Display options
Cite
Akkoc Y, Gozuacik D. Autophagy and Hepatic Tumor Microenvironment Associated Dormancy. J Gastrointest Cancer. 2021;doi: 10.1007/s12029-021-00774-z.
Akkoc, Y., & Gozuacik, D. (2021). Autophagy and Hepatic Tumor Microenvironment Associated Dormancy. Journal of gastrointestinal cancer, . https://doi.org/10.1007/s12029-021-00774-z
Akkoc, Yunus, and Gozuacik, Devrim. "Autophagy and Hepatic Tumor Microenvironment Associated Dormancy." Journal of gastrointestinal cancer vol. (2021). doi: https://doi.org/10.1007/s12029-021-00774-z
Akkoc Y, Gozuacik D. Autophagy and Hepatic Tumor Microenvironment Associated Dormancy. J Gastrointest Cancer. 2021 Dec 18; doi: 10.1007/s12029-021-00774-z. Epub 2021 Dec 18. PMID: 34921672.
Copy Download .nbib Format: NLM
Share it on

J Gastrointest Cancer. 2021 Dec 18; doi: 10.1007/s12029-021-00774-z. Epub 2021 Dec 18.

Autophagy and Hepatic Tumor Microenvironment Associated Dormancy.

Journal of gastrointestinal cancer

Yunus Akkoc, Devrim Gozuacik

Affiliations

  1. Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, 34010, Turkey. [email protected].
  2. Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, 34010, Turkey.
  3. Koç University School of Medicine, Istanbul, 34010, Turkey.

PMID: 34921672 DOI: 10.1007/s12029-021-00774-z

Abstract

The goal of successful cancer treatment is targeting the eradication of cancer cells. Although surgical removal of the primary tumors and several rounds of chemo- and radiotherapy reduce the disease burden, in some cases, asymptomatic dormant cancer cells may still exist in the body. Dormant cells arise from the disseminated tumor cells (DTCs) from the primary lesion. DTCs escape from immune system and cancer therapy and reside at the secondary organ without showing no sign of proliferation. However, under some conditions. dormant cells can be re-activated and enter a proliferative state even after decades. As a stress response mechanism, autophagy may help the adaptation of DTCs at this futile foreign microenvironment and may control the survival and re-activation of dormant cells. Studies indicate that hepatic microenvironment serves a favorable condition for cancer cell dormancy. Although, no direct study was pointing out the role of autophagy in liver-assisted dormancy, involvement of autophagy in both liver microenvironment, health, and disease conditions has been indicated. Therefore, in this review article, we will summarize cancer dormancy and discuss the role and importance of autophagy and hepatic microenvironment in this context.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords: Autophagy; Dormancy; Liver; Tumor microenvironment

References

  1. Klein CA. Framework models of tumor dormancy from patient-derived observations. Curr Opin Genet Dev. 2011;21:42–9. https://doi.org/10.1016/j.gde.2010.10.011 . - PubMed
  2. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20:69–84. https://doi.org/10.1038/s41580-018-0080-4 . - PubMed
  3. Chaffer CL, San Juan BP, Lim E, Weinberg RA. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016;35:645–54. https://doi.org/10.1007/s10555-016-9648-7 . - PubMed
  4. Winkler J, Abisoye-Ogunniyan A, Metcalf KJ, Werb Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat Commun. 2020;11:5120. https://doi.org/10.1038/s41467-020-18794-x . - PubMed
  5. Brown M, Assen FP, Leithner A, Abe J, Schachner H, Asfour G, Bago-Horvath Z, Stein JV, Uhrin P, Sixt M, Kerjaschki D. Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science. 2018;359:1408–11. https://doi.org/10.1126/science.aal3662 . - PubMed
  6. Wyckoff JB, Jones JG, Condeelis JS, Segall JE. A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res. 2000;60:2504–11. - PubMed
  7. Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833:3481–98. https://doi.org/10.1016/j.bbamcr.2013.06.026 . - PubMed
  8. Kim YN, Koo KH, Sung JY, Yun UJ, Kim H. Anoikis resistance: an essential prerequisite for tumor metastasis. Int J Cell Biol. 2012;2012: 306879. https://doi.org/10.1155/2012/306879 . - PubMed
  9. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90. https://doi.org/10.1016/j.cell.2009.11.007 . - PubMed
  10. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8:98–101. - PubMed
  11. Holmgren L, O’Reilly MS, Folkman J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995;1:149–53. https://doi.org/10.1038/nm0295-149 . - PubMed
  12. Hadfield G. The dormant cancer cell. Br Med J. 1954;2:607–10. https://doi.org/10.1136/bmj.2.4888.607 . - PubMed
  13. Townson JL, Chambers AF. Dormancy of solitary metastatic cells. Cell Cycle. 2006;5:1744–50. https://doi.org/10.4161/cc.5.16.2864 . - PubMed
  14. Gath HJ, Brakenhoff RH. Minimal residual disease in head and neck cancer. Cancer Metastasis Rev. 1999;18:109–26. https://doi.org/10.1023/a:1006268621730 . - PubMed
  15. Galluzzi L, Yamazaki T, Kroemer G. Linking cellular stress responses to systemic homeostasis. Nat Rev Mol Cell Biol. 2018;19:731–45. https://doi.org/10.1038/s41580-018-0068-0 . - PubMed
  16. Akkoc Y, Gozuacik D. Autophagy and liver cancer. Turk J Gastroenterol. 2018;29:270–82. https://doi.org/10.5152/tjg.2018.150318 . - PubMed
  17. Kocaturk NM, Akkoc Y, Kig C, Bayraktar O, Gozuacik D, Kutlu O. Autophagy as a molecular target for cancer treatment. Eur J Pharm Sci. 2019;134:116–37. https://doi.org/10.1016/j.ejps.2019.04.011 . - PubMed
  18. Akkoc Y, Peker N, Akcay A, Gozuacik D. Autophagy and cancer dormancy. Front. Oncol. 2021;11: 627023. https://doi.org/10.3389/fonc.2021.627023 . - PubMed
  19. Disibio G, French SW. Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab Med. 2008;132:931–9. https://doi.org/10.1043/1543-2165(2008)132[931:MPOCRF]2.0.CO;25858/2008-132-931-MPOCRF . - PubMed
  20. Budczies J, von Winterfeld M, Klauschen F, Bockmayr M, Lennerz JK, Denkert C, Wolf T, Warth A, Dietel M, Anagnostopoulos I, Weichert W, Wittschieber D, Stenzinger A. The landscape of metastatic progression patterns across major human cancers. Oncotarget. 2015;6:570–83. https://doi.org/10.18632/oncotarget.2677 . - PubMed
  21. Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, Abbruzzese JL. Metastatic patterns in adenocarcinoma. Cancer. 2006;106:1624–33. https://doi.org/10.1002/cncr.21778 . - PubMed
  22. Wisse E. An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J Ultrastruct Res. 1970;31:125–50. https://doi.org/10.1016/s0022-5320(70)90150-4 . - PubMed
  23. Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci U S A. 1985;82:8681–5. https://doi.org/10.1073/pnas.82.24.8681 . - PubMed
  24. Rockey DC. The molecular basis of portal hypertension. Trans Am Clin Climatol Assoc. 2017;128:330–45. - PubMed
  25. Jungermann K, Kietzmann T. Role of oxygen in the zonation of carbohydrate metabolism and gene expression in liver. Kidney Int. 1997;51:402–12. https://doi.org/10.1038/ki.1997.53 . - PubMed
  26. Kietzmann T. Metabolic zonation of the liver: The oxygen gradient revisited. Redox Biol. 2017;11:622–30. https://doi.org/10.1016/j.redox.2017.01.012 . - PubMed
  27. Martinez-Hernandez A, Amenta PS. The extracellular matrix in hepatic regeneration. FASEB J. 1995;9:1401–10. https://doi.org/10.1096/fasebj.9.14.7589981 . - PubMed
  28. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75. https://doi.org/10.1038/nature06639 . - PubMed
  29. Appelmans F, Wattiaux R, De Duve C. Tissue fractionation studies. 5. The association of acid phosphatase with a special class of cytoplasmic granules in rat liver. Biochem J. 1955;59:438–45. https://doi.org/10.1042/bj0590438 . - PubMed
  30. De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955;60:604–17. https://doi.org/10.1042/bj0600604 . - PubMed
  31. Straus W. Rapid cytochemical identification of phagosomes in various tissues of the rat and their differentiation from mitochondria by the peroxidase method. J Biophys Biochem Cytol. 1959;5:193–204. https://doi.org/10.1083/jcb.5.2.193 . - PubMed
  32. Straus W. Cytochemical observations on the relationship between lysosomes and phagosomes in kidney and liver by combined staining for acid phosphatase and intravenously injected horseradish peroxidase. J Cell Biol. 1964;20:497–507. https://doi.org/10.1083/jcb.20.3.497 . - PubMed
  33. Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol. 1962;12:198–202. https://doi.org/10.1083/jcb.12.1.198 . - PubMed
  34. Novikoff AB, Essner E. Cytolysomes and mitochondrial degeneration. J Cell Biol. 1962;15:140–6. https://doi.org/10.1083/jcb.15.1.140 . - PubMed
  35. Miller LL. Glucagon: a protein catabolic hormone in the isolated perfused rat liver. Nature. 1960;185:248. https://doi.org/10.1038/185248a0 . - PubMed
  36. De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92. https://doi.org/10.1146/annurev.ph.28.030166.002251 . - PubMed
  37. Bayraktar O, Oral O, Kocaturk NM, Akkoc Y, Eberhart K, Kosar A, Gozuacik D. IBMPFD disease-causing mutant VCP/p97 proteins are targets of autophagic-lysosomal degradation. PLoS ONE. 2016;11: e0164864. https://doi.org/10.1371/journal.pone.0164864 . - PubMed
  38. Peker N, Gozuacik D. Autophagy as a cellular stress response mechanism in the nervous system. J Mol Biol. 2020;432:2560–88. https://doi.org/10.1016/j.jmb.2020.01.017 . - PubMed
  39. Jiang S, Heller B, Tagliabracci VS, Zhai L, Irimia JM, DePaoli-Roach AA, Wells CD, Skurat AV, Roach PJ. Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism. J Biol Chem. 2010;285:34960–71. https://doi.org/10.1074/jbc.M110.150839 . - PubMed
  40. Jiang S, Wells CD, Roach PJ. Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: Identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem Biophys Res Commun. 2011;413:420–5. https://doi.org/10.1016/j.bbrc.2011.08.106 . - PubMed
  41. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–5. https://doi.org/10.1038/nature07976 . - PubMed
  42. Pfeifer U. Inverted diurnal rhythm of cellular autophagy in liver cells of rats fed a single daily meal. Virchows Arch B Cell Pathol. 1972;10:1–3. https://doi.org/10.1007/BF02899710 . - PubMed
  43. Naito T, Kuma A, Mizushima N. Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle. J Biol Chem. 2013;288:21074–81. https://doi.org/10.1074/jbc.M113.456228 . - PubMed
  44. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282:668–75. https://doi.org/10.1056/NEJM197003192821209 . - PubMed
  45. Schworer CM, Shiffer KA, Mortimore GE. Quantitative relationship between autophagy and proteolysis during graded amino acid deprivation in perfused rat liver. J Biol Chem. 1981;256:7652–8. - PubMed
  46. Donati A, Cavallini G, Paradiso C, Vittorini S, Pollera M, Gori Z, Bergamini E. Age-related changes in the regulation of autophagic proteolysis in rat isolated hepatocytes. J Gerontol A Biol Sci Med Sci. 2001;56:B288–93. https://doi.org/10.1093/gerona/56.7.b288 . - PubMed
  47. Vittorini S, Paradiso C, Donati A, Cavallini G, Masini M, Gori Z, Pollera M, Bergamini E. The age-related accumulation of protein carbonyl in rat liver correlates with the age-related decline in liver proteolytic activities. J Gerontol A Biol Sci Med Sci. 1999;54:B318–23. https://doi.org/10.1093/gerona/54.8.b318 . - PubMed
  48. Kudchodkar SB, Levine B. Viruses and autophagy. Rev Med Virol. 2009;19:359–78. https://doi.org/10.1002/rmv.630 . - PubMed
  49. Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P. Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol. 2000;10:211–31. https://doi.org/10.1006/scbi.2000.0321 . - PubMed
  50. Gozuacik D, Murakami Y, Saigo K, Chami M, Mugnier C, Lagorce D, Okanoue T, Urashima T, Brechot C, Paterlini-Brechot P. Identification of human cancer-related genes by naturally occurring Hepatitis B Virus DNA tagging. Oncogene. 2001;20:6233–40. https://doi.org/10.1038/sj.onc.1204835 . - PubMed
  51. Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25:3834–47. https://doi.org/10.1038/sj.onc.1209562 . - PubMed
  52. Li J, Liu Y, Wang Z, Liu K, Wang Y, Liu J, Ding H, Yuan Z. Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment. J Virol. 2011;85:6319–33. https://doi.org/10.1128/JVI.02627-10 . - PubMed
  53. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Kominami E, Tanaka K. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007;131:1149–63. https://doi.org/10.1016/j.cell.2007.10.035 . - PubMed
  54. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, Cattoretti G, Levine B. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112:1809–20. https://doi.org/10.1172/JCI20039 . - PubMed
  55. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100:15077–82. https://doi.org/10.1073/pnas.2436255100 . - PubMed
  56. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006;10:51–64. https://doi.org/10.1016/j.ccr.2006.06.001 . - PubMed
  57. Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ, Chio II, Hwang CI, Tiriac H, Baker LA, Engle DD, Feig C, Kultti A, Egeblad M, Fearon DT, Crawford JM, Clevers H, Park Y, Tuveson DA. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96. https://doi.org/10.1084/jem.20162024 . - PubMed
  58. Shan T, Lu H, Ji H, Li Y, Guo J, Chen X, Wu T. Loss of stromal caveolin-1 expression: a novel tumor microenvironment biomarker that can predict poor clinical outcomes for pancreatic cancer. PLoS ONE. 2014;9: e97239. https://doi.org/10.1371/journal.pone.0097239 . - PubMed
  59. Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, Kleer CG, Brody JR, Lisanti MP. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol. 2009;174:2023–34. https://doi.org/10.2353/ajpath.2009.080873 . - PubMed
  60. Karakas HE, Kim J, Park J, Oh JM, Choi Y, Gozuacik D, Cho YK. A microfluidic chip for screening individual cancer cells via eavesdropping on autophagy-inducing crosstalk in the stroma niche. Sci Rep. 2017;7:2050. https://doi.org/10.1038/s41598-017-02172-7 . - PubMed
  61. Sousa CM, Biancur DE, Wang X, Halbrook CJ, Sherman MH, Zhang L, Kremer D, Hwang RF, Witkiewicz AK, Ying H, Asara JM, Evans RM, Cantley LC, Lyssiotis CA, Kimmelman AC. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016;536:479–83. https://doi.org/10.1038/nature19084 . - PubMed
  62. Spiliotaki M, Mavroudis D, Kapranou K, Markomanolaki H, Kallergi G, Koinis F, Kalbakis K, Georgoulias V, Agelaki S. Evaluation of proliferation and apoptosis markers in circulating tumor cells of women with early breast cancer who are candidates for tumor dormancy. Breast Cancer Res. 2014;16:485. https://doi.org/10.1186/s13058-014-0485-8 . - PubMed
  63. Lwin T, Hazlehurst LA, Dessureault S, Lai R, Bai W, Sotomayor E, Moscinski LC, Dalton WS, Tao J. Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood. 2007;110:1631–8. https://doi.org/10.1182/blood-2006-11-060350 . - PubMed
  64. Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 2011;25:801–13. https://doi.org/10.1101/gad.2034211 . - PubMed
  65. Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L. ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res. 2003;63:1684–95. - PubMed
  66. Balz LM, Bartkowiak K, Andreas A, Pantel K, Niggemann B, Zanker KS, Brandt BH, Dittmar T. The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-gamma1 signalling in breast cancer cell migration and dissemination. J Pathol. 2012;227:234–44. https://doi.org/10.1002/path.3991 . - PubMed
  67. Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, Schewe DM, Aguirre-Ghiso JA. TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat Cell Biol. 2013;15:1351–61. https://doi.org/10.1038/ncb2861 . - PubMed
  68. Dey-Guha I, Alves CP, Yeh AC, Salony SX, Darp R, Ramaswamy S. A mechanism for asymmetric cell division resulting in proliferative asynchronicity. Mol Cancer Res. 2015;13:223–30. https://doi.org/10.1158/1541-7786.MCR-14-0474 . - PubMed
  69. Schewe DM, Aguirre-Ghiso JA. ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci U S A. 2008;105:10519–24. https://doi.org/10.1073/pnas.0800939105 . - PubMed
  70. Sadasivam S, DeCaprio JA. The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat Rev Cancer. 2013;13:585–95. https://doi.org/10.1038/nrc3556 . - PubMed
  71. Adam AP, George A, Schewe D, Bragado P, Iglesias BV, Ranganathan AC, Kourtidis A, Conklin DS, Aguirre-Ghiso JA. Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence. Cancer Res. 2009;69:5664–72. https://doi.org/10.1158/0008-5472.CAN-08-3820 . - PubMed
  72. Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A, Shen R, Brogi E, Brivanlou AH, Giancotti FG. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell. 2012;150:764–79. https://doi.org/10.1016/j.cell.2012.06.035 . - PubMed
  73. Litchfield LM, Riggs KA, Hockenberry AM, Oliver LD, Barnhart KG, Cai J, Pierce WM Jr, Ivanova MM, Bates PJ, Appana SN, Datta S, Kulesza P, McBryan J, Young LS, Klinge CM. Identification and characterization of nucleolin as a COUP-TFII coactivator of retinoic acid receptor beta transcription in breast cancer cells. PLoS ONE. 2012;7: e38278. https://doi.org/10.1371/journal.pone.0038278 . - PubMed
  74. Sosa MS, Parikh F, Maia AG, Estrada Y, Bosch A, Bragado P, Ekpin E, George A, Zheng Y, Lam HM, Morrissey C, Chung CY, Farias EF, Bernstein E, Aguirre-Ghiso JA. NR2F1 controls tumour cell dormancy via SOX9- and RARbeta-driven quiescence programmes. Nat Commun. 2015;6:6170. https://doi.org/10.1038/ncomms7170 . - PubMed
  75. Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L. Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell. 2001;12:863–79. https://doi.org/10.1091/mbc.12.4.863 . - PubMed
  76. Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K. Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone. J Exp Med. 2011;208:2641–55. https://doi.org/10.1084/jem.20110840 . - PubMed
  77. Malladi S, Macalinao DG, Jin X, He L, Basnet H, Zou Y, de Stanchina E, Massague J. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell. 2016;165:45–60. https://doi.org/10.1016/j.cell.2016.02.025 . - PubMed
  78. Ren D, Dai Y, Yang Q, Zhang X, Guo W, Ye L, Huang S, Chen X, Lai Y, Du H, Lin C, Peng X, Song L. Wnt5a induces and maintains prostate cancer cells dormancy in bone. J Exp Med. 2019;216:428–49. https://doi.org/10.1084/jem.20180661 . - PubMed
  79. Sharma S, Xing F, Liu Y, Wu K, Said N, Pochampally R, Shiozawa Y, Lin HK, Balaji KC, Watabe K. Secreted protein acidic and rich in cysteine (SPARC) mediates metastatic dormancy of prostate cancer in bone. J Biol Chem. 2016;291:19351–63. https://doi.org/10.1074/jbc.M116.737379 . - PubMed
  80. Shiozawa Y, Pedersen EA, Patel LR, Ziegler AM, Havens AM, Jung Y, Wang J, Zalucha S, Loberg RD, Pienta KJ, Taichman RS. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche. Neoplasia. 2010;12:116–27. https://doi.org/10.1593/neo.91384 . - PubMed
  81. Taichman RS, Patel LR, Bedenis R, Wang J, Weidner S, Schumann T, Yumoto K, Berry JE, Shiozawa Y, Pienta KJ. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS ONE. 2013;8: e61873. https://doi.org/10.1371/journal.pone.0061873 . - PubMed
  82. Yumoto K, Eber MR, Wang J, Cackowski FC, Decker AM, Lee E, Nobre AR, Aguirre-Ghiso JA, Jung Y, Taichman RS. Axl is required for TGF-beta2-induced dormancy of prostate cancer cells in the bone marrow. Sci Rep. 2016;6:36520. https://doi.org/10.1038/srep36520 . - PubMed
  83. La Belle FA, Calhoun BC, Sharma A, Chang JC, Almasan A, Schiemann WP. Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression. Nat Commun. 2019;10:3668. https://doi.org/10.1038/s41467-019-11640-9 . - PubMed
  84. Lu Z, Baquero MT, Yang H, Yang M, Reger AS, Kim C, Levine DA, Clarke CH, Liao WS, Bast RC Jr. DIRAS3 regulates the autophagosome initiation complex in dormant ovarian cancer cells. Autophagy. 2014;10:1071–92. https://doi.org/10.4161/auto.28577 . - PubMed
  85. Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills GB, Liao WS, Bast RC Jr. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest. 2008;118:3917–29. https://doi.org/10.1172/JCI35512 . - PubMed
  86. Shimizu T, Sugihara E, Yamaguchi-Iwai S, Tamaki S, Koyama Y, Kamel W, Ueki A, Ishikawa T, Chiyoda T, Osuka S, Onishi N, Ikeda H, Kamei J, Matsuo K, Fukuchi Y, Nagai T, Toguchida J, Toyama Y, Muto A, Saya H. IGF2 preserves osteosarcoma cell survival by creating an autophagic state of dormancy that protects cells against chemotherapeutic stress. Cancer Res. 2014;74:6531–41. https://doi.org/10.1158/0008-5472.CAN-14-0914 . - PubMed
  87. Vera-Ramirez L, Vodnala SK, Nini R, Hunter KW, Green JE. Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence. Nat Commun. 2018;9:1944. https://doi.org/10.1038/s41467-018-04070-6 . - PubMed
  88. Yu Z, Zhou R, Zhao Y, Pan Y, Liang H, Zhang JS, Tai S, Jin L, Teng CB. Blockage of SLC31A1-dependent copper absorption increases pancreatic cancer cell autophagy to resist cell death. Cell Prolif. 2019;52: e12568. https://doi.org/10.1111/cpr.12568 . - PubMed
  89. Wang L, Hoque A, Luo RZ, Yuan J, Lu Z, Nishimoto A, Liu J, Sahin AA, Lippman SM, Bast RC Jr, Yu Y. Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. Clin Cancer Res. 2003;9:3660–6. - PubMed
  90. Washington MN, Suh G, Orozco AF, Sutton MN, Yang H, Wang Y, Mao W, Millward S, Ornelas A, Atkinson N, Liao W, Bast RC Jr, Lu Z. ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts. Cell Death Dis. 2015;6: e1836. https://doi.org/10.1038/cddis.2015.208 . - PubMed
  91. Gupta A, Roy S, Lazar AJ, Wang WL, McAuliffe JC, Reynoso D, McMahon J, Taguchi T, Floris G, Debiec-Rychter M, Schoffski P, Trent JA, Debnath J, Rubin BP. Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci U S A. 2010;107:14333–8. https://doi.org/10.1073/pnas.1000248107 . - PubMed
  92. Correa RJ, Valdes YR, Peart TM, Fazio EN, Bertrand M, McGee J, Prefontaine M, Sugimoto A, DiMattia GE, Shepherd TG. Combination of AKT inhibition with autophagy blockade effectively reduces ascites-derived ovarian cancer cell viability. Carcinogenesis. 2014;35:1951–61. https://doi.org/10.1093/carcin/bgu049 . - PubMed
  93. Chatterjee M, van Golen KL. Farnesyl transferase inhibitor treatment of breast cancer cells leads to altered RhoA and RhoC GTPase activity and induces a dormant phenotype. Int J Cancer. 2011;129:61–9. https://doi.org/10.1002/ijc.25655 . - PubMed
  94. Aqbi HF, Tyutyunyk-Massey L, Keim RC, Butler SE, Thekkudan T, Joshi S, Smith TM, Bandyopadhyay D, Idowu MO, Bear HD, Payne KK, Gewirtz DA, Manjili MH. Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy. Oncotarget. 2018;9:22113–22. https://doi.org/10.18632/oncotarget.25197 . - PubMed
  95. Ikawa K, Terashima Y, Sasaki K, Tashiro S. Genetic detection of liver micrometastases that are undetectable histologically. J Surg Res. 2002;106:124–30. https://doi.org/10.1006/jsre.2002.6459 . - PubMed
  96. Noltenius C, Noltenius H. Dormant tumor cells in liver and brain. An autopsy study on metastasizing tumors. Pathol Res Pract. 1985;179:504–11. https://doi.org/10.1016/S0344-0338(85)80191-6 . - PubMed
  97. Aqbi HF, Coleman C, Zarei M, Manjili SH, Graham L, Koblinski J, Guo C, Xie Y, Guruli G, Bear HD, Idowu MO, Habibi M, Wang XY, Manjili MH. Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets. Breast Cancer Res. 2020;22:116. https://doi.org/10.1186/s13058-020-01357-9 . - PubMed
  98. Clark AM, Ma B, Taylor DL, Griffith L, Wells A. Liver metastases: microenvironments and ex-vivo models. Exp Biol Med (Maywood). 2016;241:1639–52. https://doi.org/10.1177/1535370216658144 . - PubMed
  99. Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, Morris VL, Groom AC, Chambers AF. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 2002;62:2162–8. - PubMed
  100. Martin MD, Kremers GJ, Short KW, Rocheleau JV, Xu L, Piston DW, Matrisian LM, Gorden DL. Rapid extravasation and establishment of breast cancer micrometastases in the liver microenvironment. Mol Cancer Res. 2010;8:1319–27. https://doi.org/10.1158/1541-7786.MCR-09-0551 . - PubMed
  101. Ma B, Wheeler SE, Clark AM, Whaley DL, Yang M, Wells A. Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling. Hepatology. 2016;64:1725–42. https://doi.org/10.1002/hep.28755 . - PubMed
  102. Yates CC, Shepard CR, Stolz DB, Wells A. Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. Br J Cancer. 2007;96:1246–52. https://doi.org/10.1038/sj.bjc.6603700 . - PubMed
  103. Clark AM, Heusey HL, Griffith LG, Lauffenburger DA, Wells A. IP-10 (CXCL10) can trigger emergence of dormant breast cancer cells in a metastatic liver microenvironment. Front Oncol. 2021;11: 676135. https://doi.org/10.3389/fonc.2021.676135 . - PubMed
  104. Ma B, Wells A. The mitogen-activated protein (MAP) kinases p38 and extracellular signal-regulated kinase (ERK) are involved in hepatocyte-mediated phenotypic switching in prostate cancer cells. J Biol Chem. 2014 Apr 18;289(16):11153-11161. https://doi.org/10.1074/jbc.M113.540237 . Epub 2014 Mar 11. PMID: 24619413; PMCID: PMC4036254. - PubMed
  105. Clark AM, Kumar MP, Wheeler SE, Young CL, Venkataramanan R, Stolz DB, Griffith LG, Lauffenburger DA, Wells A. A model of dormant-emergent metastatic breast cancer progression enabling exploration of biomarker signatures. Mol Cell Proteomics. 2018;17:619–30. https://doi.org/10.1074/mcp.RA117.000370 . - PubMed
  106. Chao Y, Wu Q, Shepard C, Wells A. Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. Clin Exp Metastasis. 2012;29:39–50. https://doi.org/10.1007/s10585-011-9427-3 . - PubMed
  107. Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Van den Heuvel E, Harris AL, Jackson DG, Colpaert CG, van Marck EA, Dirix LY, Vermeulen PB. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br J Cancer. 2004;90:1429–36. https://doi.org/10.1038/sj.bjc.6601727 . - PubMed
  108. Wendel C, Hemping-Bovenkerk A, Krasnyanska J, Mees ST, Kochetkova M, Stoeppeler S, Haier J. CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model. PLoS One. 2012;7(1):e30046. https://doi.org/10.1371/journal.pone.0030046 . Epub 2012 Jan 13. PMID: 22253872; PMCID: PMC3258260. - PubMed
  109. Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology. 2008 Sep;48(3):920–30. https://doi.org/10.1002/hep.22351 . PMID: 18613151; PMCID: PMC2695448. - PubMed
  110. DeLeve LD, Wang X, Hu L, McCuskey MK, McCuskey RS. Rat liver sinusoidal endothelial cell phenotype is maintained by paracrine and autocrine regulation. Am J Physiol Gastrointest Liver Physiol. 2004 Oct;287(4):G757–63. https://doi.org/10.1152/ajpgi.00017.2004 . Epub 2004 Jun 10. PMID: 15191879.  - PubMed
  111. Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandl S, Bachmann MH, Borowsky AD, Ruebner B, Cardiff RD, Yang Q, Bishop JM, Contag CH, Felsher DW. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004 Oct 28;431(7012):1112–7. https://doi.org/10.1038/nature03043 . Epub 2004 Oct 10. PMID:15475948. - PubMed
  112. Lenk L, Pein M, Will O, Gomez B, Viol F, Hauser C, Egberts JH, Gundlach JP, Helm O, Tiwari S, Weiskirchen R, Rose-John S, Röcken C, Mikulits W, Wenzel P, Schneider G, Saur D, Schäfer H, Sebens S. The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma. Oncoimmunology. 2017 Oct26;7(1):e1368603. https://doi.org/10.1080/2162402X.2017.1368603 . PMID: 29296518; PMCID: PMC5739558. - PubMed
  113. Knaack H, Lenk L, Philipp LM, Miarka L, Rahn S, Viol F, Hauser C, Egberts JH, Gundlach JP, Will O, Tiwari S, Mikulits W, Schumacher U, Hengstler JG, Sebens S. Liver metastasis of pancreatic cancer: the hepatic microenvironment impacts differentiation and self-renewal capacity of pancreatic ductal epithelial cells. Oncotarget. 2018;9:31771–86. https://doi.org/10.18632/oncotarget.25884 . - PubMed
  114. Fabian A, Stegner S, Miarka L, Zimmermann J, Lenk L, Rahn S, Buttlar J, Viol F, Knaack H, Esser D, Schauble S, Grossmann P, Marinos G, Hasler R, Mikulits W, Saur D, Kaleta C, Schafer H, Sebens S. Metastasis of pancreatic cancer: an uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells. Cancer Lett. 2019;453:95–106. https://doi.org/10.1016/j.canlet.2019.03.039 . - PubMed
  115. Kondo T, Okabayashi K, Hasegawa H, Tsuruta M, Shigeta K, Kitagawa Y. The impact of hepatic fibrosis on the incidence of liver metastasis from colorectal cancer. Br J Cancer. 2016 Jun 28;115(1):34–9. https://doi.org/10.1038/bjc.2016.155 . Epub 2016 Jun 9. PMID: 27280634; PMCID: PMC4931372 - PubMed
  116. Hu X, Marietta A, Dai WX, Li YQ, Ma XJ, Zhang L, Cai SJ, Peng JJ. Prediction of hepatic metastasis and relapse in colorectal cancers based on concordance analyses with liver fibrosis scores. Clin Transl Med. 2020 Feb 5;9(1):13. https://doi.org/10.1186/s40169-020-0264-3 . PMID: 32025991; PMCID: PMC7002812. - PubMed
  117. Harun N, Nikfarjam M, Muralidharan V, Christophi C. Liver regeneration stimulates tumor metastases. J Surg Res. 2007 Apr;138(2):284–90. https://doi.org/10.1016/j.jss.2006.06.024 . Epub 2007 Jan 24. PMID: 17254608. - PubMed
  118. Bertolotti M, Lonardo A, Mussi C, Baldelli E, Pellegrini E, Ballestri S, Romagnoli D, Loria P. Nonalcoholic fatty liver disease and aging: epidemiology to management. World J Gastroenterol. 2014 Oct 21;20(39):14185–204. https://doi.org/10.3748/wjg.v20.i39.14185 . PMID: 25339806; PMCID: PMC4202348. - PubMed
  119. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017 Jul;14(7):397–411. https://doi.org/10.1038/nrgastro.2017.38 . Epub 2017 May 10. PMID: 28487545 - PubMed
  120. Fishbein A, Wang W, Yang H, Yang J, Hallisey VM, Deng J, Verheul SML, Hwang SH, Gartung A, Wang Y, Bielenberg DR, Huang S, Kieran MW, Hammock BD, Panigrahy D. Resolution of eicosanoid/cytokine storm prevents carcinogen and inflammation-initiated hepatocellular cancer progression. Proc Natl Acad Sci U S A. 2020;117:21576–87. https://doi.org/10.1073/pnas.2007412117 . - PubMed
  121. De Minicis S, Seki E, Uchinami H, Kluwe J, Zhang Y, Brenner DA, Schwabe RF. Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology. 2007 May;132(5):1937–46. https://doi.org/10.1053/j.gastro.2007.02.033 . Epub 2007 Feb 21. PMID: 17484886. - PubMed
  122. Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology. 2004 Dec;40(6):1312–21. https://doi.org/10.1002/hep.20488 . PMID: 15565659 - PubMed
  123. Khazali AS, Clark AM, Wells A. Inflammatory cytokine IL-8/CXCL8 promotes tumour escape from hepatocyte-induced dormancy. Br J Cancer. 2018 Feb 20;118(4):566–76. https://doi.org/10.1038/bjc.2017.414 . Epub 2017 Nov 23. PMID: 29169181; PMCID: PMC5830588. - PubMed
  124. Pommier A, Anaparthy N, Memos N, Kelley ZL, Gouronnec A, Yan R, Auffray C, Albrengues J, Egeblad M, Iacobuzio-Donahue CA, Lyons SK, Fearon DT. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science. 2018 Jun 15;360(6394):eaao4908. https://doi.org/10.1126/science.aao4908 . Epub 2018 May 17. PMID: 29773669; PMCID: PMC6547380. - PubMed
  125. Melhem A, Muhanna N, Bishara A, Alvarez CE, Ilan Y, Bishara T, Horani A, Nassar M, Friedman SL, Safadi R. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol. 2006 Jul;45(1):60–71. https://doi.org/10.1016/j.jhep.2005.12.025 . Epub 2006 Feb 8. PMID: 16515819. - PubMed
  126. Chen Z, Zhang P, Xu Y, Yan J, Liu Z, Lau WB, Lau B, Li Y, Zhao X, Wei Y, Zhou S. Surgical stress and cancer progression: the twisted tango. Mol Cancer. 2019;18:132. https://doi.org/10.1186/s12943-019-1058-3 . - PubMed
  127. Bohm F, Kohler UA, Speicher T, Werner S. Regulation of liver regeneration by growth factors and cytokines. EMBO Mol Med. 2010;2:294–305. https://doi.org/10.1002/emmm.201000085 . - PubMed
  128. Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, Penfold ME, Shido K, Rabbany SY, Rafii S. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature. 2014;505:97–102. https://doi.org/10.1038/nature12681 . - PubMed
  129. Yang L, Magness ST, Bataller R, Rippe RA, Brenner DA. NF-kappaB activation in Kupffer cells after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol. 2005;289:G530–8. https://doi.org/10.1152/ajpgi.00526.2004 . - PubMed
  130. Oe S, Lemmer ER, Conner EA, Factor VM, Leveen P, Larsson J, Karlsson S, Thorgeirsson SS. Intact signaling by transforming growth factor beta is not required for termination of liver regeneration in mice. Hepatology. 2004;40:1098–105. https://doi.org/10.1002/hep.20426 . - PubMed
  131. Wheeler SE, Clark AM, Taylor DP, Young CL, Pillai VC, Stolz DB, Venkataramanan R, Lauffenburger D, Griffith L, Wells A. Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system. Br J Cancer. 2014;111:2342–50. https://doi.org/10.1038/bjc.2014.533 . - PubMed
  132. Taylor DP, Clark A, Wheeler S, Wells A. Hepatic nonparenchymal cells drive metastatic breast cancer outgrowth and partial epithelial to mesenchymal transition. Breast Cancer Res Treat. 2014;144:551–60. https://doi.org/10.1007/s10549-014-2875-0 . - PubMed
  133. Clark AM, Wheeler SE, Young CL, Stockdale L, Shepard Neiman J, Zhao W, Stolz DB, Venkataramanan R, Lauffenburger D, Griffith L, Wells A. A liver microphysiological system of tumor cell dormancy and inflammatory responsiveness is affected by scaffold properties. Lab Chip. 2016;17:156–68. https://doi.org/10.1039/c6lc01171c . - PubMed
  134. Chen WLK, Edington C, Suter E, Yu J, Velazquez JJ, Velazquez JG, Shockley M, Large EM, Venkataramanan R, Hughes DJ, Stokes CL, Trumper DL, Carrier RL, Cirit M, Griffith LG, Lauffenburger DA. Integrated gut/liver microphysiological systems elucidates inflammatory inter-tissue crosstalk. Biotechnol Bioeng. 2017;114:2648–59. https://doi.org/10.1002/bit.26370 . - PubMed
  135. Toiyama Y, Fujikawa H, Kawamura M, Matsushita K, Saigusa S, Tanaka K, Inoue Y, Uchida K, Mohri Y, Kusunoki M. Evaluation of CXCL10 as a novel serum marker for predicting liver metastasis and prognosis in colorectal cancer. Int J Oncol. 2012;40:560–6. https://doi.org/10.3892/ijo.2011.1247 . - PubMed
  136. Hintermann E, Bayer M, Pfeilschifter JM, Luster AD, Christen U. CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. J Autoimmun. 2010;35:424–35. https://doi.org/10.1016/j.jaut.2010.09.003 . - PubMed
  137. Khazali AS, Clark AM, Wells A. Inflammatory cytokine IL-8/CXCL8 promotes tumour escape from hepatocyte-induced dormancy. Br J Cancer. 2018;118:566–76. https://doi.org/10.1038/bjc.2017.414 . - PubMed
  138. Song MS, Song SJ, Kim SY, Oh HJ, Lim DS. The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J. 2008;27:1863–74. https://doi.org/10.1038/emboj.2008.115 . - PubMed
  139. Xiong W, Sun LP, Chen XM, Li HY, Huang SA, Jie SH. Comparison of microRNA expression profiles in HCC-derived microvesicles and the parental cells and evaluation of their roles in HCC. J Huazhong Univ Sci Technolog Med Sci. 2013;33:346–52. https://doi.org/10.1007/s11596-013-1122-y . - PubMed
  140. Zhou C, Huang Y, Chen Y, Xie Y, Wen H, Tan W, Wang C. miR-602 mediates the RASSF1A/JNK pathway, thereby promoting postoperative recurrence in nude mice with liver cancer. Onco Targets Ther. 2020;13:6767–76. https://doi.org/10.2147/OTT.S243651 . - PubMed
  141. Ashokachakkaravarthy K, Pottakkat B. Mitotic quiescence in hepatic cancer stem cells: an incognito mode. Oncol Rev. 2020;14:452. https://doi.org/10.4081/oncol.2020.452 . - PubMed
  142. Liu J, Wang K, Yan Z, Xia Y, Li J, Shi L, Zou Q, Wan X, Jiao B, Wang H, Wu M, Zhang Y, Shen F. Axl expression stratifies patients with poor prognosis after hepatectomy for hepatocellular carcinoma. PLoS ONE. 2016;11: e0154767. https://doi.org/10.1371/journal.pone.0154767 . - PubMed
  143. Wu G, Ma Z, Hu W, Wang D, Gong B, Fan C, Jiang S, Li T, Gao J, Yang Y. Molecular insights of Gas6/TAM in cancer development and therapy. Cell Death Dis. 2017;8: e2700. https://doi.org/10.1038/cddis.2017.113 . - PubMed
  144. Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, Gunda V, Pierobon M, Waters AM, George SD, Tomar G, Papke B, Hobbs GA, Yan L, Hayes TK, Diehl JN, Goode GD, Chaika NV, Wang Y, Zhang GF, Witkiewicz AK, Knudsen ES, Petricoin EF 3rd, Singh PK, Macdonald JM, Tran NL, Lyssiotis CA, Ying H, Kimmelman AC, Cox AD, Der CJ. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019;25:628–40. https://doi.org/10.1038/s41591-019-0368-8 . - PubMed
  145. Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, Burrell LD, Lum DH, Whisenant JR, Gilcrease GW 3rd, Cavalieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL, McMahon M. Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25:620–7. https://doi.org/10.1038/s41591-019-0367-9 . - PubMed
  146. Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell’antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25:717–29. https://doi.org/10.1101/gad.2016111 . - PubMed
  147. Boone BA, Bahary N, Zureikat AH, Moser AJ, Normolle DP, Wu WC, Singhi AD, Bao P, Bartlett DL, Liotta LA, Espina V, Loughran P, Lotze MT, Zeh HJ 3rd. Safety and biologic response of pre-operative autophagy inhibition in combination with gemcitabine in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2015;22:4402–10. https://doi.org/10.1245/s10434-015-4566-4 . - PubMed
  148. Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM, Enzinger PC, Fuchs CS, McCleary NJ, Meyerhardt JA, Ng K, Schrag D, Sikora AL, Spicer BA, Killion L, Mamon H, Kimmelman AC. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist. 2014;19:637–8. https://doi.org/10.1634/theoncologist.2014-0086 . - PubMed

Publication Types