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Hamilton et al. Dissemination of small cell lung cancer

presupposes no complete switch in phenotype, but INDUCTION OF EXTRAVASATION AND
rather a type of transition which may be as minimal MESENCHYMAL-EPITHELIAL TRANSITION
as a slight downregulation of epithelial features. EMT
phenotypes have been reported among heterogeneous In general, the secondary lesions induced by CTCs
CTC populations and increased fractions of cells with show an epithelial phenotype similar to the originating
such mesenchymal features have been demonstrated primary tumor. Provided that the metastases were
[40]
to correlate with a poorer prognosis in breast cancer established by cells which underwent EMT, at some
patients. [24] point during tumor spread and extravasation this
transition has to be reversed through a process
It may still be possible that tumor cells with epithelial termed mesenchymal-epithelial transition (MET). This
characteristics enter the bloodstream without process has not been observed directly, but has been
undergoing EMT. An alternative model, termed inferred from the mesenchymal traits of disseminated/
“cooperative migration”, posits that EMT-type cells help CTCs and the histology of secondary lesions. The
[45]
epithelial cells to gain access to the circulation, but to factors causing this supposedly phenotypic switch,
reside at the bulk tumor. Excessive numbers of CTCs along with their possible derivation from the cancer
have been observed in SCLC, which is frequently cells themselves (seed) or the metastatic site (soil) are
associated with local inflammation and in inflammatory largely unknown. In the case of SCLC CTC lines, the
breast cancer. Thus, immune cells and inflammation cells are positive for EpCAM, E-cadherin and proteins
may promote release of tumor cells into the circulation involved in cell junctions and form spontaneously
possibly without EMT. The SCLC CTC cell lines have typical large spheroids with diameters of up to 1-2 mm
been found to recruit macrophages and to lack a in regular tissue culture medium without any factors
phenotypic switch with full expression of mesenchymal preventing adhesion to cell culture flasks. Although
[43]
traits. [34,42] In conclusion, complete or partial EMT is not expression of vimentin and NCAM is observed, the
proven to be a prerequisite to disseminate tumor cells, formation of these organized and large spheres is a
and therapeutic options to inhibit such a transition typical epithelial feature not observed in SCLC tumor
need to be considered cautiously. [43] cell lines in vitro. Since these tumorospheres develop
from CTCs of relapsed SCLC patients within a short
SURVIVAL CTCS IN THE CIRCULATION time, and are found in cell suspension derived from
xenografts induced by such CTCs, they seem not to
The great majority of CTCs seem to be short-lived and stem from an in vitro transition in tissue culture but to
to perish in the circulation. Of the several forms of CTCs present the original in vivo phenotype. Thus, these
shed by the primary tumor, only about 0.1% survive metastasis-inducing CTCs seem to be present as
in the circulation and only about 0.01% is responsible cancer cells exhibiting an epithelial phenotype and
for metastasis. [8,10] This attrition has been attributed to organization and may be trapped in capillaries or
shear stress and an unfavorable microenvironment too reside in protected sites, possibly in a dormant state.
different from the local tumor conditions. CTCs in the Tumorospheres exceeding diameters of 2 mm during
hematogenous circulation must survive a variety of their development tend to disintegrate and may be the
stresses, and epithelial cells may undergo anoikis in the source of non-proliferating cell clusters observed in the
absence of cellular attachment. The vast majority of blood of metastatic cancer patients. [10]
[44]
CTCs are likely to become trapped in various capillary
beds. They are destroyed by hemodynamic shear METASTASIS AND DRUG RESISTANCE
forces and predation by cells of the innate immune
system – specifically natural killer cells. Consistent with Metastases not only damage secondary organs and
this view, a great deal of CTC-associated material is exacerbate the deleterious effects of malignancies
detectable in CTC-positive tumor patients. Reported in general but frequently exhibit chemoresistance to
[10]
half-lives have ranged from several hours, according to reinitiation of primary or second-line chemotherapy
experimental animal models, to long-term persistence. agents. Especially in SCLC, excellent response rates
The SCLC CTC lines show continuing disposal of to initial chemotherapy can be followed by relapses
microparticles and cellular fragments, thus generating within approximately one year, which exhibit broad
CTC associated materials under optimal conditions in chemoresistance and result in failure of treatment. [1,38]
tissue culture in the absence of shear stress. Partial
[42]
disintegration of CTC tumorospheres may function Attempts have been made to characterize the
as a source of decoy material to protect other CTCs chemosensitivity of CTCs in short term cultures in
and the bulk tumor from attacks by both the immune various tumor entities. However, CTCs are specialized
[46]
system and chemotherapeutics. cells different from the tumor bulk and most likely also
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 16, 2016 449