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Page 8 of 12 Ossoliński et al. J Cancer Metastasis Treat 2019;5:1 I http://dx.doi.org/10.20517/2394-4722.2018.63

Figure 3. Flowchart for MSI analysis of interstitial fluid, urine and blood plasma samples on AuNPET target. Step 1: semi-manual
application of diluted samples onto AuNPET target with the aid of 3D translation stage; 2: programming of four-pixel array per sample
spot; 3, 4, 5: LDI MS measurements in imaging mode producing series of spectra; 6: data processing. MSI: mass spectrometry imaging;
AuNPET: gold nanoparticle-enhanced target; SALDI: surface-assisted, laser desorption ionization; LDI: laser desorption/ionization

ensure further development. First adaptive mechanism has been described by Otto Warburg in 1920 who
discovered that malignant cells produces energy predominantly through anaerobic pathway (glycolysis),
even in the presence of oxygen (Warburg effect). This increased utilization of glucose in cancer cells formed
basis for positron emission tomography (PET), nuclear medicine imaging system, which uses radiolabeled
analog of glucose to diagnose cancer. However, since then numerous studies have demonstrated association
between alteration in glutamine, lipid and cholesterol metabolism and cancerogenesis. This is accompanied
by increased uptake of exogenous lipids and activation of its intracellular synthesis. With respect to PCa,
alterations of lipid and cholesterol metabolism has been broadly studied. Fatty acid beta-oxidation pathway
is believed to be dominant energetic source for PCa, which is considered to be non-glycolytic type of
[29]
tumor [27,28] . This hypothesis is supported by low uptake of fluorodeoxyglucose on PET imaging .

Dysregulation in cholesterol metabolism has been implicated in the pathogenesis of PCa. It is essential for
cell proliferation by participation in membrane formation and steroid biosynthesis which is cornerstone
of prostate cancerogenesis. It is also believed that it can play a major role in cancer progression to the
castration resistant state by fueling intratumoral androgen biosynthesis in androgen deprived patient [30,31] .
[32]
This is possible due to activity of CYP17A1 enzyme, which is overexpressed in castrate resistant PCa .
Cholesterol biosynthesis pathway including production of squalene by condensing two molecules of
farnesyl pyrophosphate by squalene synthase (farnesyl diphosphate farnesyltransferase 1). Squalene is then
transformed with the aid of squalene monooxygenase (SQLE) to lanosterol. In the final step, lanosterol is
converted to cholesterol through a 19-step process.

Decreased cancer/control ratio of serum squalene was observed in this study. Increased utilization of
squalene by PCa cell should be accompanied by increased activity of SQLE. This observation is consistent
[33]
with the study by Stopsack et al. which showed that men with high SQLE expression are 8.3 times more
likely to develop lethal PCa.