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Peri. J Cancer Metastasis Treat 2019;5:40 I http://dx.doi.org/10.20517/2394-4722.2019.14 Page 5 of 7
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Interestingly, some basic research studies have evaluated whether a microenvironment with a low [Na ] may
affect cell proliferation and invasion ability. A study performed in prostate cancer cells in vitro demonstrated
for instance that the exposure to a slightly hypertonic milieu induced a dormant state. Cell dormancy
represents a limiting step of the metastatic process by preventing the proliferation of isolated cells outside
the primary tumor. Conversely, the authors demonstrated that in the presence of a hypotonic milieu,
[40]
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obtained for instance by reducing [Na ] in the culture medium, cell cloning significantly increased .
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[41]
Another study showed that low [Na ] reduced neuroblastoma cell adhesion and increased invasion ability .
A micro-array analysis was performed, in order to analyze the gene expression pattern of cells exposed to
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low [Na ] compared to normal [Na ]. Among the genes that had different expression levels in the presence
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of reduced [Na ], the heme-oxigenase 1 gene (HMOX-1), a marker of oxidative stress, was the gene with the
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greatest variation. In fact, HMOX-1 gene expression showed a 200-fold increase in cells exposed to low [Na ].
Immunocytochemistry for HMOX-1 protein confirmed these results. It is known that oxidative stress favors
carcinogenesis, cancer growth and invasion, angiogenesis, and overall creates a permissive environment for
[42]
cancer cells . Accordingly, selective inhibition of HMOX-1 has been proposed as a therapeutic target for
[43]
cancer treatment . Although additional studies are needed in order to confirm these data, in view of the
above described results from basic research it can be hypothesized that also in vivo low [Na ] might promote
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cancer cell progression through the same mechanisms. If so, then we might probably say that patients die
not only with hyponatremia, but also for hyponatremia.
CONCLUSION
In recent years evidence indicating that hyponatremia is a predictor of a worse outcome in cancer patients
has accumulated. There is emerging evidence, mainly from basic research studies at this time, that
hyponatremia may by itself increase the risk of mortality of patients, rather than being a simple bystander of
the progression of the disease. However, robust confirmatory data from clinical practice are certainly needed
in order to definitively validate the hypothesis that cancer patients may die for hyponatremia.

Meanwhile, the author is truly convinced that it is worth to correct hyponatremia in patients, including
cancer patients, because of the overall beneficial effect on the quality of life, which includes clinical
improvement, such as amelioration of neurocognitive and motor performance, reduced length of stay in the
hospital and re-admission probability [44-46] .

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
The author declares that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.