**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

*Translational Research in Cancer*

after radiotherapy in ESCC patients [112]. The apical sodium-dependent bile acid transporters (**SLC10A2**), which mediate bile acid transport [113], are not expressed in the normal squamous epithelium of the esophagus [114], whereas their expression increases in Barrett's Esophagus, to decline in EA [115]. Divalent metal transporter1 (DMT1, **SLC11A2**) overexpression was associated with metastatization in EC [116]. One of the main causes of chemotherapy failure is drug efflux mediated by ATP-binding cassette transporters (ABC) [117]. It was recently shown that **ABCG2** together with V-ATPase are overexpressed in ESCC and are associated with grading, TNM stage and metastatization. **ABCB1** and ABCG2 are expressed in primary GC and GC cell lines [118] in which their expression is associated with tumor differentiation. ABCB1 expression is higher in diffuse type GC [119]. ABCG2 represents a target for a several chemotherapy drugs [120]: for example, cisplatin increases *ABCG2* mRNA *in vitro* and this is associated with patients' outcome [121]. In PDAC, **ABCB4, ABCB11, ABCC1, ABCC3, ABCC5, ABCC10** and ABCG2 are up-regulated, while **ABCA3, ABCC6**, CFTR (**ABCC7**) and **ABCC8** are down-regulated: such deregulation contributes to PDAC poor response to therapy [122]. The Solute Carrier transporters (SLC) is a family of transporters frequently deregulated in PDAC. **SLC7A5** (the L-type aminoacid transporter 1) are overexpressed in PDAC and are associated with molecular and clinico-pathological features (such as Ki-67, p53, CD34, CD98, VEGF size, stage) and prognosis [122]. **SLC22A3** and **SLC22A18** are up-regulated in PDAC with respect to healthy pancreas while **SLC22A1**, **SLC22A2**, **SLC22A11**, **SLC28A1**, **SLC28A3** and **SLC29A1** are down-regulated [122]. In particular, SLC28A1 overexpression was associated with poor overall survival whereas SLC22A3 and SLC29A3 overexpression was observed in patients treated with Gemcitabine with longer overall survival. PC patients with low expression of SMCT1 (**SLC5A8**) have poorer survival with respect to patients with high SLC5A8 levels [123]. The human equilibrative nucleoside transporter 1 (**SLC29A1**) is associated to longer time to progression and it was shown that it could predict gemcitabine effects in non-resectable PDAC patients, if evaluated in samples obtained by fine-needle aspiration [124]. Different conclusions were drawn when analyzing SLC29A1 expression in patients treated with chemo-radiotherapy [125]. In GC, **SLC7A5** overexpression was detected and it was found to be associated with clinico-pathological features such as size, lymph node involvement, TNM stage and local invasion [126]. **SLC16A1** was found to be expressed both in healthy stomach and GC, and it could be hypothesized a role in gastric physiology for this transporter [119]. In metastatic GC, **SLC16A3** is downregulated [119] and is associated with intestinal type. 4F2hc (**SLC3A2**) was found to be over-expressed in GC cell lines and in primary GC, with no significant correlation with clinico-pathological features. Since the study was conducted on a small number

of samples, it could not allow definitive conclusions [127].

**in hematologic malignancies**

for the implication of K+

**4. Ion channels and transporters with clinical relevance** 

As reported for solid tumors, a schematic overview of ion channels and transporters expressed in hematologic tumors is reported in **Figure 2**. Early evidence

the myeloblastic leukemia cell line ML-1 [128]. In leukemias, it was shown that **KCa3.1** might represent a useful target since its blockade impairs leukemic cells proliferation [129] while *KCNN4* overexpression was detected in follicular lymphomas [130]. A significant **Kv10.1** expression was detected in myelodysplastic syndromes, CML and almost half of a cohort of AML samples and blocking the channel results in the inhibition of both cell proliferation and migration. Smith

channels in leukemia cell proliferation was obtained in

**50**

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].
