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Page 6 of 16 Nagayama. J Cancer Metastasis Treat 2021;7:6 I http://dx.doi.org/10.20517/2394-4722.2020.114
[33]
[32]
1-controls of apoptosis and of p53 . It is also reported that Atg4 KO itself did not induce any tumor
[34]
development, but increased incidence of chemically induced fibrosarcoma .
Of interest, Atg5 or Atg7 KO mice were crossed with other genetically engineered mice having various
oncogenes or a loss-of-function mutation of tumor suppressor gene such as the mutant RAS, BRAF or
p53 . In most of these double mutant mice, tumor development was accelerated but tumors did not
[35]
progress to malignancy and, instead, turned to be benign oncocytic tumors [36-40] . Oncocytic tumor has
abundant mitochondria, which is thus likely attributed to defective mitophagy, a selective autophagy.
Therefore, impaired mitophagy and/or accumulated mitochondria appear to block progression from benign
to malignancy. Accumulation of deformed and dysfunctional mitochondria was also observed in liver
adenomas in liver-specific Atg7 KO mice mentioned above [29,30] .

Altogether, it is clear that autophagy works as a tumor suppressor in the early step of tumorigenesis.
However, there is always an exception; development of some tumors such as RAS-driven cancers are
[41]
reported to be dependent on autophagy activation .

[42]
Impaired autophagy is also strongly associated with abnormal DNA damage repair , especially abnormal
homologous recombination , which may also explain the propensity of autophagy-defective mice to
[43]
tumor development. Indeed, genomic instability was suggested by the presence of γH2AX foci (indicating
DNA double strand breaks) in liver adenomas in Atg7 KO mice [29,30] .

In thyroid
In thyroid cancer, there is no published study on cancer development using autophagy KO mice. In
our preliminary study, no thyroid tumor development was observed in thyroid-specific autophagy KO
mice (Atg5 thyr-KO ) at 12 months nor in Atg5 flox/flox mice subjected to intrathyroidal injection of adenovirus
expressing Cre recombinase under TG promoter in the 18-month-experimental period (unpublished data).
Instead, a study on a human genetic disease provides a clue as to the relationship between autophagy and
thyroid carcinogenesis. Thus, a previous study has shown that, in human Cowden syndrome with the
mutant succinate dehydrogenase D-G12S or D-H50R, suppression of autophagy by these mutations and
subsequent ROS elevation and phosphatase and tensin homolog (PTEN) inactivation may be involved
[44]
in thyroid tumorigenesis . Furthermore, SNPs in autophagy-related genes such as Atg5 and Atg16L are
reported to be associated with development of thyroid cancer and RAI resistance [45,46] .

As mentioned above, oncocytoma is usually a benign tumor. However, the thyroid is an exception,
where it is sometimes malignant (called Hürthle cell carcinoma). In this regard, we have recently found
that accumulation of mitochondria in thyroid oncocytic tumor is caused (1) by defective expression of
[48]
[47]
mitochondria-eating protein (MIEAP) , which play a central role in a non-canonical mitophagy ;
and (2) by enhanced biogenesis of mitochondria which compensates defective function of mitochondria
[49]
complex I . It is reported that the defective PARK2-mediated canonical mitophagy by a loss-of-function
mutation in PARK2 gene also causes mitochondrial accumulation in a thyroid malignant oncocytoma
cell line XTC. UC1, but loss of function mutation in autophagy-related genes including PARK2 is rare
in thyroid oncocytoma in humans [50,51] . Therefore, in experimental mouse models of cancer in non-
thyroid tissues (see above), a defect in canonical mitophagy may be sufficient, but in human thyroid,
both defective mitophagy (i.e., a defect in either MIEAP-mediated non-canonical or PARK2-mediated
canonical mitophagy) and increased compensated mitochondrial biogenesis may be required for oncocytic
phenotype.