Small cell lung cancer: Circulating tumor cells of extended stage patients express a mesenchymal-epithelial transition phenotype

Hamilton, Gerhard; Hochmair, Maximilian; Rath, Barbara H.; Klameth, Lukas; Zeillinger, Robert

doi:10.1080/19336918.2016.1155019

Cited by 58 publications

(65 citation statements)

References 36 publications

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“…All six SCLC CTC cell lines established so far exhibit spontaneous formation of tumorospheres with diameters of up to 1-2 mm which provide protection of the cells by limited access of chemotherapeutics and quiescent and hypoxic tumor cells (117,118). Tumorospheres exhibit increased chemoresistance in vitro to cytotoxic drugs compared to the corresponding cells in form of single cell suspensions.…”

Section: Mechanisms Of Chemoresistance In Sclcmentioning

confidence: 99%

Circulating tumor cell interactions with macrophages: implications for biology and treatment

Hamilton¹,

Rath²

2017

Transl. Lung Cancer Res.

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CTCs. SCLC has an unfavorable prognosis due to rapid dissemination and early chemoresistant relapses. SCLC CTCs recruit macrophages and elicit secretion of various cytokines and the six CTC lines expresschitinase-3-like-1 (CHI3L1), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) in abundance. CHI3L1 is cytokine/growth factor expressed in inflammation and cancer and found to be correlated to metastasis and a dismal prognosis. In conclusion, SCLC CTCs have acquired the essential means for aggressiveness and invasion in a tumor microenvironment specifically shaped by macrophages and inflammation.

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Section: Mechanisms Of Chemoresistance In Sclcmentioning

confidence: 99%

Circulating tumor cell interactions with macrophages: implications for biology and treatment

Hamilton¹,

Rath²

2017

Transl. Lung Cancer Res.

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“…[56] Markerindependent CTC enrichment demonstrate a spectrum of CTC EMT phenotypes with alterations which may be as minor as increases in vimentin and concurrent decreases in E-cadherin without a true cell-type switch. [57] Two other distinct modes of invasion possibly implicated invasion comprise "Collective invasion" and a mode of "amoeboid" invasion. [58] Indeed, some carcinoma cells exhibit a partial mesenchymal state a phenotype absent from normal tissues.…”

Section: Emtmentioning

confidence: 99%

“…[101] However, SCLC CTCs lack stem cell markers, such as CD133, CD44, ABCG2 and exhibit a shift towards an epithelial-mesenchymal phenotype without a real cell-type switch. [57,102] Moreover, the SCLC CTCs are chemosensitive, except one case with primary platinum resistance, and form large multicellular aggregates, termed tumorospheres, which contain quiescent and hypoxic cells. These 3D-structures are highly chemoresistant compared to the same cells as single cell suspensions.…”

Section: Sclcmentioning

confidence: 99%

Circulating Tumor Cells in the Parallel Invasion Model Supporting Early Metastasis

Hamilton¹,

Rath²

2018

Oncomedicine

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Circulating tumor cells (CTCs) seem to comprise metastasis-initiating cells and their count and phenotype represent an indicator of prognosis and response to therapy in cancer patients. In the classical model of tumor dissemination, specialized cells at the invasive front undergo epithelial-mesenchymal transition (EMT) and enter peripheral tumor-coalescing blood vessels to establish metastatic lesions by extravasation of CTCs. Thus, dissemination of cancer cells occurs after prolonged tumor development and following access to neighboring blood vessels via transit through stromal tissue. However, clinical and new experimental data indicate early tumor dissemination immediately after an angiogenic switch has occurred and an intravasation of tumor cells in the tumor core region. Accordingly, CTCs may have direct access through fenestrated and irregular intratumoral vessels and, therefore, the metastasis-initiating cells become active a long time before lesions are detected clinically. This model of cancer cell intravasation is better compatible with the release of CTC clusters and apoptotic CTCs and, furthermore, spares the requirement for an elusive and complicated EMT/MET program. Similarly, the intravasation of large number of CTCs observed in metastatic disease may be alleviated by an intratumoral process instead of a stromal crossing. This early metastasis model changes the possible pathways targeted for the prevention and inhibition of metastasis and the significance of CTCs which are detected and analyzed late after the initial phase of tumor dissemination.

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“…The SCLC CTC cell lines have been found to recruit macrophages and to lack a phenotypic switch with full expression of mesenchymal traits. [34,42] In conclusion, complete or partial EMT is not proven to be a prerequisite to disseminate tumor cells, and therapeutic options to inhibit such a transition need to be considered cautiously. [43] …”

Section: Emt In Tumor Cell Sheddingmentioning

confidence: 99%

“…The SCLC CTC lines show continuing disposal of microparticles and cellular fragments, thus generating CTC associated materials under optimal conditions in tissue culture in the absence of shear stress. [42] Partial disintegration of CTC tumorospheres may function as a source of decoy material to protect other CTCs and the bulk tumor from attacks by both the immune system and chemotherapeutics.…”

Section: Survival Ctcs In the Circulationmentioning

confidence: 99%

Insights into mechanisms of tumor dissemination from circulating tumor cell lines of small cell lung cancer

Hamilton¹,

Rath²

2016

JCMT

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Despite the fact that the majority of cancer patients succumb to metastatic disease, most aspects of tumor metastasis are not understood in detail at present. Cell biologic steps of dissemination are difficult to characterize in human tumors and research is in large part confined to cell line and experimental animal studies. Epithelial-mesenchymal transition (EMT), intravasation of malignant cells, dissemination as circulating tumor cells (CTCs) and eventually mesenchymal-epithelial transition (MET) at distal sites are steps believed to be involved in metastasis. Small cell lung cancer (SCLC) is distinguished by early dissemination and excessive numbers of CTCs, which allowed for the ex vivo expansion of six permanent CTC lines taken from relapsed patients. Cells exhibit an epithelial phenotype with partial EMT traits and are chemoresistant due to formation of large tumorospheres. Since cells may have invaded without undergoing EMT, the role of MET is uncertain. These SCLC CTC cell lines seem to represent the metastasis-inducing cancer cells; these are the minute subpopulation of CTCs capable of surviving in the circulation and transitioning to metastases, leading in turn to resistance and failure of therapy. Full characterization of these lines is expected to provide the markers to find the relevant CTCs among the highly heterogeneous population observable in the context of tumor recurrence. Key words:Cancer metastasis, small cell lung cancer, circulating tumor cells, epithelial-mesenchymal transition, tumorosphere, chemotherapy, drug resistance ABSTRACTArticle history:

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Small cell lung cancer: Circulating tumor cells of extended stage patients express a mesenchymal-epithelial transition phenotype

Cited by 58 publications

References 36 publications

Circulating tumor cell interactions with macrophages: implications for biology and treatment

Circulating tumor cell interactions with macrophages: implications for biology and treatment

Circulating Tumor Cells in the Parallel Invasion Model Supporting Early Metastasis

Insights into mechanisms of tumor dissemination from circulating tumor cell lines of small cell lung cancer

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