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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 3 of 24
[2]
[1]
This corresponds to about 95,000 and 40,000 women in Europe (EU 28) and the United States , dying
every year, respectively [18,19,34] . As of today, there are no effective, curative therapies for metastatic disease.
[35]
Therapy-resistance and therapy-related toxicity limit therapeutic options .

METASTATIC DISSEMINATION
Cancer metastases is a multistage process. Cancer cells have to first escape from the primary tumor, survive
in the circulation as circulating tumor cells (CTC), seed at distant sites as DTC and grow to colonize the
new tissue and form secondary tumors [36-38] . Growing evidence indicates that metastases are formed by a
subset of tumor cells with “stem cell-like” features [39-41] that also associated with resistance to treatments and
dormancy [42-44] . Accordingly, molecules controlling stem cell maintenance and differentiation [10,22,45] have been
implicated in metastasis, including Wnts, BMPs, TGFb family members, Notch, CD44 and integrins [46,47] .
Cancer stem cells (CSCs), in contrast to normal adult stem cells, seem able to revert the hierarchy so that a
differentiated cancer cell can revert and recover the stem-like features, while normal, differentiated somatic
cells are not able to do so. Thus, CSCs may be rather defined by function than lineage and may represent
a form of adaptation of cancer cells to cellular or microenvironmental stress [48-50] . This plasticity may be
one reason why by eliminating CSCs as proposed as a new therapeutic approach to eradicate cancer, may
actually not be as effective as anticipated [51-54] . Acquisition of CSCs traits has been associated with Epithelial-
to-Mesenchymal Transition (EMT), a condition endowing cancer cells with increased migratory, invasive,
metastatic and therapy resistance capacities [53,55,56] . For example, breast cancer cells undergoing EMT acquire
[57]
a cell surface phenotype (i.e., CD44 /CD24 ) associated with CSCs properties . Accordingly, EMT is
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low
a reversible process, as cells that disseminated through EMT and lost epithelial features, can revert back
to their epithelial phenotype through an opposite process called Mesenchymal-to-Epithelial Transition
[8]
(MET) . Both CSCs and EMT are features that are heavily influenced by the microenvironment such as the
vascular niches or inflammation (See below).
[58]
The genetic and epigenetic basis of metastasis is still not fully elucidated . A current paradigm relies on
the notion that the accumulation and selection of genetic mutations and epigenetic alterations is the basis of
[59]
clonal evolution at the primary site and metastatic dissemination is its ultimate expression . This notion
is supported by the clinical observation that primary tumor size is a main risk factor for metastasis. This
suggests that metastasis formation occurs rather in late disease stage as the end product of an evolutionary
processes in the primary tumor (linear model of metastasis) [8,37,60,61] . According to this model many
driver mutations found in the primary tumor are present at the metastatic site, and only a few additional
mutations accumulate between primary tumor and metastases [62-64] , including in breast cancer [65-68] . In
the other hand, comparative genomic hybridization analysis in breast and other cancers revealed that
DTCs display significantly more genetic aberration than in the primary tumors [69-72] . These observations
imply that metastatic cells disseminate early during tumor development and then progress independently
from the primary tumor through multiple steps of genetic mutations. Therefore, the parallel progression
[60]
model of metastasis has been proposed . Importantly, the two models are not mutually exclusive: a first
vague of cancer cells may disseminate early during tumor formation, for example at the time of oncogene
activation or EMT induction [73-75] , followed by the late dissemination of cells that acquired metastatic
properties through local evolution [64,76] . Recently, evidence for the parallel progression model in breast
cancer was reported by using experimental models. By studying metastasis in a HER2-driven murine model
[77]
of breast cancer, Harper et al. showed that cancer cells migrate away from early lesions shortly after
HER2 activation. In this model over 80% of the metastases were derived from early disseminated cancer
+
[77]
cells. Using the MMTV-HER2 breast tumor model, Harper et al. identified a subpopulation of ERBB2 /
low
p-p38 /p-ATF /TWIST1 /E-CAD early cancer cells that are invasive and can spread to distant organs
low
low
high
+
(early disseminated cancer cells - eDCC). By using intra-vital imaging they showed that ErbB2 eDCC
precursors invaded locally, intravasated and lodged in target organs through a WNT-dependent EMT-
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high
like dissemination program. Strikingly, although the majority of eDCCs were TWIST1 /E-CAD and