Small Cell Lung Cancers Form Chemotherapy-Resistant Circulating Tumor Spheres Interview with:

Prof. Gerhard Hamilton Department of Obstetrics and Gynecology Medical University of Vienna 

Prof. Hamilton

Prof. Gerhard Hamilton
Department of Obstetrics and Gynecology
Medical University of Vienna What is the background for this study? What are the main findings?

Response: Small cell lung cancer (SCLC) is a highly aggressive tumor (15 % of all lung cancers) mainly of patients with high tobacco consumption which shows an extremely poor survival (< 5% 2-year survival rate). Unfortunately the
low survival rates of advanced SCLC cases has not improved significantly during the last decades, with platinum drugs/etoposide and topotecan employed for first- and second-line chemotherapy, respectively. All kinds of new chemotherapeutics, targeted drugs and immunotherapies either failed or resulted in prolongation of survival of several months at best. SCLC responds well to first-line therapy but relapses within a short time as chemoradioresistant tumor. The failure of hundreds of registered studies seem to be linked to the lack of knowledge of the mechanism of resistance of SCLCs and proper ways to reverse the refractoriness.

Small cell lung cancer is distinguished by excessive numbers of circulating tumor cells (CTCs) in advanced stages. CTCs contain the founder of metastasis and seem to constitute a highly chemoresistant cell population. Thus, we ware able to establish a panel of permanent CTC lines in vitro for the first time (8 SCLC lines so far from blood samples). Although CTCs were considered to be chemoresistant we detected that they are chemosensitive in vitro in form of single cell suspensions. However, all CTC lines developed spontaneously into large multicellular aggregates, termed tumorospheres, which grow up to 1-2 mm in size and exhibit high chemoradioresistance due to limited drug perfusion as well as content of quiescent and hypoxic cells. Resistance to irradiation seems to be caused by lack of oxygen, such limiting the generation of oxygen radicals. High resistance mediated by the occurrence of tumorospheres easily explains the failure of a large number of drugs – if one is not able to achieve a sufficient concentration of a drug in cancer cells and the cells are quiescent, the respective compounds will not be able to destroy the target cells, regardless of their chemical nature. What should clinicians and patients take away from your report?

Response: In the light of little progress for decades in the therapy of small cell lung cancer, entirely new strategies should be applied considering unconventional ways of developing drug resistance by malignancies. This mechanism detected in SCLC CTCs may have relevance for other related tumors such as glioblastoma or peripheral neuroectodermal tumors as well. A mechanism of drug resistance based on formation of a 3D structure by cancer cells will go undetected by sequencing the genome or transcriptome. A panel of CTC cell lines is necessary to study the cell biology of tumor dissemination and drug resistance. What recommendations do you have for future research as a result of this study?

Response: Its nice to sequence genomes and detect driver mutations and respective inhibitors but small cell lung cancer relies on the loss of suppressor genes. The cell biology of multicellular tumor aggregates and the connection to drug resistance was a big issue in the 1990s but has been largely neglected later-on. An important step to successfully treat advanced/metastatic tumors seems to be to devise methods for efficient drug delivery to complex tumor structures/stroma such as under trial for pancreatic cancer and hyaluronidase. For the tumorospheres at lot of questions need to be resolved as to their appearance, localization and methods to disperse and make the individual cancer cells accessible to cytotoxic compounds. 

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Lukas Klameth, Barbara Rath, Maximilian Hochmaier, Doris Moser, Marlene Redl, Felicitas Mungenast, Katharina Gelles, Ernst Ulsperger, Robert Zeillinger, Gerhard Hamilton. Small cell lung cancer: model of circulating tumor cell tumorospheres in chemoresistance. Scientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-05562-z

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