, and small size) which make them ideal for in vivo applications. Furthermore, the present review focuses on reviewing the main applications of antibodies and antibody fragments for solid cancer diagnosis, both in vitro and in vivo. Furthermore, we review the scientific evidence showing that ion channels represent an almost unexplored class of ideal targets for both in vitro and in vivo diagnostic purposes. In particular, we review the applications, in solid cancers, of monoclonal antibodies and engineered antibody fragments targeting the voltage-dependent ion channel Kv 11.1, also known as hERG1.

• antibodies
• cancer diagnostics
• engineered antibody fragments
• hERG1
• in vivo imaging

Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication of Kv in physiological and pathophysiological cell growth is the subject of study, as Kv are proposed as therapeutic targets for tumor regression. Though it is widely accepted that Kv channels control proliferation by allowing cell cycle progression, their role is controversial. Kv expression is altered in many cancers, and their participation, as well as their use as tumor markers, is worthy of effort. There is an ever-growing list of Kv that remodel during tumorigenesis. This review focuses on the actual knowledge of Kv channel expression and their relationship with neoplastic proliferation. In this work, we provide an update of what is currently known about these proteins, thereby paving the way for a more precise understanding of the participation of Kv during cancer development.

• K+ channels
• cancer
• cell cycle
• proliferation
• tumor progression

• Animals
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition/genetics
• Humans
• MAP Kinase Kinase 1/genetics
• MAP Kinase Kinase 2/genetics
• MAP Kinase Kinase Kinase 2
• MAP Kinase Kinase Kinases/genetics
• MAP Kinase Signaling System/genetics
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Potassium Channels, Inwardly Rectifying/genetics
• Prognosis
• Protein Serine-Threonine Kinases/genetics
• Signal Transduction/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Ubiquitin-Protein Ligases/genetics
• Ubiquitination/genetics

• Z01 BC010015 Intramural NIH HHS

Gastric cancer (GC) is a common disease with few effective treatment choices and poor prognosis, and has the second-highest mortality rates among all cancers worldwide. Dysregulation and/or malfunction of ion channels or aquaporins (AQPs) are common in various human cancers. Furthermore, ion channels are involved in numerous important aspects of the tumor aggressive phonotype, such as proliferation, cell cycle, apoptosis, motility, migration, and invasion. Indeed, by localizing in the plasma membrane, ion channels or AQPs can sense and respond to extracellular environment changes; thus, they play a crucial role in cell signaling and cancer progression. These findings have expanded a new area of pharmaceutical exploration for various types of cancer, including GC. The involvement of multiple ion channels, such as voltage-gated potassium and sodium channels, intracellular chloride channels, ‘transient receptor potential’ channels, and AQPs, which have been shown to facilitate the pathogenesis of other tumors, also plays a role in GC. In this review, an overview of ion channel and aquaporin expression and function in carcinogenesis of GC is presented. Studies of ion channels or AQPs will advance our understanding of the molecular genesis of GC and may identify novel and effective targets for the clinical application of GC.

• Aquaporin
• Calcium
• Chloride
• Gastric cancer
• Ion channels
• Potassium
• Sodium
• Therapeutic target

• Animals
• Biomarkers, Tumor/biosynthesis
• Biomarkers, Tumor/genetics
• Cell Proliferation/genetics
• ERG1 Potassium Channel
• Early Detection of Cancer
• Ether-A-Go-Go Potassium Channels/biosynthesis
• Ether-A-Go-Go Potassium Channels/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Neoplasms/genetics
• Neoplasms/pathology
• Translational Research, Biomedical

• Gastric cancer
• ISL-1
• Immunohistochemistry
• Overall survival
• Prognostic biomarker

• Biomarkers
• Cancer
• Ion channels
• Transporters

• Cancer
• Metastasis
• Potassium channel
• Tumorigenesis

The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human health. GC is frequently not diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for improving prognoses in patients with GC. Gastroscopy with biopsy is an appropriate method capable of aiding the diagnosis of specific early GC tumor types; however, the stress caused by this method together with it being excessively expensive makes it difficult to use it as a routine method for screening for GC on a population basis. The currently used tumor marker assays for detecting GC are simple and rapid, but their use is limited by their low sensitivity and specificity. In recent years, several markers have been identified and tested for their clinical relevance in the management of GC. Here, we review the serum-based tumor markers for GC and their clinical significance, focusing on discoveries from microarray/proteomics research. We also review tissue-based GC tumor markers and their clinical application, focusing on discoveries from immunohistochemical research. This review provides a brief description of various tumor markers for the purposes of diagnosis, prognosis and therapeutics, and we include markers already in clinical practice and various forthcoming biomarkers.

• Tumor marker
• Prognosis
• Gastric cancer
• Serum-based
• Tissue-based

• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Humans
• Neoplasm Staging
• Predictive Value of Tests
• Reproducibility of Results
• Stomach Neoplasms/blood
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/therapy

Recent studies show that ion channels/transporters play important roles in fundamental cellular functions that would be involved in the cancer process. We review the evidence for their expression and functioning in human gastric cancer (GC), and evaluate the potential of cellular physiological approach in clinical management. Various types of ion channels, such as voltage-gated K⁺ channels, intracellular Cl^- channels and transient receptor potential channels have been found to express in GC cells and tissues, and to control cell cycles. With regard to water channels, aquaporin 3 and 5 play an important role in the progression of GC. Regulators of intracellular pH, such as anion exchanger, sodium-hydrogen exchanger, vacuolar H⁺-ATPases and carbonic anhydrases are also involved in tumorigenesis of GC. Their pharmacological manipulation and gene silencing affect cellular behaviours, suggesting their potential as therapeutic targets for GC. Our studies indicate the intracellular Cl^- concentration could act as a mediator of cellular signaling and control cell cycle progression in GC cells. Further, we demonstrate the cytocidal effects of hypotonic shock on GC cells, and indicate that the blockade of Cl^- channels/transporters enhances these effects by inhibiting regulatory volume decrease. A deeper understanding of molecular mechanisms may lead to the discovery of these cellular physiological approaches as a novel therapeutic strategy for GC.

• Gastric cancer
• Ion channels
• Water channels
• Intracellular pH
• Intracellular chloride
• Osmolality

• Animals
• Antineoplastic Agents/therapeutic use
• Drug Design
• Humans
• Hydrogen-Ion Concentration
• Ion Channels/drug effects
• Ion Channels/metabolism
• Molecular Targeted Therapy
• Osmolar Concentration
• Signal Transduction/drug effects
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Treatment Outcome

• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Animals
• Cell Line, Tumor
• ERG1 Potassium Channel
• Enzyme-Linked Immunosorbent Assay
• Ether-A-Go-Go Potassium Channels/metabolism
• Heterografts
• Humans
• Immunohistochemistry
• Mice
• Mice, Nude
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Transfection
• Vascular Endothelial Growth Factor A/metabolism

• 06-0491 Worldwide Cancer Research

Normal cell-cycle progression is a crucial task for every multicellular organism, as it determines body size and shape, tissue renewal and senescence, and is also crucial for reproduction. On the other hand, dysregulation of the cell-cycle progression leading to uncontrolled cell proliferation is the hallmark of cancer. Therefore, it is not surprising that it is a tightly regulated process, with multifaceted and very complex control mechanisms. It is now well established that one of those mechanisms relies on ion channels, and in many cases specifically on potassium channels. Here, we summarize the possible mechanisms underlying the importance of potassium channels in cell-cycle control and briefly review some of the identified channels that illustrate the multiple ways in which this group of proteins can influence cell proliferation and modulate cell-cycle progression.

• cancer
• cell cycle
• cell division
• potassium channels
• proliferation

• Animals
• Apoptosis
• Cell Adhesion
• Cell Movement
• Cell Proliferation
• Cell Size
• Ether-A-Go-Go Potassium Channels/physiology
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasms/blood supply
• Neoplasms/metabolism
• Neoplasms/pathology
• Neovascularization, Pathologic/metabolism

Atrial natriuretic peptide (ANP) and brain NP (BNP) belong to the NP family that regulates mammalian blood volume and blood pressure. ANP signaling through NP receptor A (NPR-A)/cyclic guanosine 3′5′-monophosphate (cGMP)/ cGMP-dependent protein kinase (PKG) activates various downstream effectors involved in cell growth, apoptosis, proliferation and inflammation. Evidence has shown the critical role of plasma K⁺ channels in the regulation of tumor cell proliferation. However, the role of ANP in the proliferation of gastric cancer cells is not clear. In the present study, the expression of NPR-A in the human gastric cancer cell line, AGS, and the effect of ANP on the proliferation of AGS cells were investigated using western blotting, immunofluorescence, qPCR and patch clamp assays. The K⁺ current was also analyzed in the effect of ANP on the proliferation of AGS cells. NPR-A was expressed in the human gastric cancer AGS cell line. Lower concentrations of ANP promoted the proliferation of the AGS cells, although higher concentrations decreased their proliferation. Significant increases in the levels of cGMP activity were observed in the AGS cells treated with 10⁻¹⁰, 10⁻⁹ and 10⁻⁸ M ANP compared with the controls, but no significant differences were observed in the 10⁻⁷ and 10⁻⁶ M ANP groups. The patch clamp results showed that 10⁻⁹ M ANP significantly increased the tetraethylammonium (TEA)- and 293B-sensitive K⁺ current, while 10⁻⁶ M ANP significantly decreased the TEA- and 293B-sensitive K⁺ current. The results showed that 10⁻¹⁰ and 10⁻⁹ M ANP significantly upregulated the expression of potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) at the protein and mRNA levels, although 10⁻⁷ and 10⁻⁶ M ANP significantly downregulated the expression of KCNQ1. The data indicated that lower and higher concentrations of ANP have opposite effects on the proliferation of AGS cells through cGMP-dependent or -independent pathways. KCNQ1 upregulation and downregulation by lower and higher concentrations of ANP, respectively, have separate effects on the promotion and inhibition of proliferation.

• KCNQ1
• atrial natriuretic peptide
• gastric cancer
• proliferation

• Antineoplastic Agents/pharmacology
• Apoptosis
• Benzamides/pharmacology
• Down-Regulation
• Ether-A-Go-Go Potassium Channels/biosynthesis
• Ether-A-Go-Go Potassium Channels/drug effects
• Flow Cytometry
• Humans
• Imatinib Mesylate
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
• Patch-Clamp Techniques
• Piperazines/pharmacology
• Pyrimidines/pharmacology
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Vascular Endothelial Growth Factor A/drug effects
• Vascular Endothelial Growth Factor A/metabolism