Page 8 - Read Online

Hamilton et al. Dissemination of small cell lung cancer

liquid biopsies, would offer significant advantages.Non- lines for tumor dissemination in this highly aggressive
invasive detection and monitoring of patient tumors, malignancy.
employing cell-free circulating tumor DNA (ctDNA) or
circulating tumor cells (CTCs), have been employed DETECTION AND ENRICHMENT OF CTCS
for investigations into multiple tumor types. [2-4] CTCs
are described as cells, shed by primary or secondary In most tumor types, CTCs are rare events, with a
tumors into vasculature, that keep circulating in the frequency of approximately one CTC among 1-10
bloodstream of cancer patients. Reports indicate that million mononuclear blood cells. Therefore, these
[5]
patients with lower counts of CTCs survive longer than cancer cells have to be enriched by various methods
the patients with higher CTCs counts. For example, for further analysis. The probability to detect CTCs
lower numbers of CTCs were observed for 21 patients in a limited volume of blood has been reviewed by
with limited SCLC (median = 6, range 0-220) compared Gkountela et al. and the reported probability of
[10]
with 38 patients with extensive stage (median = 63, collecting ≥ 1 CTCs in one aliquot of 7.5 mL blood
range 0-14,040) and the absence of measurable CTCs from a patient with 500 CTCs is 50%. Therefore,
in 27% of patients was correlated with prolonged 20 mL of whole blood would have to be assessed if the
survival (hazard ratio: 3.4; P ≤ 0.001). [6] cell event were to be detected for a lower frequency
at one CTC in 10 leukocytes. The frequency of the
7
Furthermore, CTC counts have been proposed as CTC population measured in an aliquot may not be a
a surrogate marker for assessment of responses statistical representative of the entire sample.
to therapy in cancer patients to facilitate more rapid
drug evaluation. The Food and Drug Administration There are a number of questions remaining for the
approved CellSearch system (Veridex, Raritan, NJ, detection of CTCs and their relationship to their parent
©
USA) enumerates intact CTCs for a prognosis of bulk tumors. CTCs seem to stem from the frontier of
overall survival for breast, prostate and colon cancer. the tumor and it is generally known that the tumor
[7]
For example, CTC count is a robust independent margin is different from the main tumor mass. Most of
prognostic factor for progression-free recovery and the CTCs populations analyzed exhibit heterogeneity,
overall survival in patients with early and metastatic pointing to release of different cell populations from
breast cancer. Additionally, CTCs have been detected distinct regions of the tumor or of metastatic lesions.
[8]
[11]
in patients with chronic obstructive pulmonary disease CTCs can also form clusters including immune cells in
before the actual occurrence of malign lesions, thus the circulation, or be engulfed by the platelets before
allowing for early diagnosis of lung cancer. However, eventually adhering to the walls of the capillaries and
[9]
an advantage of the analysis of ctDNA in liquid biopsy is initiating extravasation. [12]
the detection of molecular changes which are occurring
within the tumors in real time, especially during The role of CTCs as prognostic marker and as
development of drug resistance to targeted agents. [2,3] possible surrogate indicators for response to therapy
Numerous techniques for the enrichment of CTCs have is discussed in numerous reviews. [10,13,14] CTCs which
been developed relying on immunological markers, are shed from tumors are mediators of metastatic
size, rigidity or dielectric properties. These techniques dissemination and form micrometastasis at distant
have been used for genetic characterization, marker organs. In positive selection, surface markers of
[15]
analysis and short-term cultures for investigation of CTCs are targeted, whereas, in negative selection,
their cell biology. [10,11] Despite a host of studies dealing depletion of blood cells other than CTCs is achieved
with CTCs, many questions regarding their generation, by targeting their surface markers. The CellSearch
[10]
®
shedding, survival in the circulation, chemosensitivity system is by far the most common system for extraction
and mechanisms of induction of secondary lesion and enumeration of CTCs for clinical investigations.
[7]
remain to be fully resolved. CTCs which have downregulated EpCAM remain
undetected throughout this process. [16,17] By alternative
Research on tumor dissemination and CTCs has methods, cell size-based sorting is accomplished
been hampered by the scarcity or heterogeneity of using microfluidic technology, as with the Parsortix
the enriched cells, as well as the inability to define the system (Angle, Guildford, UK). [18,19] Isolation by
characteristics of the actual metastasis-inducing CTCs Size of Tumor cells (ISET ) is a another filter-based
®
that are expected to be most relevant for the prognosis established method which is used for such cell size-
of the patients. In this study, we have established based sorting. [20]
for the first time six CTC cell lines from a variety of
patients with extended metastatic SCLC and present CTCs derived from breast cancer patients are
here the implications of the phenotype of these cell among the most extensively studied for diagnosis
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 16, 2016 447