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Neuregulin Signaling in the Tumor Microenvironment

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Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1270))

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Abstract

Neuregulins, members of the largest subclass of growth factors of the epidermal growth factor family, mediate a myriad of cellular functions including survival, proliferation, and differentiation in normal tissues through binding to receptor tyrosine kinases of the ErbB family. However, aberrant neuregulin signaling in the tumor microenvironment is increasingly recognized as a key player in initiation and malignant progression of human cancers. In this chapter, we focus on the role of neuregulin signaling in the hallmarks of cancer, including cancer initiation and development, metastasis, as well as therapeutic resistance. Moreover, role of neuregulin signaling in the regulation of tumor microenvironment and targeting of neuregulin signaling in cancer from the therapeutic perspective are also briefly discussed.

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References

  1. Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1(1):46–54

    Article  CAS  Google Scholar 

  2. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–774

    CAS  Google Scholar 

  3. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21(3):309–322

    Article  CAS  Google Scholar 

  4. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19(11):1423–1437

    Article  CAS  Google Scholar 

  5. Montero JC, Rodriguez-Barrueco R, Ocana A, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A (2008) Neuregulins and cancer. Clin Cancer Res 14(11):3237–3241

    Article  CAS  Google Scholar 

  6. Seroogy KB, Dickerson JW, Cassella SN, Zhang-Auberson L (2013) Neuregulins. In: Handbook of biologically active peptides. Elsevier Academic Press, Amsterdam, pp 1633–1638

    Chapter  Google Scholar 

  7. Stove C, Bracke M (2004) Roles for neuregulins in human cancer. Clin Exp Metastasis 21(8):665–684

    Article  CAS  Google Scholar 

  8. Breuleux M (2007) Role of heregulin in human cancer. Cell Mol Life Sci 64(18):2358–2377

    Article  CAS  Google Scholar 

  9. Kawakami H, Yonesaka K (2016) HER3 and its ligand, heregulin, as targets for cancer therapy. Recent Pat Anticancer Drug Discov 11(3):267–274

    Article  CAS  Google Scholar 

  10. Jones MR, Lim H, Shen Y, Pleasance E, Ch’ng C, Reisle C, Leelakumari S, Zhao C, Yip S, Ho J, Zhong E, Ng T, Ionescu D, Schaeffer DF, Mungall AJ, Mungall KL, Zhao Y, Moore RA, Ma Y, Chia S, Ho C, Renouf DJ, Gelmon K, Jones SJM, Marra MA, Laskin J (2017) Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer. Ann Oncol 28(12):3092–3097

    Article  CAS  Google Scholar 

  11. Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284(1):14–30

    Article  CAS  Google Scholar 

  12. Esper RM, Pankonin MS, Loeb JA (2006) Neuregulins: versatile growth and differentiation factors in nervous system development and human disease. Brain Res Rev 51(2):161–175

    Article  CAS  Google Scholar 

  13. Wen D, Peles E, Cupples R, Suggs SV, Bacus SS, Luo Y, Trail G, Hu S, Silbiger SM, Levy RB (1992) Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell 69(3):559–572

    Article  CAS  Google Scholar 

  14. Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD (1993) ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 72(5):801–815

    Article  CAS  Google Scholar 

  15. Marchionni MA, Goodearl AD, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M, Danehy F, Misumi D, Sudhalter J, Kobayashi K, Wroblewski D, Lynch C, Baldassare M, Hiles I, Davis JB, Hsuan JJ, Totty NF, Otsu M, McBurney RN, Waterfield MD, Stroobant P, Gwynne D (1993) Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 362(2618):312–318

    Article  CAS  Google Scholar 

  16. Ho WH, Armanini MP, Nuijens A, Phillips HS, Osheroff PL (1995) Sensory and motor neuron-derived factor. A novel heregulin variant highly expressed in sensory and motor neurons. J Biol Chem 270(24):14523–14532

    Article  CAS  Google Scholar 

  17. Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Levy RB, Yarden Y (1992) Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell 69(1):205–216

    Article  CAS  Google Scholar 

  18. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD (1992) Identification of heregulin, a specific activator of p185erbB2. Science 256(5060):1205–1210

    Article  CAS  Google Scholar 

  19. Carraway KL, Sliwkowski MX, Akita R, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC, Cerione RA (1994) The erbB3 gene product is a receptor for heregulin. J Biol Chem 269(19):14303–14306

    CAS  Google Scholar 

  20. Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D (1994) ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem 269(40):25226–25233

    CAS  Google Scholar 

  21. Carraway KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C (1997) Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 387(6632):512–516

    Article  CAS  Google Scholar 

  22. Chang H, Riese DJ, Gilbert W, Stern DF, McMahan UJ (1997) Ligands for ErbB-family receptors encoded by a neuregulin-like gene. Nature 387(6632):509–512

    Article  CAS  Google Scholar 

  23. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ (1997) Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci U S A 94(18):9562–9567

    Article  CAS  Google Scholar 

  24. Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC, Yarden Y (1999) Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 18(17):2681–2689

    Article  CAS  Google Scholar 

  25. Watanabe E, Maeda N, Matsui F, Kushima Y, Noda M, Oohira A (1995) Neuroglycan C, a novel membrane-spanning chondroitin sulfate proteoglycan that is restricted to the brain. J Biol Chem 270(45):26876–26882

    Article  CAS  Google Scholar 

  26. Kinugasa Y, Ishiguro H, Tokita Y, Oohira A, Ohmoto H, Higashiyama S (2004) Neuroglycan C, a novel member of the neuregulin family. Biochem Biophys Res Commun 321(4):1045–1049

    Article  CAS  Google Scholar 

  27. Uchida T, Wada K, Akamatsu T, Yonezawa M, Noguchi H, Mizoguchi A, Kasuga M, Sakamoto C (1999) A novel epidermal growth factor-like molecule containing two follistatin modules stimulates tyrosine phosphorylation of erbB-4 in MKN28. Biochem Biophys Res Commun 266(2):593–602

    Article  CAS  Google Scholar 

  28. Ring HZ, Chang H, Guilbot A, Brice A, LeGuern E, Francke U (1999) The human neuregulin-2 (NRG2) gene: cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-tooth disease linked to 5q. Hum Genet 104(4):326–332

    Article  CAS  Google Scholar 

  29. Busfield SJ, Michnick DA, Chickering TW, Revett TL, Ma J, Woolf EA, Comrack CA, Dussault BJ, Woolf J, Goodearl AD, Gearing DP (1997) Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus. Mol Cell Biol 17(7):4007–4014

    Article  CAS  Google Scholar 

  30. Higashiyama S, Horikawa M, Yamada K, Ichino N, Nakano N, Nakagawa T, Miyagawa J, Matsushita N, Nagatsu T, Taniguchi N, Ishiguro H (1997) A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4. J Biochem 122(3):675–680

    Article  CAS  Google Scholar 

  31. Gizatullin RZ, Muravenko OV, Al-Amin AN, Wang F, Protopopov AI, Kashuba VI, Zelenin AV, Zabarovsky ER (2000) Human NRG3 gene Map position 10q22-q23. Chromosom Res 8(6):560

    Article  CAS  Google Scholar 

  32. Memon AA, Sorensen BS, Melgard P, Fokdal L, Thykjaer T, Nexo E (2004) Expression of HER3, HER4 and their ligand heregulin-4 is associated with better survival in bladder cancer patients. Br J Cancer 91(12):2034–2041

    Article  CAS  Google Scholar 

  33. Hayes NV, Blackburn E, Smart LV, Boyle MM, Russell GA, Frost TM, Morgan BJ, Baines AJ, Gullick WJ (2007) Identification and characterization of novel spliced variants of neuregulin 4 in prostate cancer. Clin Cancer Res 13(11):3147–3155

    Article  CAS  Google Scholar 

  34. Montero JC, Yuste L, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A (2000) Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci 16(5):631–648

    Article  CAS  Google Scholar 

  35. Shirakabe K, Wakatsuki S, Kurisaki T, Fujisawa-Sehara A (2001) Roles of Meltrin beta/ADAM19 in the processing of neuregulin. J Biol Chem 276(12):9352–9358

    Article  CAS  Google Scholar 

  36. Fleck D, Voss M, Brankatschk B, Giudici C, Hampel H, Schwenk B, Edbauer D, Fukumori A, Steiner H, Kremmer E, Haug-Kröper M, Rossner MJ, Fluhrer R, Willem M, Haass C (2016) Proteolytic processing of Neuregulin 1 type III by three intramembrane-cleaving proteases. J Biol Chem 291(1):318–333

    Article  CAS  Google Scholar 

  37. Willem M (2016) Proteolytic processing of Neuregulin-1. Brain Res Bull 126(Pt 2):178–182

    Article  CAS  Google Scholar 

  38. Zhou BB, Peyton M, He B, Liu C, Girard L, Caudler E, Lo Y, Baribaud F, Mikami I, Reguart N, Yang G, Li Y, Yao W, Vaddi K, Gazdar AF, Friedman SM, Jablons DM, Newton RC, Fridman JS, Minna JD, Scherle PA (2006) Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell 10(1):39–50

    Article  CAS  Google Scholar 

  39. Montero JC, Rodriguez-Barrueco R, Yuste L, Juanes PP, Borges J, Esparis-Ogando A, Pandiella A (2007) The extracellular linker of pro-Neuregulin-alpha2c is required for efficient sorting and juxtacrine function. Mol Biol Cell 18(2):380–393

    Article  CAS  Google Scholar 

  40. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2(2):127–137

    Article  CAS  Google Scholar 

  41. Carpenter G (2003) ErbB-4: mechanism of action and biology. Exp Cell Res 284(1):66–77

    Article  CAS  Google Scholar 

  42. Citri A, Skaria KB, Yarden Y (2003) The deaf and the dumb: the biology of ErbB-2 and ErbB-3. Exp Cell Res 284(1):54–65

    Article  CAS  Google Scholar 

  43. Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12(8):553–563

    Article  CAS  Google Scholar 

  44. Arteaga CL, Engelman JA (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25(3):282–303

    Article  CAS  Google Scholar 

  45. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Leahy DJ (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421(6924):756–760

    Article  CAS  Google Scholar 

  46. Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Kofler M, Jorissen RN, Nice EC, Burgess AW, Ward CW (2003) The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 11(2):495–505

    Article  CAS  Google Scholar 

  47. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA (2010) ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci U S A 107(17):7692–7697

    Article  CAS  Google Scholar 

  48. Schulze WX, Deng L, Mann M (2005) Phosphotyrosine interactome of the ErbB-receptor kinase family. Mol Syst Biol 1:2005.0008

    Article  CAS  Google Scholar 

  49. Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19(13):3159–3167

    Article  CAS  Google Scholar 

  50. DeFazio A, Chiew YE, Sini RL, Janes PW, Sutherland RL (2000) Expression of c-erbB receptors, heregulin and oestrogen receptor in human breast cell lines. Int J Cancer 87(4):487–498

    Article  CAS  Google Scholar 

  51. Bieche I, Onody P, Tozlu S, Driouch K, Vidaud M, Lidereau R (2003) Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer 106(5):758–765

    Article  CAS  Google Scholar 

  52. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 100(15):8933–8938

    Article  CAS  Google Scholar 

  53. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM (2008) A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 68(14):5878–5887

    Article  CAS  Google Scholar 

  54. Liu B, Ordonez-Ercan D, Fan Z, Huang X, Edgerton SM, Yang X, Thor AD (2009) Estrogenic promotion of ErbB2 tyrosine kinase activity in mammary tumor cells requires activation of ErbB3 signaling. Mol Cancer Res 7(11):1882–1892

    CAS  Google Scholar 

  55. Liu B, Ordonez-Ercan D, Fan Z, Edgerton SM, Yang X, Thor AD (2007) Down-regulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer 120(9):1874–1882

    Article  CAS  Google Scholar 

  56. Wang S, Huang X, Lee C-K, Liu B (2010) Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene 29(29):4225–4236

    Article  CAS  Google Scholar 

  57. Buonanno A, Fischbach GD (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol 11(3):287–296

    Article  CAS  Google Scholar 

  58. Yang Y, Spitzer E, Meyer D, Sachs M, Niemann C, Hartmann G, Weidner KM, Birchmeier C, Birchmeier W (1995) Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland. J Cell Biol 131(1):215–226

    Article  CAS  Google Scholar 

  59. Kogata N, Zvelebil M, Howard BA (2013) Neuregulin 3 and erbb signalling networks in embryonic mammary gland development. J Mammary Gland Biol Neoplasia 18(2):149–154

    Article  Google Scholar 

  60. Kramer R, Bucay N, Kane DJ, Martin LE, Tarpley JE, Theill LE (1996) Neuregulins with an Ig-like domain are essential for mouse myocardial and neuronal development. Proc Natl Acad Sci U S A 93(10):4833–4838

    Article  CAS  Google Scholar 

  61. Patel NV, Acarregui MJ, Snyder JM, Klein JM, Sliwkowski MX, Kern JA (2000) Neuregulin-1 and human epidermal growth factor receptors 2 and 3 play a role in human lung development in vitro. Am J Respir Cell Mol Biol 22(4):432–440

    Article  CAS  Google Scholar 

  62. Kim D, Chi S, Lee KH, Rhee S, Kwon YK, Chung CH, Kwon H, Kang MS (1999) Neuregulin stimulates myogenic differentiation in an autocrine manner. J Biol Chem 274(22):15395–15400

    Article  CAS  Google Scholar 

  63. Noguchi H, Sakamoto C, Wada K, Akamatsu T, Uchida T, Tatsuguchi A, Matsui H, Fukui H, Fujimori T, Kasuga M (1999) Expression of heregulin alpha, erbB2, and erbB3 and their influences on proliferation of gastric epithelial cells. Gastroenterology 117(5):1119–1127

    Article  CAS  Google Scholar 

  64. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354

    Article  CAS  Google Scholar 

  65. Hynes NE, MacDonald G (2009) ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 21(2):177–184

    Article  CAS  Google Scholar 

  66. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):67–70

    Article  Google Scholar 

  67. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134

    Article  CAS  Google Scholar 

  68. Witsch E, Sela M, Yarden Y (2010) Roles for growth factors in cancer progression. Physiology (Bethesda) 25(2):85–101

    CAS  Google Scholar 

  69. Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, Weinberg RA (1984) The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312(5994):513–516

    Article  CAS  Google Scholar 

  70. Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD (1984) Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307(5951):521–527

    Article  CAS  Google Scholar 

  71. Andrechek ER, Hardy WR, Siegel PM, Rudnicki MA, Cardiff RD, Muller WJ (2000) Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc Natl Acad Sci U S A 97(7):3444–3449

    Article  CAS  Google Scholar 

  72. Finkle D, Quan ZR, Asghari V, Kloss J, Ghaboosi N, Mai E, Wong WL, Hollingshead P, Schwall R, Koeppen H, Erickson S (2004) HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin Cancer Res 10(7):2499–2511

    Article  CAS  Google Scholar 

  73. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  Google Scholar 

  74. Thor AD, Schwartz LH, Koerner FC, Edgerton SM, Skates SJ, Yin S, McKenzie SJ, Panicali DL, Marks PJ, Fingert HJ, Wood WC (1989) Analysis of c-erbB-2 expression in breast carcinomas with clinical follow-up. Cancer Res 49(24 Pt 1):7147–7152

    CAS  Google Scholar 

  75. Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70

    Article  CAS  Google Scholar 

  76. Sugawa N, Ekstrand AJ, James CD, Collins VP (1990) Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci U S A 87(21):8602–8606

    Article  CAS  Google Scholar 

  77. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139

    Article  CAS  Google Scholar 

  78. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500

    Article  CAS  Google Scholar 

  79. Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, Chaudhuri S, Pujara K, Guillory J, Edgar KA, Janakiraman V, Scholz RP, Bowman KK, Lorenzo M, Li H, Wu J, Yuan W, Peters BA, Kan Z, Stinson J, Mak M, Modrusan Z, Eigenbrot C, Firestein R, Stern HM, Rajalingam K, Schaefer G, Merchant MA, Sliwkowski MX, de Sauvage FJ, Seshagiri S (2013) Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23(5):603–617

    Article  CAS  Google Scholar 

  80. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216):1069–1075

    Article  CAS  Google Scholar 

  81. Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41(10):1127–1132

    Article  CAS  Google Scholar 

  82. Krane IM, Leder P (1996) NDF/heregulin induces persistence of terminal end buds and adenocarcinomas in the mammary glands of transgenic mice. Oncogene 12(8):1781–1788

    CAS  Google Scholar 

  83. Aguilar Z, Akita RW, Finn RS, Ramos BL, Pegram MD, Kabbinavar FF, Pietras RJ, Pisacane P, Sliwkowski MX, Slamon DJ (1999) Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells. Oncogene 18(44):6050–6062

    Article  CAS  Google Scholar 

  84. Li Q, Ahmed S, Loeb JA (2004) Development of an autocrine neuregulin signaling loop with malignant transformation of human breast epithelial cells. Cancer Res 64(19):7078–7085

    Article  CAS  Google Scholar 

  85. Atlas E, Cardillo M, Mehmi I, Zahedkargaran H, Tang C, Lupu R (2003) Heregulin is sufficient for the promotion of tumorigenicity and metastasis of breast cancer cells in vivo. Mol Cancer Res 1(3):165–175

    CAS  Google Scholar 

  86. Schmitt M, Walker MP, Richards RG, Bocchinfuso WP, Fukuda T, Medina D, Kittrell FS, Korach KS, DiAugustine RP (2006) Expression of heregulin by mouse mammary tumor cells: role in activation of ErbB receptors. Mol Carcinog 45(7):490–505

    Article  CAS  Google Scholar 

  87. Richman J, Dowsett M (2019) Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat Rev Clin Oncol 16(5):296–311

    Article  CAS  Google Scholar 

  88. Carroll JS, Hickey TE, Tarulli GA, Williams M, Tilley WD (2017) Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer 17(1):54–64

    Article  CAS  Google Scholar 

  89. Tang CK, Perez C, Grunt T, Waibel C, Cho C, Lupu R (1996) Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells. Cancer Res 56(14):3350–3358

    CAS  Google Scholar 

  90. Balañá ME, Lupu R, Labriola L, Charreau EH, Elizalde PV (1999) Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas. Oncogene 18(46):6370–6379

    Article  Google Scholar 

  91. Labriola L, Salatino M, Proietti CJ, Pecci A, Coso OA, Kornblihtt AR, Charreau EH, Elizalde PV (2003) Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. Mol Cell Biol 23(3):1095–1111

    Article  CAS  Google Scholar 

  92. Proietti CJ, Rosemblit C, Beguelin W, Rivas MA, Díaz Flaqué MC, Charreau EH, Schillaci R, Elizalde PV (2009) Activation of Stat3 by heregulin/ErbB-2 through the co-option of progesterone receptor signaling drives breast cancer growth. Mol Cell Biol 29(5):1249–1265

    Article  CAS  Google Scholar 

  93. Weinstein EJ, Leder P (2000) The extracellular region of heregulin is sufficient to promote mammary gland proliferation and tumorigenesis but not apoptosis. Cancer Res 60(14):3856–3861

    CAS  Google Scholar 

  94. Centa A, Rodríguez-Barrueco R, Montero JC, Pandiella A (2018) The immunoglobulin-like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation. Mol Oncol 12(7):1061–1076

    Article  CAS  Google Scholar 

  95. De Iuliis F, Salerno G, Taglieri L, Lanza R, Cardelli P, Scarpa S (2017) Circulating neuregulin-1 and galectin-3 can be prognostic markers in breast cancer. Int J Biol Markers 32(3):e333–e336

    Article  CAS  Google Scholar 

  96. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  Google Scholar 

  97. Morgensztern D, Ng SH, Gao F, Govindan R (2010) Trends in stage distribution for patients with non-small cell lung cancer: a National Cancer Database survey. J Thorac Oncol 5(1):29–33

    Article  Google Scholar 

  98. Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK (2014) Non- small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14(8):535–546

    Article  CAS  Google Scholar 

  99. Skoulidis F, Heymach JV (2019) Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer 19(9):495–509

    Article  CAS  Google Scholar 

  100. Altorki NK, Markowitz GJ, Gao D, Port JL, Saxena A, Stiles B, McGraw T, Mittal V (2019) The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer 19(1):9–31

    Article  CAS  Google Scholar 

  101. Cancer Genome Atlas Research Network (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511(7511):543–550

    Article  CAS  Google Scholar 

  102. Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431(7008):525–526

    Article  CAS  Google Scholar 

  103. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E et al (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150(6):1107–1120

    Article  CAS  Google Scholar 

  104. Sithanandam G, Anderson LM (2008) The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther 15(7):413–448

    Article  CAS  Google Scholar 

  105. al Moustafa AE, Alaoui-Jamali M, Paterson J, O’Connor-McCourt M (1999) Expression of P185erbB-2, P160erbB-3, P180erbB-4, and heregulin alpha in human normal bronchial epithelial and lung cancer cell lines. Anticancer Res 19(1A):481–486

    Google Scholar 

  106. Gollamudi M, Nethery D, Liu J, Kern JA (2004) Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines. Lung Cancer 43(2):135–143

    Article  Google Scholar 

  107. Fernandez-Cuesta L, Plenker D, Osada H, Sun R, Menon R, Leenders F et al (2014) CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4(4):415–422

    Article  CAS  Google Scholar 

  108. Duruisseaux M, McLeer-Florin A, Antoine M, Alavizadeh S, Poulot V, Lacave R, Rabbe N, Cadranel J, Wislez M (2016) NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma. Cancer Med 5(12):3579–3585

    Article  CAS  Google Scholar 

  109. Trombetta D, Graziano P, Scarpa A, Sparaneo A, Rossi G, Rossi A et al (2018) Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression. Oncotarget 9(11):9661–9671

    Article  Google Scholar 

  110. Jonna S, Feldman RA, Swensen J, Gatalica Z, Korn WM, Borghaei H, Ma PC, Nieva JJ, Spira AI, Vanderwalde AM, Wozniak AJ, Kim ES, Liu SV (2019) Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res 25(16):4966–4972

    Article  CAS  Google Scholar 

  111. Pan Y, Zhang Y, Ye T, Zhao Y, Gao Z, Yuan H, Zheng D, Zheng S, Li H, Li Y, Jin Y, Sun Y, Chen H (2019) Detection of novel NRG1, EGFR and MET fusions in lung adenocarcinomas in the Chinese population. J Thorac Oncol 14(11):2003–2008

    Article  CAS  Google Scholar 

  112. van Lengerich B, Agnew C, Puchner EM, Huang B, Jura N (2017) EGF and NRG induce phosphorylation of HER3/ERBB3 by EGFR using distinct oligomeric mechanisms. Proc Natl Acad Sci U S A 114(14):E2836–E2845

    Article  CAS  Google Scholar 

  113. Trombetta D, Rossi A, Fabrizio FP, Sparaneo A, Graziano P, Fazio VM, Muscarella LA (2017) NRG1-ErbB lost in translation: a new paradigm for lung cancer? Curr Med Chem 24(38):4213–4228

    Article  CAS  Google Scholar 

  114. Sakai K, Mori S, Kawamoto T, Taniguchi S, Kobori O, Morioka Y, Kuroki T, Kano K (1986) Expression of epidermal growth factor receptors on normal human gastric epithelia and gastric carcinomas. J Natl Cancer Inst 77(5):1047–1052

    CAS  Google Scholar 

  115. De Vita F, Giuliani F, Silvestris N, Catalano G, Ciardiello F, Orditura M (2010) Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target. Cancer Treat Rev 36(Suppl 3):S11–S15

    Article  Google Scholar 

  116. Yun S, Koh J, Nam SK, Park JO, Lee SM, Lee K, Lee KS, Ahn SH, Park DJ, Kim HH, Choe G, Kim WH, Lee HS (2018) Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients. Gastric Cancer 21(2):225–236

    Article  CAS  Google Scholar 

  117. Hayashi M, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J, Kawano T, Sugihara K (2008) High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res 14(23):7843–7849

    Article  CAS  Google Scholar 

  118. Han ME, Kim HJ, Shin DH, Hwang SH, Kang CD, Oh SO (2015) Overexpression of NRG1 promotes progression of gastric cancer by regulating the self-renewal of cancer stem cells. J Gastroenterol 50(6):645–656

    Article  CAS  Google Scholar 

  119. Khelwatty SA, Essapen S, Seddon AM, Modjtahedi H (2013) Prognostic significance and targeting of HER family in colorectal cancer. Front Biosci (Landmark Ed) 18:394–421

    Article  CAS  Google Scholar 

  120. Maurer CA, Friess H, Kretschmann B, Zimmermann A, Stauffer A, Baer HU, Korc M, Büchler MW (1998) Increased expression of erbB3 in colorectal cancer is associated with concomitant increase in the level of erbB2. Hum Pathol 29(8):771–777

    Article  CAS  Google Scholar 

  121. Lee JC, Wang ST, Chow NH, Yang HB (2002) Investigation of the prognostic value of coexpressed erbB family members for the survival of colorectal cancer patients after curative surgery. Eur J Cancer 38(8):1065–1071

    Article  CAS  Google Scholar 

  122. Grivas PD, Antonacopoulou A, Tzelepi V, Sotiropoulou-Bonikou G, Kefalopoulou Z, Papavassiliou AG, Kalofonos H (2007) HER-3 in colorectal tumourigenesis: from mRNA levels through protein status to clinicopathologic relationships. Eur J Cancer 43(17):2602–2611

    Article  CAS  Google Scholar 

  123. Beji A, Horst D, Engel J, Kirchner T, Ullrich A (2012) Towards the prognostic significance and therapeutic potential of HER3 receptor tyrosine kinase in human colon cancer. Clin Cancer Res 18(4):956–968

    Article  CAS  Google Scholar 

  124. Venkateswarlu S, Dawson DM, St Clair P, Gupta A, Willson JK, Brattain MG (2002) Autocrine heregulin generates growth factor independence and blocks apoptosis in colon cancer cells. Oncogene 21(1):78–86

    Article  CAS  Google Scholar 

  125. De Boeck A, Pauwels P, Hensen K, Rummens JL, Westbroek W, Hendrix A, Maynard D, Denys H, Lambein K, Braems G, Gespach C, Bracke M, De Wever O (2013) Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. Gut 62(4):550–560

    Article  CAS  Google Scholar 

  126. Yonezawa M, Wada K, Tatsuguchi A, Akamatsu T, Gudis K, Seo T, Mitsui K, Nagata K, Tanaka S, Fujimori S, Sakamoto C (2009) Heregulin-induced VEGF expression via the ErbB3 signaling pathway in colon cancer. Digestion 80(4):215–225

    Article  CAS  Google Scholar 

  127. Mitsui K, Yonezawa M, Tatsuguchi A, Shinji S, Gudis K, Tanaka S, Fujimori S, Sakamoto C (2014) Localization of phosphorylated ErbB1-4 and heregulin in colorectal cancer. BMC Cancer 14:863

    Article  CAS  Google Scholar 

  128. Guo Y, Duan Z, Jia Y, Ren C, Lv J, Guo P, Zhao W, Wang B, Zhang S, Li Y, Li Z (2018) HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer. Oncol Lett 15(5):6629–6635

    Google Scholar 

  129. Makohon-Moore A, Iacobuzio-Donahue CA (2016) Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer 16(9):553–565

    Article  CAS  Google Scholar 

  130. Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK et al (2013) Recent progress in pancreatic cancer. CA Cancer J Clin 63(5):318–348

    Article  Google Scholar 

  131. Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P et al (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540):495–501

    Article  CAS  Google Scholar 

  132. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL et al (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491(7424):399–405

    Article  CAS  Google Scholar 

  133. Yachida S, White CM, Naito Y, Zhong Y, Brosnan JA, Macgregor-Das AM et al (2012) Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res 18(22):6339–6347

    Article  CAS  Google Scholar 

  134. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11(11):761–774

    Article  CAS  Google Scholar 

  135. Friess H, Wang L, Zhu Z, Gerber R, Schroder M, Fukuda A et al (1999) Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas. Ann Surg 230(6):767–774

    Article  CAS  Google Scholar 

  136. Heining C, Horak P, Uhrig S, Codo PL, Klink B, Hutter B et al (2018) NRG1 fusions in KRAS wild-type pancreatic cancer. Cancer Discov 8(9):1087–1095

    Article  CAS  Google Scholar 

  137. Jones MR, Williamson LM, Topham JT, Lee MKC, Goytain A, Ho J et al (2019) NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma. Clin Cancer Res 25(15):4674–4681

    CAS  Google Scholar 

  138. Aguirre AJ (2019) Oncogenic NRG1 fusions: a new Hope for targeted therapy in pancreatic cancer. Clin Cancer Res 25(15):4589–4591

    Article  CAS  Google Scholar 

  139. Westphal M, Meima L, Szonyi E, Lofgren J, Meissner H, Hamel W, Nikolics K, Sliwkowski MX (1997) Heregulins and the ErbB-2/3/4 receptors in gliomas. J Neuro-Oncol 35(3):335–346

    Article  CAS  Google Scholar 

  140. von Achenbach C, Weller M, Szabo E (2018) Epidermal growth factor receptor and ligand family expression and activity in glioblastoma. J Neurochem 147(1):99–109

    Article  CAS  Google Scholar 

  141. Hansen MR, Linthicum FH (2004) Expression of neuregulin and activation of erbB receptors in vestibular schwannomas: possible autocrine loop stimulation. Otol Neurotol 25(2):155–159

    Article  Google Scholar 

  142. Stonecypher MS, Chaudhury AR, Byer SJ, Carroll SL (2006) Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis. J Neuropathol Exp Neurol 65(2):162–175

    Article  CAS  Google Scholar 

  143. Lapointe S, Perry A, Butowski NA (2018) Primary brain tumours in adults. Lancet 392(10145):432–446

    Article  Google Scholar 

  144. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507

    Article  CAS  Google Scholar 

  145. Liu B, Wang L, Shen LL, Shen MZ, Guo XD, Wang T, Liang QC, Wang C, Zheng J, Li Y, Jia LT, Zhang H, Gao GD (2012) RNAi-mediated inhibition of presenilin 2 inhibits glioma cell growth and invasion and is involved in the regulation of Nrg1/ErbB signaling. Neuro-Oncology 14(8):994–1006

    Article  CAS  Google Scholar 

  146. Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6(4):259–269

    Article  CAS  Google Scholar 

  147. Yin F, Zhang JN, Wang SW, Zhou CH, Zhao MM, Fan WH, Fan M, Liu S (2015) MiR-125a-3p regulates glioma apoptosis and invasion by regulating Nrg1. PLoS One 10(1):e0116759

    Article  Google Scholar 

  148. Srinivasan R, Benton E, McCormick F, Thomas H, Gullick WJ (1999) Expression of the c-erbB-3/HER-3 and cerbB-4/HER-4 growth factor receptors and their ligands, neuregulin-1 a, neuregulin-1 h, and betacellulin, in normal endometrium and endometrial cancer. Clin Cancer Res 5(10):2877–2883

    CAS  Google Scholar 

  149. Hsieh SY, He JR, Hsu CY, Chen WJ, Bera R, Lin KY, Shih TC, Yu MC, Lin YJ, Chang CJ, Weng WH, Huang SF (2011) Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma. Hepatology 53(2):504–516

    Article  CAS  Google Scholar 

  150. Gilbertson RJ, Clifford SC, MacMeekin W, Meekin W, Wright C, Perry RH, Kelly P, Pearson AD, Lunec J (1998) Expression of the ErbB-neuregulin signaling network during human cerebellar development: implications for the biology of medulloblastoma. Cancer Res 58(17):3932–3941

    CAS  Google Scholar 

  151. Buac K, Xu M, Cronin J, Weeraratna AT, Hewitt SM, Pavan WJ (2009) NRG1/ERBB3 signaling in melanocyte development and melanoma: inhibition of differentiation and promotion of proliferation. Pigment Cell Melanoma Res 22(6):773–784

    Article  CAS  Google Scholar 

  152. Gilmour LM, Macleod KG, McCaig A, Sewell JM, Gullick WJ, Smyth JF, Langdon SP (2002) Neuregulin expression, function, and signaling in human ovarian cancer cells. Clin Cancer Res 8(12):3933–3942

    CAS  Google Scholar 

  153. Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, Moustafa Z, Thomas RK, Greulich H, Schinzel A, Zaghlul S, Batt D, Ettenberg S, Meyerson M, Schoeberl B, Kung AL, Hahn WC, Drapkin R, Livingston DM, Liu JF (2010) An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17(3):298–310

    Article  CAS  Google Scholar 

  154. Kolb A, Kleeff J, Arnold N, Giese NA, Giese T, Korc M, Friess H (2007) Expression and differential signaling of heregulins in pancreatic cancer cells. Int J Cancer 120(3):514–523

    Article  CAS  Google Scholar 

  155. Fluge O, Akslen LA, Haugen DR, Varhaug JE, Lillehaug JR (2000) Expression of heregulins and associations with the ErbB family of tyrosine kinase receptors in papillary thyroid carcinomas. Int J Cancer 87(6):763–770

    Article  CAS  Google Scholar 

  156. He H, Li W, Liyanarachchi S, Wang Y, Yu L, Genutis LK, Maharry S, Phay JE, Shen R, Brock P, de la Chapelle A (2018) The role of NRG1 in the predisposition to papillary thyroid carcinoma. J Clin Endocrinol Metab 103(4):1369–1379

    Article  CAS  Google Scholar 

  157. Leung HY, Weston J, Gullick WJ, Williams G (1997) A potential autocrine loop between heregulin-a and erbB-3 receptor in human prostatic adenocarcinoma. Br J Urol 79(2):212–216

    Article  CAS  Google Scholar 

  158. Shames DS, Carbon J, Walter K, Jubb AM, Kozlowski C, Januario T, Do A, Fu L, Xiao Y, Raja R, Jiang B, Malekafzali A, Stern H, Settleman J, Wilson TR, Hampton GM, Yauch RL, Pirzkall A, Amler LC (2013) High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck. PLoS One 8(2):e56765

    Article  CAS  Google Scholar 

  159. Hijazi MM, Young PE, Dougherty MK, Bressette DS, Cao TT, Pierce JH, Wong LM, Alimandi M, King CR (1998) NRG-3 in human breast cancers: activation of multiple erbB family proteins. Int J Omcol 13(5):1061–1067

    CAS  Google Scholar 

  160. Turajlic S, Swanton C (2016) Metastasis as an evolutionary process. Science 352(6282):169–175

    Article  CAS  Google Scholar 

  161. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564

    Article  CAS  Google Scholar 

  162. Valastyan S, Weinberg RA (2011) Tumor metastasis: molecular insights and evolving paradigms. Cell 147(2):275–292

    Article  CAS  Google Scholar 

  163. Sethi N, Kang Y (2011) Unravelling the complexity of metastasis-molecular understanding and targeted therapies. Nat Rev Cancer 11(10):735–748

    Article  CAS  Google Scholar 

  164. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273

    Article  CAS  Google Scholar 

  165. Massagué J (2008) TGFβ in cancer. Cell 134(2):215–230

    Article  CAS  Google Scholar 

  166. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142

    Article  CAS  Google Scholar 

  167. Ritch PA, Carroll SL, Sontheimer H (2003) Neuregulin-1 enhances motility and migration of human astrocytic glioma cells. J Biol Chem 278(23):20971–20978

    Article  CAS  Google Scholar 

  168. Zhao WJ, Schachner M (2013) Neuregulin 1 enhances cell adhesion molecule l1 expression in human glioma cells and promotes their migration as a function of malignancy. J Neuropathol Exp Neurol 72(3):244–255

    Article  CAS  Google Scholar 

  169. Shi DM, Li LX, Bian XY, Shi XJ, Lu LL, Zhou HX, Pan TJ, Zhou J, Fan J, Wu WZ (2018) miR-296-5p suppresses EMT of hepatocellular carcinoma via attenuating NRG1/ERBB2/ERBB3 signaling. J Exp Clin Cancer Res 37(1):294

    Article  CAS  Google Scholar 

  170. Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14(9):611–622

    Article  CAS  Google Scholar 

  171. Hüsemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmüller G, Klein CA (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13(1):58–68

    Article  CAS  Google Scholar 

  172. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148(1–2):349–361

    Article  CAS  Google Scholar 

  173. Hosseini H, Obradović MMS, Hoffmann M, Harper KL, Sosa MS, Werner-Klein M et al (2016) Early dissemination seeds metastasis in breast cancer. Nature 540(7634):552–558

    Article  CAS  Google Scholar 

  174. Harper KL, Sosa MS, Entenberg D, Hosseini H, Cheung JF, Nobre R et al (2016) Mechanism of early dissemination and metastasis in Her2+ mammary cancer. Nature 540(7634):588–592

    Article  CAS  Google Scholar 

  175. Seoane S, Montero JC, Ocaña A, Pandiella A (2016) Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node. Oncogene 35(21):2756–2765

    Article  CAS  Google Scholar 

  176. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4(1):71–78

    Article  CAS  Google Scholar 

  177. Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631

    Article  CAS  Google Scholar 

  178. Linde N, Casanova-Acebes M, Sosa MS, Mortha A, Rahman A, Farias E, Harper K, Tardio E, Reyes Torres I, Jones J, Condeelis J, Merad M, Aguirre-Ghiso JA (2018) Macrophages orchestrate breast cancer early dissemination and metastasis. Nat Commun 9(1):21

    Article  CAS  Google Scholar 

  179. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225

    Article  CAS  Google Scholar 

  180. Wyckoff J, Wang W, Lin EY, Wang Y, Pixley F, Stanley ER, Graf T, Pollard JW, Segall J, Condeelis J (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64(19):7022–7029

    Article  CAS  Google Scholar 

  181. Lewis CE, Harney AS, Pollard JW (2016) The multifaceted role of perivascular macrophages in tumors. Cancer Cell 30(1):18–25

    Article  CAS  Google Scholar 

  182. Broz ML, Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, Barczak A, Rosenblum MD, Daud A, Barber DL, Amigorena S, Van’t Veer LJ, Sperling AI, Wolf DM, Krummel MF (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26(5):638–652

    Article  CAS  Google Scholar 

  183. Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P, Qian BZ, Oktay MH, Pollard JW, Jones JG, Condeelis JS (2015) Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov 5(9):932–943

    Article  CAS  Google Scholar 

  184. Leung E, Xue A, Wang Y, Rougerie P, Sharma VP, Eddy R, Cox D, Condeelis J (2017) Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway. Oncogene 36(19):2680–2692

    Article  CAS  Google Scholar 

  185. Robinson BD, Sica GL, Liu YF, Rohan TE, Gertler FB, Condeelis JS, Jones JG (2009) Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res 15(7):2433–2441

    Article  CAS  Google Scholar 

  186. Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS (2009) Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res 69(24):9498–9506

    Article  CAS  Google Scholar 

  187. Arwert EN, Harney AS, Entenberg D, Wang Y, Sahai E, Pollard JW, Condeelis JS (2018) A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation. Cell Rep 23(5):1239–1248

    Article  CAS  Google Scholar 

  188. Hernandez L, Smirnova T, Kedrin D, Wyckoff J, Zhu L, Stanley ER, Cox D, Muller WJ, Pollard JW, Van Rooijen N, Segall JE (2009) The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin beta1 and CXCL12. Cancer Res 69(7):3221–3227

    Article  CAS  Google Scholar 

  189. Lopez-Haber C, Barrio-Real L, Casado-Medrano V, Kazanietz MG (2016) Heregulin/ErbB3 signaling enhances CXCR4-driven Rac1 activation and breast cancer cell motility via hypoxia-inducible factor 1α. Mol Cell Biol 36(15):2011–2026

    Article  CAS  Google Scholar 

  190. Meurette O, Mehlen P (2018) Notch signaling in the tumor microenvironment. Cancer Cell 34(4):536–548

    Article  CAS  Google Scholar 

  191. Sethi N, Dai X, Winter CG, Kang Y (2011) Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19(2):192–205

    Article  CAS  Google Scholar 

  192. Cabrera RM, Mao SPH, Surve CR, Condeelis JS, Segall JE (2018) A novel neuregulin-jagged1 paracrine loop in breast cancer transendothelial migration. Breast Cancer Res 20(1):24

    Article  CAS  Google Scholar 

  193. Dhanasekaran SM, Balbin OA, Chen G, Nadal E, Kalyana-Sundaram S, Pan J et al (2014) Transcriptome metaanalysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nat Commun 5:5893

    Article  CAS  Google Scholar 

  194. Haskins JW, Nguyen DX, Stern DF (2014) Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration. Sci Signal 7(355):ra116

    Article  CAS  Google Scholar 

  195. Sun M, Behrens C, Feng L, Ozburn N, Tang X, Yin G, Komaki R, Varella-Garcia M, Hong WK, Aldape KD, Wistuba II (2009) HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors. Clin Cancer Res 15(15):4829–4837

    Article  CAS  Google Scholar 

  196. Nakaoku T, Tsuta K, Ichikawa H, Shiraishi K, Sakamoto H, Enari M et al (2014) Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 20(12):3087–3093

    Article  CAS  Google Scholar 

  197. Shin DH, Lee D, Hong DW, Hong SH, Hwang JA, Lee BI, You HJ, Lee GK, Kim IH, Lee YS, Han JY (2016) Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung. Oncotarget 7(43):69450–69465

    Article  Google Scholar 

  198. Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205(2):275–292

    Article  CAS  Google Scholar 

  199. Swanton C (2012) Intratumor heterogeneity: evolution through space and time. Cancer Res 72(19):4875–4882

    Article  CAS  Google Scholar 

  200. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13(10):714–726

    Article  CAS  Google Scholar 

  201. Colvin ME, Sasaki JC, Tran NL (1999) Chemical factors in the action of phosphoramidic mustard alkylating anticancer drugs: roles for computational chemistry. Curr Pharm Des 5(8):645–663

    CAS  Google Scholar 

  202. Okada H, Mak TW (2004) Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4(8):592–603

    Article  CAS  Google Scholar 

  203. Kartal-Yandim M, Adan-Gokbulut A, Baran Y (2016) Molecular mechanisms of drug resistance and its reversal in cancer. Crit Rev Biotechnol 36(4):716–726

    Article  CAS  Google Scholar 

  204. Lee Y, Ma J, Lyu H, Huang J, Kim A, Liu B (2014) Role of erbB3 receptors in cancer therapeutic resistance. Acta Biochim Biophys Sin Shanghai 46(3):190–198

    Article  CAS  Google Scholar 

  205. Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, Schmidt M, Mills GB, Mendelsohn J, Fan Z (2003) HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22(21):3205–3212

    Article  CAS  Google Scholar 

  206. Stagg J (2008) Mesenchymal stem cells in cancer. Stem Cell Rev 4(2):119–124

    Article  Google Scholar 

  207. Ridge SM, Sullivan FJ, Glynn SA (2017) Mesenchymal stem cells: key players in cancer progression. Mol Cancer 16(1):–31

    Google Scholar 

  208. McMillin DW, Negri JM, Mitsiades CS (2013) The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Disc 12(3):217–228

    Article  CAS  Google Scholar 

  209. Shi Y, Du L, Lin L, Wang Y (2017) Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat Rev Drug Disc 16(1):35–52

    Article  CAS  Google Scholar 

  210. Chen J, Ren Q, Cai Y, Lin T, Zuo W, Wang J, Lin R, Zhu L, Wang P, Dong H, Zhao H, Huang L, Fu Y, Yang S, Tan J, Lan X, Wang S (2018) Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1. Biochem Biophys Res Commun 501(1):212–219

    Article  CAS  Google Scholar 

  211. Bezler M, Hengstler JG, Ullrich A (2012) Inhibition of doxorubicin-induced HER3-PI3K-AKT signalling enhances apoptosis of ovarian cancer cells. Mol Oncol 6(5):516–529

    Article  CAS  Google Scholar 

  212. Weinstein IB (2000) Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 21(5):857–864

    Article  CAS  Google Scholar 

  213. Weinstein IB (2002) Cancer. Addiction to oncogenes–the Achilles heal of cancer. Science 297(5578):63–64

    Article  CAS  Google Scholar 

  214. Sharma SV, Settleman J (2007) Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev 21(24):3214–3231

    Article  CAS  Google Scholar 

  215. Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II et al (2014) Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311(19):1998–2006

    Article  CAS  Google Scholar 

  216. Bivona TG, Doebele RC (2016) A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med 22(5):472–478

    Article  CAS  Google Scholar 

  217. Rotow J, Bivona TG (2017) Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer 17(11):637–658

    Article  CAS  Google Scholar 

  218. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3(75):75ra26

    Article  Google Scholar 

  219. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C et al (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361(10):958–967

    Article  CAS  Google Scholar 

  220. de Bono JS, Ashworth A (2010) Translating cancer research into targeted therapeutics. Nature 467(7315):543–549

    Article  CAS  Google Scholar 

  221. Vlacich G, Coffey RJ (2011) Resistance to EGFR-targeted therapy: a family affair. Cancer Cell 20(4):423–425

    Article  CAS  Google Scholar 

  222. Nguyen KS, Kobayashi S, Costa DB (2009) Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer 10(4):281–289

    Article  CAS  Google Scholar 

  223. Kruser TJ, Wheeler DL (2010) Mechanisms of resistance to HER family targeting antibodies. Exp Cell Res 316(7):1083–1100

    Article  CAS  Google Scholar 

  224. Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J (2012) Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487(7408):505–509

    Article  CAS  Google Scholar 

  225. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316(5827):1039–1043

    Article  CAS  Google Scholar 

  226. Sato Y, Yashiro M, Takakura N (2013) Heregulin induces resistance to lapatinib-mediated growth inhibition of HER2-amplified cancer cells. Cancer Sci 104(12):1618–1625

    Article  CAS  Google Scholar 

  227. Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Jänne PA (2011) Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med 3(99):99ra86

    Article  CAS  Google Scholar 

  228. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566

    Article  CAS  Google Scholar 

  229. Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ et al (2008) EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 14(13):4275–4283

    Article  CAS  Google Scholar 

  230. Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703

    Article  CAS  Google Scholar 

  231. Yamada T, Takeuchi S, Nakade J, Kita K, Nakagawa T, Nanjo S, Nakamura T, Matsumoto K, Soda M, Mano H, Uenaka T, Yano S (2012) Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. Clin Cancer Res 18(13):3592–3602

    Article  CAS  Google Scholar 

  232. Kato K, Imamura F, Inoue M (2015) Analysis of ERBB ligand-induced resistance mechanism to crizotinib by primary culture of lung adenocarcinoma with EML4-ALK fusion gene. J Thorac Oncol 10(3):527–530

    Article  CAS  Google Scholar 

  233. Cheng H, Terai M, Kageyama K, Ozaki S, McCue PA, Sato T, Aplin AE (2015) Paracrine effect of NRG1 and HGF drives resistance to MEK inhibitors in metastatic uveal melanoma. Cancer Res 75(13):2737–2748

    Article  CAS  Google Scholar 

  234. Rimawi MF, Schiff R, Osborne CK (2015) Targeting HER2 for the treatment of breast cancer. Annu Rev Med 66:111–128

    Article  CAS  Google Scholar 

  235. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792

    Article  CAS  Google Scholar 

  236. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726

    Article  CAS  Google Scholar 

  237. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684

    Article  CAS  Google Scholar 

  238. Hudis CA (2007) Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med 357(1):39–51

    Article  CAS  Google Scholar 

  239. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743

    Article  CAS  Google Scholar 

  240. Hurvitz SA, Hu Y, O’Brien N, Finn RS (2013) Current approaches and future directions in the treatment of HER2-positive breast cancer. Cancer Treat Rev 39(3):219–229

    Article  CAS  Google Scholar 

  241. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127

    Article  CAS  Google Scholar 

  242. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68(22):9221–9230

    Article  CAS  Google Scholar 

  243. Huang X, Gao L, Wang S, McManaman JL, Thor AD, Yang X, Esteva FJ, Liu B (2010) Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-I receptor in breast cancer cells resistant to herceptin. Cancer Res 70(3):1204–1214

    Article  CAS  Google Scholar 

  244. Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, Arteaga CL (2007) Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res 13(16):4909–4919

    Article  CAS  Google Scholar 

  245. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15(5):429–440

    Article  CAS  Google Scholar 

  246. Ebbing EA, Medema JP, Damhofer H, Meijer SL, Krishnadath KK, van Berge Henegouwen MI, Bijlsma MF, van Laarhoven HW (2016) ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3. Oncotarget 7(9):10243–10254

    Article  Google Scholar 

  247. Watson SS, Dane M, Chin K, Tatarova Z, Liu M, Liby T, Thompson W, Smith R, Nederlof M, Bucher E, Kilburn D, Whitman M, Sudar D, Mills GB, Heiser LM, Jonas O, Gray JW, Korkola JE (2018) Microenvironment-mediated mechanisms of resistance to HER2 inhibitors differ between HER2+ breast cancer subtypes. Cell Syst 6(3):329–342

    Article  CAS  Google Scholar 

  248. Crist SB, Ghajar CM (2018) Friends with benefits: microenvironmental NRG1β and HGF mediate HER2-targeted resistance in L-HER2+ and HER2E breast cancer. Cell Syst 6(3):68–270

    Google Scholar 

  249. Hart CD, Migliaccio I, Malorni L, Guarducci C, Biganzoli L, Di Leo A (2015) Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat Rev Clin Oncol 12(9):541–552

    Article  Google Scholar 

  250. Reinert T, de Paula B, Shafaee MN, Souza PH, Ellis MJ, Bines J (2018) Endocrine therapy for ER-positive/HER2-negative metastatic breast cancer. Chin Clin Oncol 7(3):25

    Article  Google Scholar 

  251. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R (2015) ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol 12(10):573–583

    Article  CAS  Google Scholar 

  252. Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233–247

    Article  CAS  Google Scholar 

  253. Newby JC, Johnston SR, Smith IE, Dowsett M (1997) Expression of epidermal growth factor receptor and c-erbB2 during the development of tamoxifen resistance in human breast cancer. Clin Cancer Res 3(9):1643–1651

    CAS  Google Scholar 

  254. Tovey S, Dunne B, Witton CJ, Forsyth A, Cooke TG, Bartlett JM (2005) Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Clin Cancer Res 11(13):4835–4842

    Article  CAS  Google Scholar 

  255. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51

    Article  CAS  Google Scholar 

  256. Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61

    Article  CAS  Google Scholar 

  257. Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley FJ, Stanley ER, Segall JE, Condeelis JS (2005) Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res 65(12):5278–5283

    Article  CAS  Google Scholar 

  258. Jobling P, Pundavela J, Oliveira SM, Roselli S, Walker MM, Hondermarck H (2015) Nerve-cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res 75(9):1777–1781

    Article  CAS  Google Scholar 

  259. Marchesi F, Piemonti L, Mantovani A, Allavena P (2010) Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev 21(1):77–82

    Article  CAS  Google Scholar 

  260. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D (2009) Perineural invasion in cancer: a review of the literature. Cancer 115(15):3379–3391

    Article  CAS  Google Scholar 

  261. Bapat AA, Hostetter G, Von Hoff DD, Han H (2011) Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer 11(10):695–707

    Article  CAS  Google Scholar 

  262. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341(6142):1236361

    Article  Google Scholar 

  263. Zhao CM, Hayakawa Y, Kodama Y, Muthupalani S, Westphalen CB, Andersen GT et al (2014) Denervation suppresses gastric tumorigenesis. Sci Transl Med 6(250):250ra115

    Article  CAS  Google Scholar 

  264. Hayakawa Y, Sakitani K, Konishi M, Asfaha S, Niikura R, Tomita H et al (2017) Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 31(1):21–34

    Article  CAS  Google Scholar 

  265. Boilly B, Faulkner S, Jobling P, Hondermarck H (2017) Nerve dependence: from regeneration to cancer. Cancer Cell 31(3):342–354

    Article  CAS  Google Scholar 

  266. Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9(6):437–452

    Article  CAS  Google Scholar 

  267. Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK (2015) Sympathetic nervous system regulation of the tumour microenvironment. Nat Rev Cancer 15(9):563–572

    Article  CAS  Google Scholar 

  268. Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410

    Article  CAS  Google Scholar 

  269. Baeriswyl V, Christofori G (2009) The angiogenic switch in carcinogenesis. Semin Cancer Biol 19(5):329–337

    Article  CAS  Google Scholar 

  270. Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2(10):795–803

    Article  CAS  Google Scholar 

  271. De Palma M, Biziato D, Petrova TV (2017) Microenvironmental regulation of tumour angiogenesis. Nat RevCancer 17(8):457–474

    Article  CAS  Google Scholar 

  272. Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146(6):873–887

    Article  CAS  Google Scholar 

  273. Odiete O, Hill MF, Sawyer DB (2012) Neuregulin in cardiovascular development and disease. Circ Res 111(10):1376–1385

    Article  CAS  Google Scholar 

  274. Cote GM, Miller TA, Lebrasseur NK, Kuramochi Y, Sawyer DB (2005) Neuregulin-1alpha and beta isoform expression in cardiac microvascular endothelial cells and function in cardiac myocytes in vitro. Exp Cell Res 311(1):135–146

    Article  CAS  Google Scholar 

  275. Nugroho DB, Ikeda K, Barinda AJ, Wardhana DA, Yagi K, Miyata K, Oike Y, Hirata KI, Emoto N (2018) Neuregulin-4 is an angiogenic factor that is critically involved in the maintenance of adipose tissue vasculature. Biochem Biophys Res Commun 503(1):378–384

    Article  CAS  Google Scholar 

  276. Rak J, Yu JL, Klement G, Kerbel RS (2000) Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Invest Dermatol Symp Proc 5:24–33

    Article  CAS  Google Scholar 

  277. Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbelet RS (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151(6):1523–1530

    CAS  Google Scholar 

  278. Yen L, You X, Al Moustafa A, Batist G, Hynes NE, Mader S et al (2000) Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 19:3460–3469

    Article  CAS  Google Scholar 

  279. Xiong S, Grijalva R, Zhang L, Nguyen NT, Pisters PW, Pollock RE, Yu D (2001) Up-regulation of vascular endothelial growth factor in breast cancer cells by the heregulin-beta1-activated p38 signaling pathway enhances endothelial cell migration. Cancer Res 61(4):1727–1732

    CAS  Google Scholar 

  280. Tsai P, Shiah S, Lin L, Wu C, Kuo M (2003) Up-regulation of vascular endothelial growth factor C in breast cancer cells by Heregulin-Beta 1: a critical role of p38/nuclear factor-kappa B signaling pathway. J Biol Chem 278(8):5750–5759

    Article  CAS  Google Scholar 

  281. Yonezawa M, Wada K, Tatsuguchi A, Akamatsu T, Gudis K, Seo T et al (2009) Heregulin-induced VEGF expression via the ErbB3 signaling pathway in colon cancer. Digestion 80(4):215–225

    Article  CAS  Google Scholar 

  282. Chen Z, Xu XH, Hu J (2016) Role of pericytes in angiogenesis: focus on cancer angiogenesis and anti-angiogenic therapy. Neoplasma 63(2):173–182

    CAS  Google Scholar 

  283. Teichert M, Milde L, Holm A, Stanicek L, Gengenbacher N, Savant S et al (2017) Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nat Commun 8:16106

    Article  CAS  Google Scholar 

  284. Bjarnegård M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A et al (2004) Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131(8):1847–1857

    Article  CAS  Google Scholar 

  285. Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T (2016) What is a pericyte? J Cereb Blood Flow Metab 36(2):451–455

    Article  CAS  Google Scholar 

  286. Birbrair A, Zhang T, Wang ZM, Messi ML, Olson JD, Mintz A, Delbono O (2014) Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol 307(1):C25–C38

    Article  CAS  Google Scholar 

  287. LaGory E, Giaccia A (2016) The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol 18(4):356–365

    Article  CAS  Google Scholar 

  288. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21(12):3995–4004

    Article  CAS  Google Scholar 

  289. Li YM, Zhou BP, Deng J, Pan Y, Hay N, Hung MC (2005) A hypoxia-independent hypoxia-inducible factor-1 activation pathway induced by phosphatidylinositol-3 kinase/Akt in HER2 overexpressing cells. Cancer Res 65(8):3257–3263

    Article  CAS  Google Scholar 

  290. Xu MJ, Johnson DE, Grandis JR (2017) EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev 36(3):463–473

    Article  Google Scholar 

  291. Kümler I, Tuxen MK, Nielsen DL (2014) A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev 40(2):259–270

    Article  CAS  Google Scholar 

  292. Tebbutt N, Pedersen MW, Johns TG (2013) Targeting the ERBB family in cancer: couples therapy. Nat Rev Cancer 13(9):663–673

    Article  CAS  Google Scholar 

  293. Gala K, Chandarlapaty S (2014) Molecular pathways: HER3 targeted therapy. Clin Cancer Res 20(6):1410–1416

    Article  CAS  Google Scholar 

  294. Schoeberl B, Pace EA, Fitzgerald JB, Harms BD, Xu L, Nie L et al (2009) Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis. Sci Signal 2(77):ra31

    Article  CAS  Google Scholar 

  295. Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S et al (2013) An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res 73(19):6024–6035

    Article  CAS  Google Scholar 

  296. Garrett JT, Sutton CR, Kuba MG, Cook RS, Arteagam CL (2013) Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function. Clin Cancer Res 19(3):610–619

    Article  CAS  Google Scholar 

  297. Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, Wong KK (2010) An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res 70(6):2485–2494

    Article  CAS  Google Scholar 

  298. Wang S, Huang J, Lyu H, Cai B, Yang X, Li F, Tan J, Edgerton SM, Thor AD, Lee CK, Liu B (2013) Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer. Breast Cancer Res 15(5):R101

    Article  Google Scholar 

  299. Huang J, Wang S, Lyu H, Cai B, Yang X, Wang J, Liu B (2013) The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol Cancer 12(1):134

    Article  CAS  Google Scholar 

  300. Watanabe S, Yonesaka K, Tanizaki J, Nonagase Y, Takegawa N, Haratani K, Kawakami H, Hayashi H, Takeda M, Tsurutani J, Nakagawa K (2019) Targeting of the HER2/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer. Cancer Med 8(3):1258–1268

    Article  CAS  Google Scholar 

  301. Zhu Y, Choi SH, Shah K (2015) Multifunctional receptor-targeting antibodies for cancer therapy. Lancet Oncol 16(15):e543–e554

    Article  CAS  Google Scholar 

  302. Schaefer G, Haber L, Crocker LM, Shia S, Shao L, Dowbenko D et al (2011) A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell 20(4):472–486

    Article  CAS  Google Scholar 

  303. Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, Sliwkowski MX, Harari PM (2013) Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res 73(2):824–833

    Article  CAS  Google Scholar 

  304. Forster MD, Dillon MT, Kocsis J, Remenár É, Pajkos G, Rolland F, Greenberg J, Harrington KJ (2019) Patritumab or placebo, with cetuximab plus platinum therapy in recurrent or metastatic squamous cell carcinoma of the head and neck: a randomised phase II study. Eur J Cancer 123:36–47

    Article  CAS  Google Scholar 

  305. Dillon MT, Grove L, Newbold KL, Shaw H, Brown NF, Mendell J, Chen S, Beckman RA, Jennings A, Ricamara M, Greenberg J, Forster M, Harrington KJ (2019) Patritumab with cetuximab plus platinum-containing therapy in recurrent or metastatic squamous cell carcinoma of the head and neck: an open-label, phase Ib study. Clin Cancer Res 25(2):487–495

    Article  CAS  Google Scholar 

  306. Liu JF, Ray-Coquard I, Selle F, Poveda AM, Cibula D, Hirte H et al (2016) Randomized phase II trial of seribantumab in combination with paclitaxel in patients with advanced platinum-resistant or -refractory ovarian cancer. J Clin Oncol 34(36):4345–4353

    Article  CAS  Google Scholar 

  307. Abramson VG, Supko JG, Ballinger T, Cleary JM, Hilton JF, Tolaney SM et al (2017) Phase Ib study of safety and pharmacokinetics of the PI3K inhibitor SAR245408 with the HER3-neutralizing human antibody SAR256212 in patients with solid tumors. Clin Cancer Res 23(14):3520–3528

    Article  CAS  Google Scholar 

  308. Schram AM, Iasonos A, Hyman DM (2016) Picking the right patient for human epidermal growth factor receptor 3-targeted therapy in platinum-resistant ovarian cancer. J Clin Oncol 34(36):4312–4314

    Article  CAS  Google Scholar 

  309. Ma J, Lyu H, Huang J, Liu B (2014) Targeting of erbB3 receptor to overcome resistance in cancer treatment. Mol Cancer 13:105

    Article  CAS  Google Scholar 

  310. Wu Y, Zhang Y, Wang M, Li Q, Qu Z, Shi V, Kraft P, Kim S, Gao Y, Pak J, Youngster S, Horak ID, Greenberger LM (2013) Downregulation of HER3 by a novel antisense oligonucleotide, EZN-3920, improves the antitumor activity of EGFR and HER2 tyrosine kinase inhibitors in animal models. Mol Cancer Ther 12(4):427–437

    Article  CAS  Google Scholar 

  311. Jones PA, Issa JP, Baylin S (2016) Targeting the cancer epigenome for therapy. Nat Rev Genet 17(10):630–641

    Article  CAS  Google Scholar 

  312. Morel D, Almouzni G, Soria JC, Postel-Vinay S (2017) Targeting chromatin defects in selected solid tumors based on oncogene addiction, synthetic lethality and epigenetic antagonism. Ann Oncol 28(2):254–269

    Article  CAS  Google Scholar 

  313. Miranda Furtado CL, Dos Santos Luciano MC, Silva Santos RD, Furtado GP, Moraes MO, Pessoa C (2019) Epidrugs: targeting epigenetic marks in cancer treatment. Epigenetics 14(12):1164–1176

    Article  Google Scholar 

  314. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51

    Article  CAS  Google Scholar 

  315. Huang X, Gao L, Wang S, Lee CK, Ordentlich P, Liu B (2009) HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression. Cancer Res 69(21):8403–8411

    Article  CAS  Google Scholar 

  316. Huang X, Wang S, Lee CK, Yang X, Liu B (2011) HDAC inhibitor SNDX-275 enhances efficacy of trastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential to overcome trastuzumab resistance. Cancer Lett 307(1):72–79

    Article  CAS  Google Scholar 

  317. Wang S, Huang J, Lyu H, Lee CK, Tan J, Wang J, Liu B (2013) Functional cooperation of miR-125a, miR-125b, and miR-205 in entinostat-induced downregulation of erbB2/erbB3 and apoptosis in breast cancer cells. Cell Death Dis 4(3):e556

    Article  CAS  Google Scholar 

  318. Lin T, Ren Q, Zuo W, Jia R, Xie L, Lin R, Zhao H, Chen J, Lei Y, Wang P, Dong H, Huang L, Cai J, Peng Y, Yu Z, Tan J, Wang S (2019) Valproic acid exhibits anti-tumor activity selectively against EGFR/ErbB2/ ErbB3-coexpressing pancreatic cancer via induction of ErbB family members-targeting microRNAs. J Exp Clin Cancer Res 38(1):150

    Article  Google Scholar 

  319. Wahdan-Alaswad R, Liu B (2013) “Sister” miRNAs in cancers. Cell Cycle 12(24):3703–3704

    Article  CAS  Google Scholar 

  320. Tsai MS, Shamon-Taylor LA, Mehmi I, Tang CK, Lupu R (2003) Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer. Oncogene 22(5):761–768

    Article  CAS  Google Scholar 

  321. Hegde GV, de la Cruz CC, Chiu C, Alag N, Schaefer G, Crocker L, Ross S, Goldenberg D, Merchant M, Tien J, Shao L, Roth L, Tsai SP, Stawicki S, Jin Z, Wyatt SK, Carano RA, Zheng Y, Sweet-Cordero EA, Wu Y, Jackson EL (2013) Blocking NRG1 and other ligand-mediated Her4 signaling enhances the magnitude and duration of the chemotherapeutic response of non-small cell lung cancer. Sci Transl Med 5(171):171ra18

    Article  CAS  Google Scholar 

  322. Ogier C, Colombo PE, Bousquet C, Canterel-Thouennon L, Sicard P, Garambois V, Thomas G, Gaborit N, Jarlier M, Pirot N, Pugnière M, Vie N, Gongora C, Martineau P, Robert B, Pèlegrin A, Chardès T, Larbouret C (2018) Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer. Cancer Lett 432:227–236

    Article  CAS  Google Scholar 

  323. Rupaimoole R, Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 16(3):203–222

    Article  CAS  Google Scholar 

  324. Fernandez-Cuesta L, Thomas RK (2015) Molecular pathways: targeting NRG1 fusions in lung cancer. Clin Cancer Res 21(9):1989–1994

    Article  CAS  Google Scholar 

  325. Wilson FH, Politi K (2018) ERBB signaling interrupted: targeting ligand-induced pathway activation. Cancer Discov 8(6):676–678

    Article  Google Scholar 

  326. Drilon A, Somwar R, Mangatt BP, Edgren H, Desmeules P, Ruusulehto A et al (2018) Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers. Cancer Discov 8(6):686–695

    Article  CAS  Google Scholar 

  327. Shin DH, Jo JY, Han JY (2018) Dual targeting of ERBB2/ERBB3 for the treatment of SLC3A2-NRG1-mediated lung cancer. Mol Cancer Ther 17(9):2024–2033

    Article  CAS  Google Scholar 

  328. Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13(11):800–812

    Article  CAS  Google Scholar 

  329. Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D et al (2017) Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357(6356):1156–1160

    Article  CAS  Google Scholar 

  330. Raza MH, Gul K, Arshad A, Riaz N, Waheed U, Rauf A, Aldakheel F, Alduraywish S, Rehman MU, Abdullah M, Arshad M (2019) Microbiota in cancer development and treatment. J Cancer Res Clin Oncol 145(1):49–63

    Article  CAS  Google Scholar 

  331. Tsay JJ, Wu BG, Badri MH, Clemente JC, Shen N, Meyn P et al (2018) Airway microbiota is associated with upregulation of the PI3K pathway in lung cancer. Am J Respir Crit Care Med 198(9):1188–1198

    Article  CAS  Google Scholar 

  332. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A (2017) Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4):707–723

    Article  CAS  Google Scholar 

  333. O’Donnell JS, Teng MWL, Smyth MJ (2019) Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol 16(3):151–167

    Article  CAS  Google Scholar 

  334. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13(1):84–88

    Article  CAS  Google Scholar 

  335. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT et al (2016) Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov 6(2):202–216

    Article  CAS  Google Scholar 

  336. Milane L, Singh A, Mattheolabakis G, Suresh M, Amiji MM (2015) Exosome mediated communication within the tumor microenvironment. J Control Release 219:278–294

    Article  CAS  Google Scholar 

  337. Xie X, Nie H, Zhou Y, Lian S, Mei H, Lu Y, Dong H, Li F, Li T, Li B, Wang J, Lin M, Wang C, Shao J, Gao Y, Chen J, Xie F, Jia L (2019) Eliminating blood oncogenic exosomes into the small intestine with aptamer-functionalized nanoparticles. Nat Commun 10(1):5476

    Article  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Bolin Liu at Department of Genetics, Stanley S. Scott Cancer Center, Louisiana State University (LSU) Health Sciences Center, for his critical comments on the manuscript. Work of Shuiliang Wang was supported in part by the National Natural Science Foundation of China No. 81772848 and Joint Funds for the Innovation of Science and Technology from Fujian Province No.2017Y9127.

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Authors and Affiliations

  1. Fujian Provincial Key Laboratory of Transplant Biology, Affiliated Dongfang Hospital, Xiamen University School of Medicine, Fuzhou, Fujian Province, China

    Ruxue Jia, Hu Zhao & Shuiliang Wang

  2. Department of Urology, the 900th Hospital of the Joint Logistics Team, Fujian Medical University, Fuzhou, Fujian Province, China

    Ruxue Jia, Hu Zhao & Shuiliang Wang

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  1. Ruxue Jia
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  2. Hu Zhao
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Correspondence to Shuiliang Wang .

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  1. Department of Radiology, Columbia University Medical Center, New York, NY, USA, Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

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Jia, R., Zhao, H., Wang, S. (2021). Neuregulin Signaling in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1270. Springer, Cham. https://doi.org/10.1007/978-3-030-47189-7_1

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