Nailing a Fe-rocious form of cancer

doi:10.1126/science.abb7041

GSTDTAP > 气候变化

DOI	10.1126/science.abb7041
	Nailing a Fe-rocious form of cancer
	Livia Garzia; Michael D. Taylor
	2020-07-17
发表期刊	Science
出版年	2020
英文摘要	Numerous cancer types can metastasize to a remote and inhospitable part of the human central nervous system (CNS): the subarachnoid or leptomeningeal space. This covers the surface of the nervous system and contains the cerebrospinal fluid (CSF). The CSF is largely hypocellular in healthy humans and has limited metabolic resources. It provides protective buoyancy for the brain and permits circulation of micronutrients and growth factors in the ventricular system. The CSF constitutes a relatively accessible proxy of the health of the CNS, and it is routinely sampled by physicians through a lumbar puncture. On page 276 of this issue, Chi et al. ([ 1 ][1]) reveal how human cancer cells thrive in this specialized anatomical location by hijacking a high-affinity iron transport system. This work highlights how studying tumor cell properties in the context of the challenges posed by the microenvironment can reveal unknown biology and possible approaches to therapy. Lung and breast cancers can develop metastases in several organs, most commonly the bones, liver, and lungs. On rare occasions, disseminated cancer cells can reach the brain microvasculature, cross the blood-CSF barrier, and attach to the meninges, membranous layers that surround the CNS and form the subarachnoid space. Cancer cells then somehow thrive in the CSF-filled subarachnoid space and spread to the surface of the pia mater (a meningeal membrane). This leptomeningeal metastasis is an incurable condition; most patients succumb within months, and survival for 1 year is extremely rare ([ 2 ][2]). The CSF is a challenging niche for metastatic cells to grow in because it contains very low concentrations of growth factors and micronutrients, and it is patrolled by immune cells whose composition is specific to the CSF ([ 3 ][3], [ 4 ][4]). Compared to the now consistent body of knowledge about the mechanisms enabling metastasis to the brain parenchyma, the understanding of the cascade of events leading to leptomeningeal metastasis is in its infancy. The brain parenchymal microenvironment is a major force in selecting the most fit metastatic cancer cells that can proficiently colonize the brain. Glia (stromal cells), neurons, and innate immune cells actively participate in creating an inflammatory microenvironment that is permissive to the extravasation (entry into tissue from the vasculature) of cancer cells and their invasion into the brain parenchyma ([ 5 ][5], [ 6 ][6]). The brain parenchymal microenvironment favors the outgrowth of highly genetically heterogeneous tumor cells, resulting in brain metastases that display specific genetic features that prime them to grow in the brain parenchyma, such as mutations in the genes encoding phosphoinositide 3-kinase (PI3K) and the receptor tyrosine kinase HER2 ([ 7 ][7]). ![Figure][8] Iron promotes survival of metastatic cells The meningeal membranes (dura mater, arachnoid mater, and pia mater) form the subarachnoid space, which is filled with nutrient-poor cerebrospinal fluid (CSF). Chi et al. find that leptomeningeal metastases, which grow along the pia mater, express lipocalin 2 (LCN2) and its receptor, solute carrier family 22 member 17 (SLC22A17), which promotes iron capture. This reduces iron availability for macrophages and promotes survival of metastases. GRAPHIC: A. KITTERMAN/ SCIENCE Chi et al. hypothesized that single-cell transcriptomics of leptomeningeal metastases would reveal common pathways that confer to tumor cells the ability to survive and thrive in the subarachnoid space. Their analysis of five human lung and breast cancer leptomeningeal metastases reveals that distinct gene expression signatures are shared between these two cancer types, and that they converge on a high-affinity iron transport system. Iron, a high-demand micronutrient in the CSF, is sought after by various cell populations to sustain their iron-dependent cellular functions such as energy metabolism and DNA synthesis ([ 8 ][9]). In contrast to the parental, non–leptomeningeal-adapted primary tumors, tumor cells from leptomeningeal metastases express a high-affinity iron transporter, lipocalin 2 (LCN2), and its receptor, solute carrier family 22 member 17 (SLC22A17) (see the figure). This high-affinity iron-capturing system is best characterized as being expressed under physiological conditions by effectors of the innate immune response, with the purpose of efficiently binding bacterial siderophores (iron carriers), thereby outcompeting bacteria for the available iron ([ 9 ][10]). By applying comprehensive genetic and biochemical approaches in vitro and in immunocompromised mice grafted with human cells (xenografts), Chi et al. demonstrate that activation of the LCN2-SLC22A17 system is both necessary and sufficient for the survival of leptomeningeal metastases from human lung and breast cancers. Of note, this effect of the LCN2-SLC22A17 pathway on leptomeningeal metastases is mediated by its effects on iron metabolism, not by alternative cellular processes. Whether subclones of cells with high expression of LCN2 and SLC22A17 are preexisting in primary breast and lung cancers, and whether this iron-capturing system also confers increased survival of circulating tumor cells, requires further investigation. Chi et al. also demonstrate that activated inflammatory macrophages from the CSF of mice and humans with leptomeningeal metastases increase the expression of LCN2 in tumor cells during coculture. This induction is mediated by the inflammatory cytokines interleukin-6 (IL-6), IL-8, and IL-1β. Few studies have focused on the biochemical composition of the CSF in the setting of leptomeningeal metastasis, and the study of Chi et al. contributes to bridging this knowledge gap. They report that concentrations of iron bound to LCN2 in clinical samples of CSF are elevated, and that this correlates with concentrations of IL-6 and hepcidin (a hormone that regulates iron absorption). In addition to providing tumor cells with the iron they require, LCN2 and SLC22A17 expression in metastatic cells represses local macrophage activation by depriving them of iron. Given the role of innate macrophage-dependent immune responses in primary tumors and brain parenchyma metastases ([ 10 ][11], [ 11 ][12]), it is conceivable that decreased macrophage phagocytotic activity also translates to a more permissive microenvironment for metastatic outgrowth. Because cancer therapies have improved and prolonged the survival of many cancer patients, the prevalence of leptomeningeal metastases has increased steadily over the past few decades. Although leptomeningeal metastases are a rare complication of advanced cancers in adults, they are common in primary brain cancers, particularly medulloblastoma ([ 12 ][13], [ 13 ][14]). Chi et al. show that iron chelators, which reduce iron availability, confer a survival benefit to three different mouse models of leptomeningeal metastasis. Although iron chelation extended survival, it was not curative in a therapeutic or preventive setting. Understanding the alternative mechanisms by which leptomeningeal metastases circumvent iron deprivation will be valuable. The harsh microenvironment of the subarachnoid space likely imposes similar selection pressure on disseminated cells from various cancer types, and perhaps a treatment approach similar to the one tested by Chi et al. could be readily translated to a variety of patients with malignant leptomeningeal disease. 1. [↵][15]1. Y. Chi et al ., Science 369, 276 (2020). [OpenUrl][16][Abstract/FREE Full Text][17] 2. [↵][18]1. E. Le Rhun et al ., Ann. Oncol. 28, iv84 (2017). [OpenUrl][19] 3. [↵][20]1. D. Schafflick et al ., Nat. Commun. 11, 247 (2020). [OpenUrl][21][CrossRef][22] 4. [↵][23]1. H. Davson, 2. K. Welch, 3. M. B. Segal , The Physiology and Pathophysiology of the Cerebrospinal Fluid (Churchill Livingstone, 1987). 5. [↵][24]1. D. F. Quail, 2. J. A. Joyce , Cancer Cell 31, 326 (2017). [OpenUrl][25][CrossRef][26][PubMed][27] 6. [↵][28]1. M. Valiente et al ., Trends Cancer 4, 176 (2018). [OpenUrl][29][CrossRef][30] 7. [↵][31]1. P. K. Brastianos et al ., Cancer Discov. 5, 1164 (2015). [OpenUrl][32][Abstract/FREE Full Text][33] 8. [↵][34]1. J. Wang, 2. K. Pantopoulos , Biochem. J. 434, 365 (2011). [OpenUrl][35][Abstract/FREE Full Text][36] 9. [↵][37]1. B. R. Wilson, 2. A. R. Bogdan, 3. M. Miyazawa, 4. K. Hashimoto, 5. Y. Tsuji , Trends Mol. Med. 22, 1077 (2016). [OpenUrl][38][CrossRef][39][PubMed][40] 10. [↵][41]1. S. Gholamin 1 , Sci. Transl. Med. 9, eaaf2968 (2017). [OpenUrl][42][Abstract/FREE Full Text][43] 11. [↵][44]1. L. Sevenich et al ., Nat. Cell Biol. 16, 876 (2014). [OpenUrl][45][CrossRef][46][PubMed][47] 12. [↵][48]1. R. Van Ommeren, 2. L. Garzia, 3. B. L. Holgado, 4. V. Ramaswamy, 5. M. D. Taylor , Brain Pathol. 30, 691 (2020). [OpenUrl][49] 13. [↵][50]1. V. Ramaswamy et al ., Lancet Oncol. 14, 1200 (2013). [OpenUrl][51][CrossRef][52][PubMed][53][Web of Science][54] Acknowledgments: L.G. is supported by CIHR (PJT-162234), CRS (CRP-159384), and CCSRI. L.G. holds a FRQS-J2 career award. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: pending:yes [9]: #ref-8 [10]: #ref-9 [11]: #ref-10 [12]: #ref-11 [13]: #ref-12 [14]: #ref-13 [15]: #xref-ref-1-1 "View reference 1 in text" [16]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DChi%26rft.auinit1%253DY.%26rft.volume%253D369%26rft.issue%253D6501%26rft.spage%253D276%26rft.epage%253D282%26rft.atitle%253DCancer%2Bcells%2Bdeploy%2Blipocalin-2%2Bto%2Bcollect%2Blimiting%2Biron%2Bin%2Bleptomeningeal%2Bmetastasis%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaz2193%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [17]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNjkvNjUwMS8yNzYiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNjkvNjUwMS8yNTAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [18]: #xref-ref-2-1 "View reference 2 in text" [19]: {openurl}?query=rft.jtitle%253DAnn.%2BOncol.%26rft.volume%253D28%26rft.spage%253Div84%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [20]: #xref-ref-3-1 "View reference 3 in text" [21]: {openurl}?query=rft.jtitle%253DNat.%2BCommun.%26rft.volume%253D11%26rft.spage%253D247%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41467-019-14118-w%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [22]: /lookup/external-ref?access_num=10.1038/s41467-019-14118-w&link_type=DOI [23]: #xref-ref-4-1 "View reference 4 in text" [24]: #xref-ref-5-1 "View reference 5 in text" [25]: {openurl}?query=rft.jtitle%253DCancer%2BCell%26rft.volume%253D31%26rft.spage%253D326%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.ccell.2017.02.009%26rft_id%253Dinfo%253Apmid%252F28292436%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [26]: /lookup/external-ref?access_num=10.1016/j.ccell.2017.02.009&link_type=DOI [27]: /lookup/external-ref?access_num=28292436&link_type=MED&atom=%2Fsci%2F369%2F6501%2F250.atom [28]: #xref-ref-6-1 "View reference 6 in text" [29]: {openurl}?query=rft.jtitle%253DTrends%2BCancer%26rft.volume%253D4%26rft.spage%253D176%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.trecan.2018.01.003%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [30]: /lookup/external-ref?access_num=10.1016/j.trecan.2018.01.003&link_type=DOI [31]: #xref-ref-7-1 "View reference 7 in text" [32]: {openurl}?query=rft.jtitle%253DCancer%2BDiscov.%26rft_id%253Dinfo%253Adoi%252F10.1158%252F2159-8290.CD-15-0369%26rft_id%253Dinfo%253Apmid%252F26410082%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [33]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiY2FuZGlzYyI7czo1OiJyZXNpZCI7czo5OiI1LzExLzExNjQiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNjkvNjUwMS8yNTAuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [34]: #xref-ref-8-1 "View reference 8 in text" [35]: {openurl}?query=rft.jtitle%253DBiochem.%2BJ.%26rft_id%253Dinfo%253Adoi%252F10.1042%252FBJ20101825%26rft_id%253Dinfo%253Apmid%252F21348856%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [36]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6InBwYmlvY2hlbWoiO3M6NToicmVzaWQiO3M6OToiNDM0LzMvMzY1IjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzY5LzY1MDEvMjUwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [37]: #xref-ref-9-1 "View reference 9 in text" [38]: {openurl}?query=rft.jtitle%253DTrends%2BMol.%2BMed.%26rft.volume%253D22%26rft.spage%253D1077%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.molmed.2016.10.005%26rft_id%253Dinfo%253Apmid%252F27825668%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [39]: /lookup/external-ref?access_num=10.1016/j.molmed.2016.10.005&link_type=DOI [40]: /lookup/external-ref?access_num=27825668&link_type=MED&atom=%2Fsci%2F369%2F6501%2F250.atom [41]: #xref-ref-10-1 "View reference 10 in text" [42]: {openurl}?query=rft.jtitle%253DScience%2BTranslational%2BMedicine%26rft.stitle%253DSci%2BTransl%2BMed%26rft.aulast%253DGholamin%26rft.auinit1%253DS.%26rft.volume%253D9%26rft.issue%253D381%26rft.spage%253Deaaf2968%26rft.epage%253Deaaf2968%26rft.atitle%253DDisrupting%2Bthe%2BCD47-SIRP%257Balpha%257D%2Banti-phagocytic%2Baxis%2Bby%2Ba%2Bhumanized%2Banti-CD47%2Bantibody%2Bis%2Ban%2Befficacious%2Btreatment%2Bfor%2Bmalignant%2Bpediatric%2Bbrain%2Btumors%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscitranslmed.aaf2968%26rft_id%253Dinfo%253Apmid%252F28298418%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [43]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTE6InNjaXRyYW5zbWVkIjtzOjU6InJlc2lkIjtzOjE0OiI5LzM4MS9lYWFmMjk2OCI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM2OS82NTAxLzI1MC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [44]: #xref-ref-11-1 "View reference 11 in text" [45]: {openurl}?query=rft.jtitle%253DNat.%2BCell%2BBiol.%26rft.volume%253D16%26rft.spage%253D876%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fncb3011%26rft_id%253Dinfo%253Apmid%252F25086747%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [46]: /lookup/external-ref?access_num=10.1038/ncb3011&link_type=DOI [47]: /lookup/external-ref?access_num=25086747&link_type=MED&atom=%2Fsci%2F369%2F6501%2F250.atom [48]: #xref-ref-12-1 "View reference 12 in text" [49]: {openurl}?query=rft.jtitle%253DBrain%2BPathol.%26rft.volume%253D30%26rft.spage%253D691%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [50]: #xref-ref-13-1 "View reference 13 in text" [51]: {openurl}?query=rft.jtitle%253DLancet%2BOncol.%26rft.volume%253D14%26rft.spage%253D1200%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS1470-2045%252813%252970449-2%26rft_id%253Dinfo%253Apmid%252F24140199%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [52]: /lookup/external-ref?access_num=10.1016/S1470-2045(13)70449-2&link_type=DOI [53]: /lookup/external-ref?access_num=24140199&link_type=MED&atom=%2Fsci%2F369%2F6501%2F250.atom [54]: /lookup/external-ref?access_num=000326275300045&link_type=ISI
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/284336
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Livia Garzia,Michael D. Taylor. Nailing a Fe-rocious form of cancer[J]. Science,2020.
APA	Livia Garzia,&Michael D. Taylor.(2020).Nailing a Fe-rocious form of cancer.Science.
MLA	Livia Garzia,et al."Nailing a Fe-rocious form of cancer".Science (2020).