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Page 10 of 16 Rizzieri et al. J Cancer Metastasis Treat 2019;5:26 I http://dx.doi.org/10.20517/2394-4722.2019.05
[75]
composition provides a simple, suitable model to study fatty acid metabolism. Jurczyszyn et al. measured
the fatty acid composition of RBC membranes in MM patients and compared them with healthy controls.
MM patients exhibited higher levels of saturated fatty acids and n-6 polyunsaturated fatty acids (PUFA) and
lower levels of monounsaturated n-3 PUFA and trans-fatty acids, than controls. It was suggested that the
fatty acid content of the RBC membrane could serve as a diagnostic and/or predictive biomarker in MM.
Similarly, increased plasma levels of saturated fatty acids and n-6 PUFA were observed in MM patients
[76]
compared to healthy controls, indicating increased synthesis of these fatty acids in MM patients . Recently,
it has been shown that several myeloma cell lines (U266, RPMI8226, and NCI-H929) increase fatty acid
oxidation as a mechanism to maintain metabolic hemostasis and viability during conditions of decreased
glycolysis and increased lactate accumulation [77-79] .

Fatty acid synthase (FAS) expression was up-regulated in human myeloma cell lines as well as primary
myeloma cells and contributes to myeloma cell proliferation and survival. Inhibition of fatty acid b-oxidation
with etomoxir or de novo fatty acid synthesis with orlistat significantly reduced myeloma cell proliferation.
The combination of 50 mmol/L etomoxir and 20 mmol/L orlistat resulted in an additive inhibitory effect
on myeloma cell proliferation. Interestingly, the inhibitory effect was associated with reduced levels of
[79]
p21 protein and phosphorylated retinoblastoma protein . These data suggest that inhibition of fatty acid
[80]
metabolism provides a potential therapeutic approach in the treatment of MM, however O’Connor et al.
recently showed that etomoxir loses its specificity at concentrations above 5 mmol/L and results in increased
ROS production so these experiments must be interpreted with caution.

Obesity is associated with increased risks of myeloma incidence and mortality. To understand the molecular
[81]
mechanisms by which adipocytes contribute to myeloma cell survival and progression, Bullwinkle et al.
co-cultured MM cell lines with adipocytes harvested from normal, overweight, obese, or super obese
individuals. It was found that MM cells proliferated faster, displayed increased pSTAT-3/STAT-3 signaling,
and had enhanced adipocyte endothelial tube formation and cell adhesion when co-culturing with
conditioned media from obese and super obese individuals.

FUTURE DIRECTIONS
Several areas of future research provide promise in the development of novel treatments for MM.

Lactate research
As the primary molecule thought to induce the hypoxic microenvironment surrounding many cancer cells,
lactate is one of the most heavily researched metabolites in MM cells. In 1991 it was discovered that high
serum LDH levels could identify myeloma patients that were at increased risk for early progression after
[83]
[82]
treatment . Furthermore, LDH has been identified as a marker that identifies higher risk patients . The
increased anaerobic respiration in the hypoxic microenvironment of myeloma cells is thought to be linked
to the HIF1-a transcription factor, and leads to an increase in lactic acid production. In MM, HIF1-a activity
increases glycolytic metabolites, inhibits production of TCA intermediates, and activates IL-6 which all
contribute to tumor growth and survival [84,85] . Notably, hypoxia has been shown to promote myeloma cell
dissemination from the bone marrow to the peripheral blood through the downregulation of E-cadherin
[86]
and the upregulation of the epithelial to mesenchymal transition proteins SNAIL, FOXC2, and TGFb1 .
Hypoxic conditions also promote upregulation of VEGF leading to increased angiogenesis in a mechanism
that is thought to be related to HIF1-a activation [86-89] .

Transporters of lactate are also possible metabolic targets in myeloma. The MCT family of transporters are
involved in lactate transport in and out of the cell. MCT1 and MCT4 are preferentially expressed in myeloma
cells. Inhibition of MCT1 with a-cyano-4-hydroxycinnamic acid led to reduced lactate incorporation and
induced apoptosis in myeloma cell lines [90,91] . Increased lactate is secreted out of MM cells through the MCT