Characterization of the cell of origin for small cell lung cancer

Park, Kwon Sik; Liang, Mei‐Chih; Raiser, David M.; Zamponi, Raffaella; Roach, Rebecca R.; Curtis, Stephen J.; Walton, Zandra E.; Schaffer, Bethany E.; Roake, Caitlin M.; Zmoos, Anne Flore; Kriegel, Christina; Wong, Kwok-Kin; Sage, Julien; Kim, Carla F.

doi:10.4161/cc.10.16.17012

Cited by 169 publications

(153 citation statements)

References 50 publications

(63 reference statements)

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“…4K). These observations confirm and extend previous reports (12)(13)(14)(15) suggesting that PNECs can be the cells of origin for SCLC, offering insight into the complex interactions between tumor suppressors in tumor development.…”

Section: Pulmonary Neuroendocrine Cells Have Very Limited Potential Tosupporting

confidence: 81%

“…Perhaps the most important clinical connection comes from the observation that characteristic markers of PNECs are frequently expressed in human small-cell lung cancer (SCLC), a highly aggressive form of lung cancer related to cigarette smoking (11). This finding led to the speculation that PNECs could be the cells of origin for SCLC, an idea that has been supported by mouse studies (12)(13)(14)(15). Despite this insight, the ability to reliably trace the early events that underlie changes in PNEC behavior and their progression toward tumor development in a defined genetic setting has not been achieved.…”

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confidence: 85%

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Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Song

Yao

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

247

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Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanisms underlying them have been elucidated. Importantly, PNECs have long been speculated to constitute the cells of origin of human small-cell lung cancer (SCLC) and recent mouse models support this hypothesis. However, a genetic system that permits tracing the early events of PNEC transformation has not been available. To address these key issues, we developed a genetic tool in mice by introducing a fusion protein of Cre recombinase and estrogen receptor (CreER) into the calcitonin gene-related peptide (CGRP) locus that encodes a major peptide in PNECs. The CGRP CreER mouse line has enabled us to manipulate gene activity in PNECs. Lineage tracing using this tool revealed the plasticity of PNECs. PNECs can be colabeled with alveolar cells during lung development, and following lung injury, PNECs can contribute to Clara cells and ciliated cells. Contrary to the current model, we observed that elimination of PNECs has no apparent consequence on Clara cell recovery. We also created mouse models of SCLC in which CGRP CreER was used to ablate multiple tumor suppressors in PNECs that were simultaneously labeled for following their fate. Our findings suggest that SCLC can originate from differentiated PNECs. Together, these studies provide unique insight into PNEC lineage and function and establish the foundation of investigating how PNECs contribute to lung homeostasis, injury/repair, and tumorigenesis.progenitor | naphthalene | cell of origin | tumor suppressor gene

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Section: Pulmonary Neuroendocrine Cells Have Very Limited Potential Tosupporting

confidence: 81%

mentioning

confidence: 85%

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Song

Yao

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

247

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“…16,17 Although the SCLC cell of origin has not been formally identified, there are some reports supporting the hypothesis that cells of the neuroendocrine cell lineage give rise to SCLC. 18,19 These reports imply the existence of a neuroendocrine cell lineage-specific expression mechanism of TTF1 in SCLC.…”

mentioning

confidence: 91%

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

Sakaeda

Sato

Ishii

et al. 2013

Laboratory Investigation

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Thyroid transcription factor 1 (TTF1) plays crucial roles in thyroid, lung, and developing brain morphogenesis. Because TTF1-expressing neoplasms are generated from organs and tissues that normally express TTF1, such as the thyroid follicular epithelium and peripheral lung airway epithelium, TTF1 is widely used as a cell lineage-specific and diagnostic marker for thyroid carcinomas and for lung adenocarcinomas with terminal respiratory unit (TRU) differentiation. However, among lung neuroendocrine tumors, small-cell carcinomas (small-cell lung cancers (SCLCs)), most of which are generated from the central airway, also frequently express TTF1 at high levels. To clarify how SCLCs express TTF1, we investigated the molecular mechanisms of its expression using cultivated lung cancer cells and focusing upon neural cellspecific transcription factors. Both SCLC cells and lung adenocarcinoma cells predominantly expressed isoform 2 of TTF1, and TTF1 promoter assays in SCLC cells revealed that the crucial region for activation of the promoter, which is adjacent to the transcription start site of TTF1 isoform 2, has potent FOX-, LHX-, and BRN2-binding sites. Transfection experiments using expression vectors for FOXA1, FOXA2, LHX2, LHX6, and BRN2 showed that BRN2 substantially upregulated TTF1 expression, whereas FOXA1/2 weakly upregulated TTF1 expression. BRN2 and FOXA1/2 binding to the TTF1 promoter was confirmed through chromatin immunoprecipitation experiments, and TTF1 expression in SCLC cells was considerably downregulated after BRN2 knockdown. Furthermore, the TTF1 promoter in SCLC cells was scarcely methylated, and immunohistochemical examinations using a series of primary lung tumors indicated that TTF1 and BRN2 were coexpressed only in SCLC cells. These findings suggest that TTF1 expression in SCLC is a cell lineage-specific phenomenon that involves the developing neural cell-specific homeoprotein BRN2.

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“…Small-cell lung cancer (SCLC), which originates from neuroendocrine cells of the lung (1,2), is one of the most lethal subtypes of cancer. Each year, more than 25,000 patients are diagnosed with SCLC in the United States alone, and these patients typically live only 6-12 months after diagnosis.…”

Section: Introductionmentioning

confidence: 99%

CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer

Weiskopf

Jahchan

Schnorr

et al. 2016

Journal of Clinical Investigation

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Characterization of the cell of origin for small cell lung cancer

Cited by 169 publications

References 50 publications

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis

Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer

CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer

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