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Hamilton et al. Dissemination of small cell lung cancer

from the developing metastases. It was universally confined to SCLC or is common to other tumor types,
assumed that CTCs survive as chemoresistant cells remains to be investigated.
and may predict the responsiveness of resulting
secondary lesions. Surprisingly, the SCLC CTC lines CONCLUSION
were found to be highly chemosensitive to agents of
common use in this tumor entity, except the CTC line Mechanisms of tumor metastasis have been
established from a patient refractory to initial therapy investigated using numerous cell culture studies and
with cisplatin. Thus, some tumor cells have survived research employing experimental animal models as well
[39]
the initial cycles of chemotherapy, possibly in an as analyses of clinical specimens. Models have been
inflammatory environment, and seem to develop a kind proposed for the discrete steps of tumor metastasis,
of chemoresistance not accomplished at the cellular but the actual dissemination of malignancies in patients
[34]
level. Tumorospheres are known to be comprised is difficult to assess. Clearly, CTCs are instrumental in
of a small region of proliferating cells and layers of translocation of tumor cells to distal sites and in the
quiescent cells surrounding an inner hypoxic core induction of secondary lesions. Although CTC counts
which provides protection against irradiation due to the have shown prognostic significance, their limited
lack of reactive oxygen species [Figure 1]. [47,48] accessibility and marked heterogeneity have limited
their usefulness.
Therapy of SCLC has not been improved for the
last several decades despite the clinical testing of A panel of permanent CTC lines from SCLC
a host of chemotherapeutics covering the widest patients revealed absence of full EMT, presence of
range of clinical targets available. [1,49] More than 600 chemosensitivity, and an epithelial phenotype with
trials exploring therapeutic interventions in SCLC are formation of tumorospheres as physical barrier against
currently in the U.S. clinical trials registry, National chemoradiotherapy. Unfortunately, there are currently
Institutes of Health. Since it is not reasonable to no means available to target these spheroid structures
[50]
assume that SCLC tumors express a host of individual in a clinical setting, and further investigation is needed
molecular mechanisms, tumorospheres provide an to study the cell biology of CTC aggregates in detail,
alternative explanation for chemoresistance, in which and to study overcoming resistance using targeted
potential chemotherapeutic drugs are prevented from agents involving enzymes, cell junctions opener,
reaching their cellular target (in responsive cells) in nanomaterials and other mechanisms.
sufficient quantities. Whether the validity of this kind
[51]
of chemoresistance, in the form of tumor spheroids, is Acknowledgments
The authors wish to thank all clinical and laboratory
staff involved in the project of generating CTC cell
lines of SCLC patients and Dr. B. T. Hohenheim for
Proliferation zone endorsement.
Quiescent zone
Financial support and sponsorship
Nil.

Conflicts of interest
O 2 , Nutrients There are no conflicts of interest.

Patient consent
Waste (Lactate)
Informed patient consent was obtained throughout the
study.
Necrotic zone
Ethics approval
The respective ethics protocol (Approval of the Medical
500 μm University of Vienna Nr. 366/2003 and amendments
obtained prior to the commencement of the study) was
Figure 1: Cell physiologic conditions in an SCLC CTC tumorosphere.
This figure shows a microscopic image of a SCLC CTC BHGc10 followed throughout the study.
tumorosphere with a schematic overlay indicating regions of
proliferating, quiescent and hypoxic cells. These spheroid structures REFERENCES
grow up to diameters of 1-2 millimeters and develop gradients of
nutrient and oxygen supply as well as accumulation of metabolic
waste products. SCLC: small cell lung cancer; CTC: circulating 1. Pietanza MC, Byers LA, Minna JD, Rudin CM. Small cell lung
tumor cell cancer: will recent progress lead to improved outcomes? Clin Cancer
450 Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ December 16, 2016