BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Mucin in cancer: a stealth cloak for cancer cells

  • Wi, Dong-Han (Department of Life Science, Chung-Ang University) ;
  • Cha, Jong-Ho (Department of Biomedical Sciences, College of Medicine, Inha University) ;
  • Jung, Youn-Sang (Department of Life Science, Chung-Ang University)
  • Received : 2021.04.23
  • Accepted : 2021.06.17
  • Published : 2021.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

Mucins are high molecular-weight epithelial glycoproteins and are implicated in many physiological processes, including epithelial cell protection, signaling transduction, and tissue homeostasis. Abnormality of mucus expression and structure contributes to biological properties related to human cancer progression. Tumor growth sites induce inhospitable conditions. Many kinds of research suggest that mucins provide a microenvironment to avoid hypoxia, acidic, and other biological conditions that promote cancer progression. Given that the mucus layer captures growth factors or cytokines, we propose that mucin helps to ameliorate inhospitable conditions in tumor-growing sites. Additionally, the composition and structure of mucins enable them to mimic the surface of normal epithelial cells, allowing tumor cells to escape from immune surveillance. Indeed, human cancers such as mucinous carcinoma, show a higher incidence of invasion to adjacent organs and lymph node metastasis than do non-mucinous carcinoma. In this mini-review, we discuss how mucin provides a tumor-friendly environment and contributes to increased cancer malignancy in mucinous carcinoma.

Keywords

Acknowledgement

This work was supported by the CHUNG-ANG UNIVERSITY Grant in 2020 and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1F1A1075419) to Y-.S. Jung.

References

  1. Gum JR Jr, Hicks JW, Gillespie AM et al (1999) Goblet cell-specific expression mediated by the MUC2 mucin gene promoter in the intestine of transgenic mice. Am J Physiol 276, G666-676
  2. Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L and Hansson GC (2008) The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A 105, 15064-15069 https://doi.org/10.1073/pnas.0803124105
  3. Boland CR and Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138, 2073-2087 e2073 https://doi.org/10.1053/j.gastro.2009.12.064
  4. Kufe DW (2009) Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 9, 874-885 https://doi.org/10.1038/nrc2761
  5. Wahrenbrock M, Borsig L, Le D, Varki N and Varki A (2003) Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest 112, 853-862 https://doi.org/10.1172/JCI200318882
  6. Smagghe BJ, Stewart AK, Carter MG et al (2013) MUC1* ligand, NM23-H1, is a novel growth factor that maintains human stem cells in a more naive state. PLoS One 8, e58601 https://doi.org/10.1371/journal.pone.0058601
  7. Mekenkamp LJ, Heesterbeek KJ, Koopman M et al (2012) Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer 48, 501-509 https://doi.org/10.1016/j.ejca.2011.12.004
  8. Tran DT and Ten Hagen KG (2013) Mucin-type O-glycosylation during development. J Biol Chem 288, 6921-6929 https://doi.org/10.1074/jbc.R112.418558
  9. Robbe C, Capon C, Coddeville B and Michalski JC (2004) Structural diversity and specific distribution of O-glycans in normal human mucins along the intestinal tract. Biochem J 384, 307-316 https://doi.org/10.1042/BJ20040605
  10. Okudaira K, Kakar S, Cun L et al (2010) MUC2 gene promoter methylation in mucinous and non-mucinous colorectal cancer tissues. Int J Oncol 36, 765-775
  11. Niv Y (2016) Mucin gene expression in the intestine of ulcerative colitis patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 28, 1241-1245 https://doi.org/10.1097/MEG.0000000000000707
  12. Hugen N, Brown G, Glynne-Jones R, de Wilt JH and Nagtegaal ID (2016) Advances in the care of patients with mucinous colorectal cancer. Nat Rev Clin Oncol 13, 361-369 https://doi.org/10.1038/nrclinonc.2015.140
  13. Day FL, Jorissen RN, Lipton L et al (2013) PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. Clin Cancer Res 19, 3285-3296 https://doi.org/10.1158/1078-0432.CCR-12-3614
  14. Garrido-Laguna I, Hong DS, Janku F et al (2012) KRASness and PIK3CAness in patients with advanced colorectal cancer: outcome after treatment with early-phase trials with targeted pathway inhibitors. PLoS One 7, e38033 https://doi.org/10.1371/journal.pone.0038033
  15. Gunal A, Hui P, Kilic S et al (2013) KRAS mutations are associated with specific morphologic features in colon cancer. J Clin Gastroenterol 47, 509-514 https://doi.org/10.1097/MCG.0b013e3182703030
  16. Negri FV, Azzoni C, Bottarelli L et al (2013) Thymidylate synthase, topoisomerase-1 and microsatellite instability: relationship with outcome in mucinous colorectal cancer treated with fluorouracil. Anticancer Res 33, 4611-4617
  17. Nosho K, Kawasaki T, Ohnishi M et al (2008) PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia 10, 534-541 https://doi.org/10.1593/neo.08336
  18. Pai RK, Jayachandran P, Koong AC et al (2012) BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol 36, 744-752 https://doi.org/10.1097/PAS.0b013e31824430d7
  19. Ookawa K, Kudo T, Aizawa S, Saito H and Tsuchida S (2002) Transcriptional activation of the MUC2 gene by p53. J Biol Chem 277, 48270-48275 https://doi.org/10.1074/jbc.M207986200
  20. Pereira MB, Dias AJ, Reis CA and Schmitt FC (2001) Immunohistochemical study of the expression of MUC5AC and MUC6 in breast carcinomas and adjacent breast tissues. J Clin Pathol 54, 210-213 https://doi.org/10.1136/jcp.54.3.210
  21. Biemer-Huttmann AE, Walsh MD, McGuckin MA et al (2000) Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis. Clin Cancer Res 6, 1909-1916
  22. Losi L, Scarselli A, Benatti P et al (2004) Relationship between MUC5AC and altered expression of MLH1 protein in mucinous and non-mucinous colorectal carcinomas. Pathol Res Pract 200, 371-377 https://doi.org/10.1016/j.prp.2004.01.008
  23. Walsh MD, Clendenning M, Williamson E et al (2013) Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype. Mod Pathol 26, 1642-1656 https://doi.org/10.1038/modpathol.2013.101
  24. Renaud F, Vincent A, Mariette C et al (2015) MUC5AC hypomethylation is a predictor of microsatellite instability independently of clinical factors associated with colorectal cancer. Int J Cancer 136, 2811-2821 https://doi.org/10.1002/ijc.29342
  25. Rico SD, Hoflmayer D, Buscheck F et al (2020) Elevated MUC5AC expression is associated with mismatch repair deficiency and proximal tumor location but not with cancer progression in colon cancer. Med Mol Morphol 54, 156-165
  26. Pothuraju R, Rachagani S, Krishn SR et al (2020) Molecular implications of MUC5AC-CD44 axis in colorectal cancer progression and chemoresistance. Mol Cancer 19, 37 https://doi.org/10.1186/s12943-020-01156-y
  27. Jun S, Jung YS, Suh HN et al (2016) LIG4 mediates Wnt signalling-induced radioresistance. Nat Commun 7, 10994 https://doi.org/10.1038/ncomms10994
  28. Jung YS, Jun S, Kim MJ et al (2018) TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/beta-catenin signalling. Nat Cell Biol 20, 1421-1433 https://doi.org/10.1038/s41556-018-0219-8
  29. Jung YS, Stratton SA, Lee SH et al (2021) TMEM9-v-ATPase activates Wnt/beta-catenin signaling via APC lysosomal degradation for liver regeneration and tumorigenesis. Hepatology 73, 776-794 https://doi.org/10.1002/hep.31305
  30. Wang X, Jung YS, Jun S et al (2016) PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness. Nat Commun 7, 10633 https://doi.org/10.1038/ncomms10633
  31. Dong Y, Zhou L, Zhao D et al (2020) MUC5AC enhances tumor heterogeneity in lung adenocarcinoma with mucin production and is associated with poor prognosis. Jpn J Clin Oncol 50, 701-711 https://doi.org/10.1093/jjco/hyaa016
  32. Vincent A, Perrais M, Desseyn JL, Aubert JP, Pigny P and Van Seuningen I (2007) Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells. Oncogene 26, 6566-6576 https://doi.org/10.1038/sj.onc.1210479
  33. Pigny P, Van Seuningen I, Desseyn JL et al (1996) Identification of a 42-kDa nuclear factor (NF1-MUC5B) from HT-29 MTX cells that binds to the 3' region of human mucin gene MUC5B. Biochem Biophys Res Commun 220, 186-191 https://doi.org/10.1006/bbrc.1996.0378
  34. Desseyn JL, Aubert JP, Van Seuningen I, Porchet N and Laine A (1997) Genomic organization of the 3' region of the human mucin gene MUC5B. J Biol Chem 272, 16873-16883 https://doi.org/10.1074/jbc.272.27.16873
  35. Van Seuningen I, Perrais M, Pigny P, Porchet N and Aubert JP (2000) Sequence of the 5'-flanking region and promoter activity of the human mucin gene MUC5B in different phenotypes of colon cancer cells. Biochem J 348 Pt 3, 675-686 https://doi.org/10.1042/bj3480675
  36. Van Seuningen I, Pigny P, Perrais M, Porchet N and Aubert JP (2001) Transcriptional regulation of the 11p15 mucin genes. Towards new biological tools in human therapy, in inflammatory diseases and cancer? Front Biosci 6, D1216-1234
  37. Yuan S, Liu Q, Hu Z et al (2018) Long non-coding RNA MUC5B-AS1 promotes metastasis through mutually regulating MUC5B expression in lung adenocarcinoma. Cell Death Dis 9, 450 https://doi.org/10.1038/s41419-018-0472-6
  38. Garcia EP, Tiscornia I, Libisch G et al (2016) MUC5B silencing reduces chemo-resistance of MCF-7 breast tumor cells and impairs maturation of dendritic cells. Int J Oncol 48, 2113-2123 https://doi.org/10.3892/ijo.2016.3434
  39. Lahdaoui F, Messager M, Vincent A et al (2017) Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/beta-catenin pathway. Biochem J 474, 3733-3746 https://doi.org/10.1042/BCJ20170348
  40. Jung YS, Wang W, Jun S et al (2018) Deregulation of CRAD-controlled cytoskeleton initiates mucinous colorectal cancer via beta-catenin. Nat Cell Biol 20, 1303-1314 https://doi.org/10.1038/s41556-018-0215-z
  41. Sekine A, Akiyama Y, Yanagihara K and Yuasa Y (2006) Hath1 up-regulates gastric mucin gene expression in gastric cells. Biochem Biophys Res Commun 344, 1166-1171 https://doi.org/10.1016/j.bbrc.2006.03.238
  42. Silva EM, Begnami MD, Fregnani JH et al (2008) Cadherin-catenin adhesion system and mucin expression: a comparison between young and older patients with gastric carcinoma. Gastric Cancer 11, 149-159 https://doi.org/10.1007/s10120-008-0468-5
  43. Pai P, Rachagani S, Dhawan P and Batra SK (2016) Mucins and Wnt/beta-catenin signaling in gastrointestinal cancers: an unholy nexus. Carcinogenesis 37, 223-232 https://doi.org/10.1093/carcin/bgw005
  44. Leir SH and Harris A (2011) MUC6 mucin expression inhibits tumor cell invasion. Exp Cell Res 317, 2408-2419 https://doi.org/10.1016/j.yexcr.2011.07.021
  45. Betge J, Schneider NI, Harbaum L et al (2016) MUC1, MUC2, MUC5AC, and MUC6 in colorectal cancer: expression profiles and clinical significance. Virchows Arch 469, 255-265 https://doi.org/10.1007/s00428-016-1970-5
  46. Mehla K and Singh PK (2014) MUC1: a novel metabolic master regulator. Biochim Biophys Acta 1845, 126-135 https://doi.org/10.1016/j.bbcan.2014.01.001
  47. Nath S and Mukherjee P (2014) MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med 20, 332-342 https://doi.org/10.1016/j.molmed.2014.02.007
  48. Li Y, Ren J, Yu W et al (2001) The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. J Biol Chem 276, 35239-35242 https://doi.org/10.1074/jbc.C100359200
  49. Schroeder JA, Thompson MC, Gardner MM and Gendler SJ (2001) Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogenactivated protein kinase activation in the mouse mammary gland. J Biol Chem 276, 13057-13064 https://doi.org/10.1074/jbc.M011248200
  50. Schroeder JA, Adriance MC, Thompson MC, Camenisch TD and Gendler SJ (2003) MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion. Oncogene 22, 1324-1332 https://doi.org/10.1038/sj.onc.1206291
  51. Pochampalli MR, el Bejjani RM and Schroeder JA (2007) MUC1 is a novel regulator of ErbB1 receptor trafficking. Oncogene 26, 1693-1701 https://doi.org/10.1038/sj.onc.1209976
  52. Zhang Y, Dong X, Bai L, Shang X and Zeng Y (2020) MUC1-induced immunosuppression in colon cancer can be reversed by blocking the PD1/PDL1 signaling pathway. Oncol Lett 20, 317
  53. Rowse GJ, Tempero RM, VanLith ML, Hollingsworth MA and Gendler SJ (1998) Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model. Cancer Res 58, 315-321
  54. Agata N, Ahmad R, Kawano T, Raina D, Kharbanda S and Kufe D (2008) MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8. Cancer Res 68, 6136-6144 https://doi.org/10.1158/0008-5472.CAN-08-0464
  55. Ren J, Agata N, Chen D et al (2004) Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents. Cancer Cell 5, 163-175 https://doi.org/10.1016/S1535-6108(04)00020-0
  56. Raina D, Kharbanda S and Kufe D (2004) The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. J Biol Chem 279, 20607-20612 https://doi.org/10.1074/jbc.M310538200
  57. Yin L, Wu Z, Avigan D et al (2011) MUC1-C oncoprotein suppresses reactive oxygen species-induced terminal differentiation of acute myelogenous leukemia cells. Blood 117, 4863-4870 https://doi.org/10.1182/blood-2010-10-296632
  58. Yamada N, Nishida Y, Tsutsumida H et al (2008) MUC1 expression is regulated by DNA methylation and histone H3 lysine 9 modification in cancer cells. Cancer Res 68, 2708-2716 https://doi.org/10.1158/0008-5472.CAN-07-6844
  59. Gendler SJ (2001) MUC1, the renaissance molecule. J Mammary Gland Biol Neoplasia 6, 339-353 https://doi.org/10.1023/A:1011379725811
  60. Lagow EL and Carson DD (2002) Synergistic stimulation of MUC1 expression in normal breast epithelia and breast cancer cells by interferon-gamma and tumor necrosis factor-alpha. J Cell Biochem 86, 759-772 https://doi.org/10.1002/jcb.10261
  61. Levitin F, Stern O, Weiss M et al (2005) The MUC1 SEA module is a self-cleaving domain. J Biol Chem 280, 33374-33386 https://doi.org/10.1074/jbc.M506047200
  62. Zhang L, Vlad A, Milcarek C and Finn OJ (2013) Human mucin MUC1 RNA undergoes different types of alternative splicing resulting in multiple isoforms. Cancer Immunol Immunother 62, 423-435 https://doi.org/10.1007/s00262-012-1325-2
  63. Li Y, Bharti A, Chen D, Gong J and Kufe D (1998) Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin. Mol Cell Biol 18, 7216-7224 https://doi.org/10.1128/MCB.18.12.7216
  64. Wei X, Xu H and Kufe D (2005) Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell 7, 167-178 https://doi.org/10.1016/j.ccr.2005.01.008
  65. Ahmad R, Raina D, Joshi MD et al (2009) MUC1-C oncoprotein functions as a direct activator of the nuclear factor-kappaB p65 transcription factor. Cancer Res 69, 7013-7021 https://doi.org/10.1158/0008-5472.CAN-09-0523
  66. Ahmad R, Rajabi H, Kosugi M et al (2011) MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop. Sci Signal 4, ra9 https://doi.org/10.1126/scisignal.2001426
  67. Huang L, Ren J, Chen D, Li Y, Kharbanda S and Kufe D (2003) MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation. Cancer Biol Ther 2, 702-706
  68. Wen Y, Caffrey TC, Wheelock MJ, Johnson KR and Hollingsworth MA (2003) Nuclear association of the cytoplasmic tail of MUC1 and beta-catenin. J Biol Chem 278, 38029-38039 https://doi.org/10.1074/jbc.M304333200
  69. Wei X, Xu H and Kufe D (2006) MUC1 oncoprotein stabilizes and activates estrogen receptor alpha. Mol Cell 21, 295-305 https://doi.org/10.1016/j.molcel.2005.11.030
  70. Pelaseyed T and Hansson GC (2020) Membrane mucins of the intestine at a glance. J Cell Sci 133
  71. Shanmugam C, Jhala NC, Katkoori VR et al (2010) Prognostic value of mucin 4 expression in colorectal adenocarcinomas. Cancer 116, 3577-3586 https://doi.org/10.1002/cncr.25095
  72. Peignon G, Durand A, Cacheux W et al (2011) Complex interplay between beta-catenin signalling and Notch effectors in intestinal tumorigenesis. Gut 60, 166-176 https://doi.org/10.1136/gut.2009.204719
  73. Carraway KL 3rd, Rossi EA, Komatsu M et al (1999) An intramembrane modulator of the ErbB2 receptor tyrosine kinase that potentiates neuregulin signaling. J Biol Chem 274, 5263-5266 https://doi.org/10.1074/jbc.274.9.5263
  74. Govindarajan B and Gipson IK (2010) Membrane-tethered mucins have multiple functions on the ocular surface. Exp Eye Res 90, 655-663 https://doi.org/10.1016/j.exer.2010.02.014
  75. Haridas D, Ponnusamy MP, Chugh S, Lakshmanan I, Seshacharyulu P and Batra SK (2014) MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB J 28, 4183-4199 https://doi.org/10.1096/fj.14-257352
  76. Gipson IK, Spurr-Michaud S, Tisdale A and Menon BB (2014) Comparison of the transmembrane mucins MUC1 and MUC16 in epithelial barrier function. PLoS One 9, e100393 https://doi.org/10.1371/journal.pone.0100393
  77. Aithal A, Rauth S, Kshirsagar P et al (2018) MUC16 as a novel target for cancer therapy. Expert Opin Ther Targets 22, 675-686 https://doi.org/10.1080/14728222.2018.1498845
  78. Kim N, Hong Y, Kwon D and Yoon S (2013) Somatic mutaome profile in human cancer tissues. Genomics Inform 11, 239-244 https://doi.org/10.5808/GI.2013.11.4.239
  79. Das S, Rachagani S, Torres-Gonzalez MP et al (2015) Carboxyl-terminal domain of MUC16 imparts tumorigenic and metastatic functions through nuclear translocation of JAK2 to pancreatic cancer cells. Oncotarget 6, 5772-5787 https://doi.org/10.18632/oncotarget.3308
  80. Giannakouros P, Matte I, Rancourt C and Piche A (2015) Transformation of NIH3T3 mouse fibroblast cells by MUC16 mucin (CA125) is driven by its cytoplasmic tail. Int J Oncol 46, 91-98 https://doi.org/10.3892/ijo.2014.2707
  81. Hattrup CL and Gendler SJ (2008) Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol 70, 431-457 https://doi.org/10.1146/annurev.physiol.70.113006.100659
  82. Belisle JA, Gubbels JA, Raphael CA et al (2007) Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125). Immunology 122, 418-429 https://doi.org/10.1111/j.1365-2567.2007.02660.x
  83. Belisle JA, Horibata S, Jennifer GA et al (2010) Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes. Mol Cancer 9, 118 https://doi.org/10.1186/1476-4598-9-118
  84. Felder M, Kapur A, Gonzalez-Bosquet J et al (2014) MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress. Mol Cancer 13, 129 https://doi.org/10.1186/1476-4598-13-129
  85. Rump A, Morikawa Y, Tanaka M et al (2004) Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. J Biol Chem 279, 9190-9198 https://doi.org/10.1074/jbc.M312372200
  86. Gubbels JA, Belisle J, Onda M et al (2006) Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol Cancer 5, 50 https://doi.org/10.1186/1476-4598-5-50
  87. Chen SH, Hung WC, Wang P, Paul C and Konstantopoulos K (2013) Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Sci Rep 3, 1870 https://doi.org/10.1038/srep01870
  88. Komatsu M, Arango ME and Carraway KL (2002) Synthesis and secretion of Muc4/sialomucin complex: implication of intracellular proteolysis. Biochem J 368, 41-48 https://doi.org/10.1042/bj20020862
  89. Albrecht H and Carraway KL 3rd (2011) MUC1 and MUC4: switching the emphasis from large to small. Cancer Biother Radiopharm 26, 261-271 https://doi.org/10.1089/cbr.2011.1017
  90. Boivin M, Lane D, Piche A and Rancourt C (2009) CA125 (MUC16) tumor antigen selectively modulates the sensitivity of ovarian cancer cells to genotoxic drug-induced apoptosis. Gynecol Oncol 115, 407-413 https://doi.org/10.1016/j.ygyno.2009.08.007
  91. Comamala M, Pinard M, Theriault C et al (2011) Downregulation of cell surface CA125/MUC16 induces epithelial-to-mesenchymal transition and restores EGFR signalling in NIH:OVCAR3 ovarian carcinoma cells. Br J Cancer 104, 989-999 https://doi.org/10.1038/bjc.2011.34
  92. Reinartz S, Failer S, Schuell T and Wagner U (2012) CA125 (MUC16) gene silencing suppresses growth properties of ovarian and breast cancer cells. Eur J Cancer 48, 1558-1569 https://doi.org/10.1016/j.ejca.2011.07.004
  93. Theriault C, Pinard M, Comamala M et al (2011) MUC16 (CA125) regulates epithelial ovarian cancer cell growth, tumorigenesis and metastasis. Gynecol Oncol 121, 434-443 https://doi.org/10.1016/j.ygyno.2011.02.020
  94. Snyder LC, Astsaturov I and Weiner LM (2005) Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. Clin Colorectal Cancer 5 Suppl 2, S71-80 https://doi.org/10.3816/CCC.2005.s.010
  95. Vincenzi B, Zoccoli A, Pantano F, Venditti O and Galluzzo S (2010) Cetuximab: from bench to bedside. Curr Cancer Drug Targets 10, 80-95 https://doi.org/10.2174/156800910790980241
  96. Ling YH, Li T, Yuan Z, Haigentz M Jr, Weber TK and Perez-Soler R (2007) Erlotinib, an effective epidermal growth factor receptor tyrosine kinase inhibitor, induces p27KIP1 up-regulation and nuclear translocation in association with cell growth inhibition and G1/S phase arrest in human non-small-cell lung cancer cell lines. Mol Pharmacol 72, 248-258 https://doi.org/10.1124/mol.107.034827
  97. Yano S, Kondo K, Yamaguchi M et al (2003) Distribution and function of EGFR in human tissue and the effect of EGFR tyrosine kinase inhibition. Anticancer Res 23, 3639-3650
  98. Sipples R (2006) Common side effects of anti-EGFR therapy: acneform rash. Semin Oncol Nurs 22, 28-34 https://doi.org/10.1016/j.soncn.2006.01.013
  99. Yin L, Li Y, Ren J, Kuwahara H and Kufe D (2003) Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress. J Biol Chem 278, 35458-35464 https://doi.org/10.1074/jbc.M301987200
  100. Cherrin C, Haskell K, Howell B et al (2010) An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo. Cancer Biol Ther 9, 493-503 https://doi.org/10.4161/cbt.9.7.11100
  101. Yap TA, Yan L, Patnaik A et al (2011) First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29, 4688-4695 https://doi.org/10.1200/JCO.2011.35.5263
  102. Kazazi-Hyseni F, Beijnen JH and Schellens JH (2010) Bevacizumab. Oncologist 15, 819-825 https://doi.org/10.1634/theoncologist.2009-0317
  103. Stacker SA and Achen MG (2013) The VEGF signaling pathway in cancer: the road ahead. Chin J Cancer 32, 297-302 https://doi.org/10.5732/cjc.012.10319
  104. Wood JP, Smith AJ, Bowman KJ, Thomas AL and Jones GD (2015) Comet assay measures of DNA damage as biomarkers of irinotecan response in colorectal cancer in vitro and in vivo. Cancer Med 4, 1309-1321 https://doi.org/10.1002/cam4.477
  105. Dankort D, Filenova E, Collado M, Serrano M, Jones K and McMahon M (2007) A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21, 379-384 https://doi.org/10.1101/gad.1516407
  106. DuPage M, Dooley AL and Jacks T (2009) Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat Protoc 4, 1064-1072 https://doi.org/10.1038/nprot.2009.95
  107. Xu Y and Her C (2015) Inhibition of topoisomerase (DNA) I (TOP1): DNA damage repair and anticancer therapy. Biomolecules 5, 1652-1670 https://doi.org/10.3390/biom5031652
  108. George J, Lim JS, Jang SJ et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47-53 https://doi.org/10.1038/nature14664