Page 102 - Read Online

Davidson et al. J Cancer Metastasis Treat 2021;7:45 https://dx.doi.org/10.20517/2394-4722.2021.77 Page 5 of 19

dedifferentiated TC, pyruvate is frequently converted to lactate by lactate dehydrogenase (LDH) [39,50] . This
[15]
reaction is significant for regenerating NAD+ from NADH . The NAD+ can then serve as a cofactor for
GAPDH in glycolysis, further generating ATP. LDH is a tetramer frequently composed of LDHA and
LDHB subunits. LDHA is typically expressed in the liver and skeletal muscle while LDHB is found in the
kidneys and heart muscle . Importantly, LDHA preferentially converts pyruvate to lactate, generating
[15]
[15]
NAD+, while LDHB performs the opposite reaction . The predominantly expressed isotype may shed light
onto the preferential route of metabolism in cancer cells. There are seemingly conflicting reports on LDH
[51]
expression and function in TC. Mirebeau-Prunier et al. found that FTC cells and tissue samples exhibit
high LDHB/LDHA ratios based on mRNA levels of each isoform. Kachel et al. reported that LDHA
[52]
protein is mildly overexpressed in FTC and PTC but not ATC compared to non-tumor tissues, while only
[53]
ATC demonstrated significantly higher transcript levels of LDHA. Similarly, Coelho et al. discovered that
PTC cell lines showed no differences in LDHA transcript levels compared to normal thyroid cells.
Paradoxically, both sets of PTC cells demonstrated higher lactate production rates . Taken together, these
[53]
three studies may reflect a lack of correlation between LDH transcript expression with protein expression
[52]
and that post translational modifications are highly important for LDH activity. Indeed, Kachel et al.
showed that FGFR1 mediated phosphorylation and activity of LDHA, and p-LDHA was markedly elevated
in PTC, FTC, and ATC tumors. Cells that maintain a high LDHA/LDHB isozyme ratio may favor
converting pyruvate to lactate to continue glycolysis. Excess lactate can then be exported to the stroma via
monocarboxylate transporter 4 (MCT4) to prevent reconversion to pyruvate and acidify the tumor
[54]
microenvironment (TME) . Inhibiting lactate production and export could help balance the pH of the
TME to protect infiltrating immune cells. Indeed, limiting TME lactate levels protects naïve T cells from
[33]
apoptosis . A cancer cell that maintains a high LDHB/LDHA ratio, however, may rely on lactate produced
by cancer associated fibroblasts (CAFs) that is imported via MCT1 [54,55] . The lactate is then converted to
pyruvate and NADH. This phenomenon has been coined the “reverse Warburg effect”, in which cancer cells
are able to exploit the high energy lactate from CAFs for anabolism without requiring ATP investment to
[56]
oxidize glucose . There is strong evidence supporting MCT expression in TC. Patient derived samples
revealed that PTC, FTC, and ATC all express MCT4 for lactate export, with ATC having the highest
[28]
expression of all types of TC . However, MCT1 was only found expressed at an appreciable level in
samples from ATC patients . This is unsurprising, as all types of TC expressed a method for exporting
[55]
lactate from highly glycolytic cells. The MCT1/4 expression pattern may reveal an avenue of metabolic
plasticity in ATC, in which these highly dedifferentiated, aggressive tumors are able to shuttle lactate in and
out of the cell depending on the precise metabolic demand that is met by pyruvate dehydrogenation.

GLYCOGEN METABOLISM
In a well-fed state, cells may store excess glucose in the form of glycogen, which is normally found in high
[15]
quantities in the liver, muscle, and brain . However, many cancers have been found to metabolize glycogen
outside of these tissue types [57-60] . To date, there have been no direct reports of glycogen in TC, yet glycogen
[61]
can be detected in bovine and canine thyroids . Furthermore, there are rare cases of clear cell thyroid
carcinomas, aggressive tumors filled with solid deposits that may contain glycogen . Phosphoglucose
[62]
mutase (PGM1) appears to be one of the few reported enzymes that is overexpressed in the pathway, as
shown in PTC and FTC cells . Although not a rate-limiting enzyme, PGM1 represents an important step
[31]
in glycogen metabolism that acts in both anabolism and catabolism . PGM1 converts G6P to glucose-1-
[63]
phosphate (G1P) and then to uridine diphosphate glucose via UDP-glucose pyrophosphorylase 2 for
incorporation into glycogen. Glycogen synthase 1 forms 1-4 α glycosidic linkages with UDP-glucose onto an
already formed glycogen granule initiated by the self-glycosylating primer, glycogenin. Glycogen branching
enzyme (GBE) forms 1-6 α linkages to create branches of G1P monomers [15,35] . In a starved state, the cell
relies on glycogen phosphorylase (PYG) to cleave 1-4 α glycosidic bonds to liberate G1P monomers from