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Berardi et al. J Cancer Metastasis Treat 2019;5:79 I http://dx.doi.org/10.20517/2394-4722.2019.008 Page 3 of 33
[9]
[10]
[11]
carcinoma , breast cancer , and cervical carcinoma . The expression of a particular VGSC, SCN9A,
in prostate cancer is associated with higher risk of metastasis due to its activity promoting cell migration.
Furthermore, it is overexpressed in prostate cancer cells, compared to normal cells, representing a potential
diagnostic biomarker . VGSCs are overexpressed in non-small-cell lung cancer cells and involved in cell
[12]
invasiveness. Recent data show that the upregulation of SCN9A in non small cell lung cancer is regulated
by EGFR signaling and it is crucial for the invasive behavior of cancer cells, suggesting a potential new
[13]
biomarker and therapeutic target . Nav 1.5 (SCN5A) was found overexpressed also in colorectal cancer
(CRC) cells compared to normal colon tissues. SCNA5 was demonstrated to regulate CRC invasion process.
In fact, it is involved in activation of several pathways: Wnt signaling, steroid metabolic process, favoring
[14]
cell migration, ectoderm development, and influencing cell cycle control . Finally, a recent multicenter
study identified two single nucleotide polymorphisms of VGSC genes (the intron SNP SCN4A-rs2302237
and the SCN10A-rs12632942 SNP) that were associated with oxaliplatin-induced peripheral neuropathy
[15]
development, which is interesting as the majority of patients with CRC are given oxaliplatin .
Serum sodium concentration is also regulated by aquaporins (AQP), or water channels, a large family
of membrane proteins involved in water transportation between cells. AQP1 might be expressed in
breast cancer cells and it is associated with aggressive behavior. In fact, it correlates with higher grading,
[16]
CK14 expression, smooth muscle actin expression, basal-like group, and poor prognosis . Aquaporin’s
expression has also been investigated in CRC. In particular, AQP1, AQP3, and AQP5 are expressed in
CRC cell lines and in primary CRC. They have been described during CRC progression and in liver
[17]
metastases . AQP5 over-expression was demonstrated to be associated with worse TNM stage, grading,
and lymph node involvement . AQP3 expression is positively regulated by endothelial growth factor
[18]
[19]
pathway and it is associated with lymph node involvement, metastasis, and tumor differentiation .
Furthermore, a recent study showed that reduced AQP9 gene expression is associated with a lack of
[20]
response to adjuvant chemotherapy . AQP3 and AQP5 are also over-expressed in esophageal cancer cells
compared to normal tissue and their co-expression seems to have a negative prognostic role . The co-
[21]
expression of AQP3 and AQP5, also described in gastric cancer, is associated with lymph node involvement
and intestinal type .
[22]

Although the effect of serum sodium concentrations’ alterations on the functionality of VGSCs and AQP in
tumor cells is still unknown, many data are emerging on the effect of dysnatremic conditions in neurons.
+
In particular, a hyponatremic condition induces a modification of the axonal Na channels kinetics,
+
resulting in a decreased Na current. Moreover, the damage is proportional to the severity of hyponatremia
and concerns the recovery phase of VGSC. On the other hand, hypernatremia increases the excitability
of the membrane, reducing the response time of the channel. However, the effect of hyponatremic
condition seems to be less destructive compared to situation of hyponatremia on the activity of Na ion
[23]
channel . Syndrome of inappropriate antidiuresis (SIAD) is a rare cancer paraneoplastic syndrome
causing hyponatremia. It is associated with overexpression of AQP in renal cells. Even though no data are
available on AQP expression in cancer cells, secondary to SIAD, dysnatremia could also play a role in AQP
expression in cancer cells . These data suggest that alterations in serum sodium concentration might play
[1]
an important role on the functionality of tumor cells that overexpress sodium channels and AQPs.

Finally, the importance of sodium in oncology is also underlined by another potential development field,
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sodium magnetic resonance imaging ( NaMRI). NaMRI seems to be able to provide information on
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cells’ metabolism and their physiology, exploiting the different total tissue sodium concentration between
healthy tissue and neoplastic cells. NaMRI takes advantage of the abnormally high sodium concentration
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+
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of proliferating cells, due to altered pH and Na /H transport kinetics. Currently, the most promising
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application areas of NaMRI are the early diagnosis of brain tumors and breast cancer .
[24]