Abstract
Small cell lung cancer (SCLC) represents 15% of lung cancers and is characterized by early dissemination, development of chemoresistance and a poor prognosis. A host of diverse drugs failed invariably and its mechanisms of global chemoresistance have not been characterized so far. SCLC represents the prototype of an aggressive and highly metastatic tumor which is ultimately refractory to any treatment. High numbers of circulating tumor cells (CTCs) allowed us to establish 5 CTC cell lines (BHGc7, 10, 16, 26 and UHGc5) from patients with recurrent SCLC. These cell lines exhibit the typical SCLC markers and CTCs of all patients developed spontaneously large multicellular aggregates, termed tumorospheres. Ki67 and carbonic anhydrase 9 (CAIX) staining of tumorosphere sections revealed quiescent and hypoxic cells, respectively. Accordingly, comparison of the chemosensitivity of CTC single cell suspensions with tumorospheres demonstrated increased resistance of the clusters against chemotherapeutics commonly used for treatment of SCLC. Therefore, global chemoresistance of relapsing SCLC seems to rely on formation of large tumorospheres which reveal limited accessibility, lower growth fraction and hypoxic conditions. Since similar tumor spheroids were found in other tumor types, SCLC seems to represent a unique tumor model to study the association of CTCs, metastasis and drug resistance.
Highlights
Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor representing 15% of lung cancers which is found disseminated in most patients at the time of first presentation[1, 2]
Expression of typical SCLC markers synaptophysin (SYP), enolase-2 (ENO2) and chromogranin A (CHGA) of the circulating tumor cells (CTCs) lines BHGc7, 10, 16, 26 and UHGc5 were tested in RT-qPCR relatively to RNA from normal lung tissue (Fig. 1)
Extended disease SCLC is characterized by early failure of chemoradiotherapy and low activity of all chemotherapeutics tried in the second-line setting[1, 2]
Summary
Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor representing 15% of lung cancers which is found disseminated in most patients at the time of first presentation[1, 2]. Tumor relapse and spread in SCLC seems to be related to the extraordinary high counts of circulating tumor cells (CTCs) which exceed CTC numbers in other malignancies by orders of magnitude[8, 9]. Part of these CTCs were suggested to exhibit a general chemoresistance and to be able to induce secondary lesions. We were successful in establishing 5 CTC cell lines so far which grow continuously in tissue culture[11, 12] These SCLC CTC lines derived from different patients exhibit similar expression of proteins, cytokines and various receptors, indicating their important role in metastatic SCLC. Access to the SCLC CTC lines offers a singular opportunity to study the interrelation of CTCs, metastasis and development of resistance which may apply to other tumor types which display these processes in a more protracted manner as well
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