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Hamilton et al. Dissemination of small cell lung cancer

and treatment. The presence of CTCs, despite of approximately 20,000 CTCs/mL blood.
[21]
ongoing treatment, has proven to be an indicator of
worse overall survival; therefore, in one group of Clearly, this estimation of the release of CTCs
HER2 breast cancer patients, HER2 CTCs were reported from an experimental animal model cannot
-
+
identified and trastuzumab-based therapy applied to be extrapolated to human tumors. No form of the
these patients. [17,22,23] Most of the CTCs isolated from shedding of CTCs causes a human tumor to lose
breast cancer patients show the presence of epithelial- 10% of its size in one day, nor is a CTC count of
mesenchymal transition (EMT) markers such as ETV5, 20,000 cells/mL observed in most cancer patients. A
NOTCH1, SNAIL, TGFB1, ZEB1, and ZEB2. Breast threshold of 5 CTCs/7.5 mL blood has been defined by
[24]
©
cancer patients who showed remaining CTCs after the Cellsearch system for breast and prostate cancer,
first cycles of chemotherapy progressed rapidly to and a lower threshold of 3 CTCs/7.5 mL blood has
metastatic disease. In prostate cancer, CTCs have been defined for colon cancer patients. These figures
[25]
been proposed to act as intermediate or surrogate are for favorable or poor prognosis, respectively. [7,37]
endpoints for survival and to shorten timelines for drug Consequently, the attrition rate in the circulation based
approval. Patients with lower levels of CTCs have on this artificial animal model seems to be a considerable
[26]
shown slower disease progression in comparison overestimation. The specific mechanisms of tumor
to those having higher levels of CTCs. In colon cell shedding are not known at present. CTCs seem
[27]
cancer, CTCs were found as individual cells or as to origin as specialized cell types, different from the
clusters (CTMs) by a CK-based, immunomagnetic cell bulk of the tumor cells, from the borders of the tumor.
[28]
separation method. CTMs are of particular interest CTCs leave the particular microenvironmental milieu
as they are considered to be markers of increased characterized by inflammation, acidosis and hypoxia
metastatic potential. In lung cancer, CellSearch through the interaction of a host of participating cell
®
[29]
and ISET kits indicated a higher number of CTCs in types. Therefore, CTCs are not expected to represent
SCLC than NSCLC, reported to be associated with the bulk of tumor cells and are not typical of the cell
larger tumor size and bone metastasis. [30,31] The high biologic behavior and chemoresistance of the main
numbers of CTCs in SCLC allowed for their enrichment body of the tumor. SCLC extended disease responds
and initiation of xenografts which seem to resemble well to the first cycles of platinum-based chemotherapy
the tumor characteristics of the respective patients. [32] but recurs within approximately one year as tumors
Furthermore, a trial to establish ex vivo expanded which exhibit universal chemoradioresistance.
[38]
CTC cell lines was successful and has resulted in the Contrary to expectations, the first two SCLC CTC
availability of six lines from relapsed patients so far. [33] cell lines proved to be chemosensitive to the second-
Characteristics of the first CTC cell lines and their line chemotherapeutics topotecan and epirubicin
interaction with macrophages have been published. [34] although some tumor cells must have survived the
initial successful treatment and eventually give rise
SHEDDING OF CTCS FROM TUMORS to chemoresistant relapses. Therefore, the use
[39]
of CTCs as surrogate markers for the bulk tumor is
Release of CTCs into the circulation is frequently questionable.
termed shedding, a designation for a process for
which the details are not known. CTCs are reported EMT IN TUMOR CELL SHEDDING
to be shed from solid tumors at a daily rate of 3.2
to 4.1 × 10 per gram of tissue, based on a single A general assumption supposes that tumor cells invade
6
artificial rat model. [35] In one study, the rate of tumor through a process termed EMT. Accordingly, epithelial
[40]
cell shedding into efferent blood was measured in tumor cell downregulate epithelial markers, such as
both growing and regressing MTW9 rat mammary E-cadherin, EpCAM and cytokeratins, eventually
carcinomas. Cell shedding rates of growing versus expressing mesenchymal markers such as vimentin,
regressing tumors were not significantly different neural cell adhesion molecule (NCAM) and others. In
over a tumor size range of 2-4 g. Half of these CTCs this way, cells gain mobility and migrate to intravasate
perished within 2.4 h, although longer half-lives were and reach distant sites to establish secondary lesions.
reported in a clinical setting. [28,36] Tumor cells are EMT is regulated by a number of specific transcription
rapidly cleared from circulating blood and a 2-g MTW9 factors belonging to the SNAIL, TWIST and ZEB families
carcinoma reportedly released enough cells into the und is modulated by microenvironmental conditions,
circulation to transplant the tumor every 24 h, although inflammatory cytokines and chemotherapy. Since
[41]
the majority of the cells were reported to be apoptotic/ it has proven difficult to demonstrate tumor cells with
necrotic. [35] The cell loss via blood comprised about EMT traits in patients, incomplete EMT or transitional
10% of the tumor weight and resulted in a CTC count EMT has been proposed as a model. This model
448 Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 16, 2016