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Peyvandi et al. J Cancer Metastasis Treat 2019;5:44 I http://dx.doi.org/10.20517/2394-4722.2019.16 Page 7 of 24

tumor-suppressor mechanism in response to oncogene activation [133] . Generally, overexpression or sustained
activation of one of the tumor suppressors p53, p21, p16 INK4a , or pRB is sufficient to induce senescence [136,143-145] .
Importantly, growth arrest caused by senescence is considered as irreversible as senescent cell could not be
stimulated to resume proliferation by exposure to growth factors [136,141,143] . However, the genetic or epigenetic
alternations which cause the shift of the senescence maintaining mechanisms, such as the inactivation of
tumor suppressor genes p53 and/or p16 INK4a , could potentially push the cells to re-enter the cell cycle [136,143] .

It is not clear whether senescence is one of the mechanisms that drives tumor dormancy and late relapse, but
there are some potential links suggesting so. Senescence-associated secretory phenotype (SASP) defines the
spectrum of factors secreted by senescent cells. It consists of a mixture of chemokines, cytokines, growth
factors and proteases, many of which are pro-inflammatory [136] . The cytokine GM-CSF (granulocyte-
macrophage colony-stimulating factor, also known as CSF2), one of the components from SASP, induces
differentiation of myeloid dendritic cells, which present tumor-associated antigens (TAAs), resulting in
the activation of the immune system, enhanced immunosurveillance and improved tumor control [146,147] .
[148]
Furthermore, Braumüller et al. showed that adaptive TH1 cell are capable, via the combined secretion of
IFN-γ and TNFR to induce tumor cells senescence. In conclusion, while senesce is a mechanism capable of
negatively controlling tumor growth, its relevance in dormancy is not fully demonstrated.

MICROENVIRONMENTAL DORMANCY: DEFICIENT SUPPORT FROM THE
MICROENVIRONMENT
In this form of dormancy, the fate of the DTCs is mainly controlled by the immediate, and possibly distant,
host environment [126,149] : cancer cells proliferate but fail to grow as a tumor mass because proliferation is
[99]
balanced by cell death . This situation has been described first when disseminated cancer cells fail to
induce blood vessels [150] . During the early stage of tumor spreading, DTCs associate to preexisting (coopted)
blood vessels where oxygen and nutrient levels are highest [151] . Importantly, quiescent mature blood vessels
keep DTCs in a state of dormancy through angiocrine communication [122] . With the growing tumor
mass, however, the increasing metabolic demand call for the formation of novel blood vessels through
an angiogenic switch [152] . Several molecules, including hypoxia-inducible factor 1, vascular endothelial
growth factor (VEGF), placental growth factor and angiopoietin-1, are induced upon metabolic stress or
hypoxia and initiate endothelial cell sprouting from preexisting vessels [153] . Angiogenic endothelial sprouts
secrete periostin and TGF-β1 to create a microenvironment that promotes DTCs exit from dormancy
and accelerates proliferation [122] . Thus, the failure of initiating the angiogenic switch will keep the tumor
mass small, a condition called angiogenic dormancy [154] . Conversely, a short-term angiogenic burst may
awaken dormant tumor cells [155] . For example, in the mouse model of Lewis lung carcinoma, dormant
micrometastatic cells can be induced to to grow by the expression of VEGF and the recruitment of bone-
marrow-derived endothelial progenitor cells [156] .

Importantly, inflammatory cells recruited to the tumor microenvironment are critical inducer of the
angiogenic switch and lack of recruitment may therefore contribute to angiogenic dormancy [11,157] . In
particular the polarization of tumor associated macrophages toward the M2 phenotype results in the
formation of a metastatic niche favoring tumor cell outgrowth [158] . In addition, the angiogenic endothelium
triggers a T helper 2-mediated inflammatory response, which can accelerate metastatic outgrowth in tumor
models [159] . The hemopoietic stem cell niche also supports quiescence and survival through the CXCL12/
CXCR4 pathway and Src pathway [47,160] as well as the TGF-β2-rich bone marrow microenvironment [161] .
On the other hand, expression of VCAM1 on DTCs promotes escape from dormancy. This is due to the
recruitment of osteoclast progenitors via α4β1 integrin binding to VECAM1 causing the breakdown of the
bone matrix and stimulation of DTC to grow and form metastases [162,163] . Likewise, metastatic outgrowth
following skeletal traumas was associated with bone remodeling in the reactivation of DTCs via TNFα,
IL1β, IL6 and prostaglandin E2 production [163] . Thus, the cellular tumor microenvironment, in particular