Abstract
Cancer is a highly heterogeneous disease in terms of both response to therapy and prognosis. The introduction of molecular tools and antibodies had a great impact on cancer management in recent years for both cancer diagnosis and therapy. Ion channels and transporters (ICT) are membrane proteins aberrantly expressed in several human cancers. ICT can now represent potential cancer biomarkers as well as targets for therapeutic and diagnostic purposes. In particular, we will discuss about the potential role of ICTs as biomarkers for solid cancers (evaluated either by immunohistochemistry or molecular biology techniques) and the potential use of antibodies for diagnosis.
Keywords
- ion channels
- antibodies
- biomarkers
- cancer
- diagnosis
1. Introduction
Ion channels and transporters (ICTs) are emerging as potential cancer biomarkers. Indeed, ICTs are aberrantly expressed in several types of human cancers, and exert a relevant role in mediating interactions between tumor cells and tumor microenvironment. Such interactions drive different functions which in turn regulate neoplastic progression, such as cell proliferation and survival, cell invasiveness and pro-angiogenetic programs [1, 2, 3]. Moreover, due to their prevalent expression at the cell surface, ICTs represent good targets for antibodies, to be exploited for diagnostic purposes. Finally, being highly druggable molecules, ICTs may represent novel molecular targets for antineoplastic therapy [4, 5].
The expression and role of different ion channels in tumor cells and their different contribution to tumor progression has been thoroughly described elsewhere [6]. In this chapter, we will focus on the possibility of exploiting ICTs as cancer biomarkers, for diagnostic, prognostic or predictive purposes. Some examples, relative to either solid cancers or hematologic malignancies are provided. We will analyze the possibility of using ICT-targeting antibodies for either
2. Cancer diagnosis: a focus on antibody-based techniques
The technologies available to help physicians to detect and diagnose cancer has changed dramatically in recent years. In particular, the use of biomarkers has greatly improved diagnosis through their application for either
For the purposes of this chapter, we will briefly summarize the main techniques, either
2.1 In vitro cancer diagnosis
2.1.1 Immunohistochemistry (IHC)
IHC represents an indispensable diagnostic tool to assess the presence or absence, as well as the amount, of a specific molecular tumor marker in a tissue. After appropriate assessment of categorical scoring system and proper validation of the immunohistochemical assay, a given marker can be proposed as a potential diagnostic or prognostic factor. Indeed, many of the cancer biomarkers routinely used in cancer diagnostics are based on this technique.
2.1.2 Flow cytometry (FC)
Using a multiparametric approach, FC immunophenotyping plays an indispensable role in the diagnosis and subclassification of leukemias, as well as for minimal residual disease detection. FC, in fact, provides a rapid and detailed determination of antigen expression profiles; these information along with morphologic assessment, allow to diagnose a particular type of leukemia and/or help in distinguishing from other subtypes. Also, the identification of specific antigens has prognostic and therapeutic relevance in acute leukemias. Moreover, FC immunophenotyping is useful to monitor response to therapy, recurrence and minimal residual disease.
While IHC and FC represent the standard of care in solid cancers and hematologic malignancies, respectively, some remarkable technological breakthroughs of the last 10 years have greatly contributed to improve cancer diagnostics through either the definition of “Omics profile” or the assessment of plasma-based cancer biomarkers:
2.1.3 Omics profiles
The study of tumor genomes using high throughput profiling strategies including (but not limited to) DNA copy number, DNA methylation, and transcriptome and whole-genome sequencing—technologies that may collectively be defined as “omics”—has led to identifying genes and pathways deregulated in cancer, hence revealing those that may be useful for the detection and management of disease. In the near future, such discoveries will lead to the discovery of novel diagnostic, prognostic and predictive markers that will ultimately improve patient outcomes.
2.2 In vivo cancer diagnosis: molecular imaging
Besides
3. Ion channels and transporters with clinical relevance in solid cancer
An overview of the main ion channels and transporters expressed in different solid tumors is reported in Figure 1.
3.1 Potassium channels
K+ channels are the class of ion channels mostly de-regulated in cancers. Among them,
3.2 Sodium channels
Voltage-gated sodium channels (VGSC) were among the first channels to be demonstrated mis-expressed in BC and PCa. In particular, the predominant VGSC in BC is the “neonatal” splice variant of
3.3 Calcium channels
Calcium signal remodeling is one of the common features of proliferating cells, including cancer. Indeed many functional studies have provided different calcium signaling that can modulate cell proliferation and resistance to apoptosis [61, 62, 63]. Voltage-gated calcium channels (VGCC) that are involved in the regulation of BC cell proliferation.
3.4 Transient receptor potential (TRP) channels
TRP channels are non-selective cation channels that can be activated by different stimuli such as pH variations, temperature and pressure among others [71, 72]. Since TRP channels are involved in migration and invasiveness, they contribute to the metastatic process in different tumors [73]. Ca2+ influx through TRPCs also occurs and promotes either cell proliferation or apoptosis, depending on TRPC subtype.
3.5 Chloride channels
Anoctamin 1 (
ANO1 was also shown to play an important role in controlling PDAC cell proliferation [87]. It has been shown that chloride channel accessory 1 and 2 genes (
3.6 Ligand-gated channels
The ligand-gated nicotinic acethylcholine receptors (
3.7 Aquaporins (AQP)
3.8 Transporters
The monocarboxylate transporter
The sodium proton exchanger 1 (
4. Ion channels and transporters with clinical relevance in hematologic malignancies
As reported for solid tumors, a schematic overview of ion channels and transporters expressed in hematologic tumors is reported in Figure 2. Early evidence for the implication of K+ channels in leukemia cell proliferation was obtained in the myeloblastic leukemia cell line ML-1 [128]. In leukemias, it was shown that
During the oxidative burst following activation of K562 cells non-selective cation channel TRPM2 are activated, thus activating
5. Targeting ion channels and transporters for cancer diagnosis with antibodies
Recently, an antibody directed to a cancer-related ion channel (the purinergic receptor P2X7) was introduced into the clinical settings: it is a polyclonal antibody targeting a conformational epitope of the non-functional channel and it is likely to be approved as a first-generation therapy. Antibodies targeting ORAI1 were obtained using U2OS cells overexpressing human ORAI1 as immunogens. One of such antibodies impaired cell proliferation of T lymphocytes in peripheral blood [143, 144]. In 2014, a method for the isolation of functional antibodies against Nav1.7 was published [145].
6. Future perspectives
In a recent paper [146], an ICT molecular profile was defined for BC thus opening interesting perspectives in this field. In particular, the expression of 30 ion channel genes was shown to be associated with tumor grade. The authors were able of identifying a “IC30 gene signature” composed of 30 ion channel genes and demonstrated that IC30 might represent a prognostic biomarker predicting clinical outcome in BC, independently from clinical and pathological prognostic factors. The same approach was applied to LC and 37 ion channels genes were identified as differentially expressed in LC in comparison to healthy lung [147]. Moreover, 31 ion channel genes were identified as differentially expressed between lung adenocarcinoma and squamous-cell carcinoma samples, therefore the expression of such genes could be used for NSCLC molecular classification [147]. In NSCLC, it was shown that VDAC1 is an independent prognostic factor and it is associated with shorter overall survival [147]. VDAC1 was also found to be up-regulated in different types of carcinomas [148]. More recently, a paper describing gene expression profile in lymphomas demonstrated that
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