**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 [1–3]. 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 *in vitro* or *in vivo* cancer diagnosis.

### **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 *in vitro* diagnosis (on tumor specimens or in blood samples) or *in vivo* molecular imaging. According to the National Cancer Institute (NCI) definition (NCI Dictionary of Cancer Terms, http://www.cancer.gov/dictionary?cdrid=46636), a biomarker may be used either to help diagnosis, for example, to identify early stage cancers (Diagnostic) or to forecast how aggressive a condition is (Prognostic), or to predict how well a patient will respond to a define treatment (Predictive).

For the purposes of this chapter, we will briefly summarize the main techniques, either *in vitro* or *in vivo*, which take advantage of the use of biomarkers to obtain diagnostic, prognostic and predictive data on the cancer under study. Notably, most, although not all, of these techniques are based on the use of antibodies, targeting specific cancer-related biomarkers.

#### **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 *ex vivo* procedures (either on surgical/bioptic samples or blood), cancer *diagnosis* is mainly based on imaging procedures, such as *computed tomography,*

**45**

**Figure 1.**

*Ion Channels and Transporters as Cancer Biomarkers and Targets for Diagnostics with Antibodies*

magnetic resonance imaging and positron emission tomography. The advent of molecular imaging techniques has progressively allowed more accurate *in vivo* visualization of cancer, based on specific biological and pathological processes. Antibody-based imaging is of great utility since the combination of tumor specificity and different imaging methodologies might improve cancer diagnosis, monitoring and follow up [7–11]. The diagnostic imaging approaches currently used in cancer has been improved by the application of antibodies, thanks to the accuracy that allows antibodies to precisely identifying their targets. Some practical examples of mAbs recognizing cancer-specific biomarkers that are approved by the FDA and/or EMA and are currently used in the clinical setting have been described elsewhere [12]. Monoclonal antibodies (mAbs) have several features (big size, slow pharmacokinetics and blood clearance, not complete penetration and accumulation in tumor tissue) that can delay the time point for imaging. A different class of antibodies (single chain Fragment variable, scFv) might be useful to overcome such limitations and due to the possibility of conjugating the recombinant proteins with fluorescent dyes, scFv antibodies have been proposed for use in imaging applica-

**3. Ion channels and transporters with clinical relevance in solid cancer**

them, *KCa 1.1* channels (also known as BK channels, encoded by the *KCNMA1* gene) have shown a clinical relevance in breast (BC) and prostate cancer (PCa). In both tumor types, BK overexpression can be traced back to the amplification of the *KCNMA1* gene located in 10q22: in BC, the amplification is restricted to invasive ductal tumors, and is associated with high stage, high grade and unfavorable prognosis [14]. In BC, KCa 1.1 positively correlates with the expression of estrogen

An overview of the main ion channels and transporters expressed in different

channels are the class of ion channels mostly de-regulated in cancers. Among

*DOI: http://dx.doi.org/10.5772/intechopen.90401*

tions, especially for cancer diagnostics [8, 11, 13].

*Schematic representation of the main ICTs expressed in solid tumors.*

solid tumors is reported in **Figure 1**.

**3.1 Potassium channels**

K+

*Ion Channels and Transporters as Cancer Biomarkers and Targets for Diagnostics with Antibodies DOI: http://dx.doi.org/10.5772/intechopen.90401*

magnetic resonance imaging and positron emission tomography. The advent of molecular imaging techniques has progressively allowed more accurate *in vivo* visualization of cancer, based on specific biological and pathological processes. Antibody-based imaging is of great utility since the combination of tumor specificity and different imaging methodologies might improve cancer diagnosis, monitoring and follow up [7–11]. The diagnostic imaging approaches currently used in cancer has been improved by the application of antibodies, thanks to the accuracy that allows antibodies to precisely identifying their targets. Some practical examples of mAbs recognizing cancer-specific biomarkers that are approved by the FDA and/or EMA and are currently used in the clinical setting have been described elsewhere [12]. Monoclonal antibodies (mAbs) have several features (big size, slow pharmacokinetics and blood clearance, not complete penetration and accumulation in tumor tissue) that can delay the time point for imaging. A different class of antibodies (single chain Fragment variable, scFv) might be useful to overcome such limitations and due to the possibility of conjugating the recombinant proteins with fluorescent dyes, scFv antibodies have been proposed for use in imaging applications, especially for cancer diagnostics [8, 11, 13].
