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Page 6 of 24 Peyvandi et al. J Cancer Metastasis Treat 2019;5:44 I http://dx.doi.org/10.20517/2394-4722.2019.16

activated in quiescent cancer cells. This activation is independent of AKT and is maintained by the small
GTPase RHEB with anti-apoptotic activity and itself under control of the stress-regulated transcription
factor ATF6α and high p38 kinase activity. Thus, mTOR seems to be a critical node integrating diverse
signaling pathways regulating dormancy [111,113,114] . Recently Malladi et al. [115] have shown that human
breast and lung carcinoma cells express stem-cell like SOX transcription factors, which induces autocrine
expression of DKK1, a WNT inhibitor, resulting in a state of metastatic latency and immune evasion
consistent with dormancy.

Interaction with the extracellular matrix is also implicated in controlling dormancy [116] , paralleling the role
of cell-matrix interaction in physiological CSC niches [117] . For example, the uPAR interaction with a5b1
integrin increases ERK activity and integrin binding to fibronectin fibrils suppresses p38 activity, increases
ERK activity and promotes cell proliferation. Accordingly, low uPAR-expressing cells that are growth
arrested (dormant) in vivo, have a high p38/ERK activity ratio and fail to assemble fibronectin fibrils and
ligate a5b1 integrin [104] . Integrin a5b1 was shown to promote survival of growth-arrested breast cancer cells
reminiscent of breast cancer dormancy in bone marrow [118] . Collagen-rich matrix (fibrosis) at the metastatic
site is also a critical determinant of DTC transition from dormancy to metastatic growth [116] . For instance,
hepatocellular carcinoma cells that colonize rigid matrix resume growth and proliferation through TGF-β1
signaling, while cells colonizing a softer matrix remain dormant [116] . The proliferative switch of dormant
DTCs in response to fibrosis in a mouse model of breast cancer was shown to be also mediated by β1
integrin [116] . 3D-in vitro models and further in vivo studies demonstrated the critical role of type I collagen
in the proliferative fate of DTCs [119-121] . Another matrix protein, periostin, produced by TGF-β1-stimulated
stromal fibroblasts and angiogenic blood vessels [47,122] , can drive DTCs escape from dormancy through WNT
signaling in breast carcinoma [123] . Interfering with extracellular matrix-integrin interaction, in particular b1
integrins, has been proposed as therapeutic approach to promote dormancy, including in breast cancer [124,125] .

Autophagy appears to promote DTCs survival and dormancy by maintaining DTCs viable under conditions
of microenvironmental stress [126] . Autophagy also promotes survival of DTC against chemotherapy-induced
cell stress [126] . On the other side, in breast cancer the lack of autophagy is associated with early tumor
recurrence and escape from dormancy [127] . It is important to note, that cellular dormancy is not just a feature
of cancer cells but it also occurs in normal cells. For example, hair follicle (bulge) stem cells, muscle stem
cells (satellite cells), hematopoietic and liver stem cells are rather quiescent under homeostatic conditions
and can be rapidly activated during tissue regeneration and repair [128-130] . These observations raised the idea
that cancer cells may hijack the signaling cascade used physiologically by these cells to enter, maintain and
exit dormancy during homeostatic and regenerative conditions [103,131] .

SENESCENCE, A SPECIAL FORM OF CELLULAR DORMANCY?
The term senescence was originally introduced to describe primary human fibroblasts in culture, that
after reaching a maximal number of passages (cell divisions) entered a state of permanent growth
arrest [132,133] . Senescent cells remain metabolically and synthetically active but show significant alterations in
morphology [132-134] . Following these original observations, scientists discovered that replicative senescence
is driven by telomere shortening [135] . Telomerase, an enzyme reconstituting telomers, is expressed in
germ line cells, early embryonic cells, but not in normal cells, and is re-expressed in most cancer cells [134] .
Besides telomere shortening, other stimuli have been found to induce the senescence [136] including DNA
damage [137] , chemotherapy [138] and oncogene activation [139] . Despite the nature of the stimulus initiating
the senescence cascade, the signals ultimately converge to the p53/p21 and/or p16 INK4a /pRB pathways [136] .
The tumor suppressor proteins DEC1 (Deleted in Esophageal Cancer) and Decoy Receptor 2 are also used
12V
as senescence markers in some cell types [140] . Importantly, when oncogenic HRAS (HRAS ) was used to
transform immortalized embryo fibroblasts into tumorigenic cells [141] , unexpectedly, it induced senescence
in normal cells associated with the accumulation of p53 and p16 INK4a[142] . Thus, senescence may act as a