Contact Normalization or Escape from the Matrix

  • Harini Krishnan
  • Gary S. GoldbergEmail author


Cancer is a complex process that involves interactions between numerous cell types. In many cases, tumor cell expansion is prevented by other cells in the microenvironment. The growth and morphology of genetically transformed cells can be normalized by junctional communication with surrounding nontransformed cells. Tumor cells need to overcome this process, called “contact normalization”, before they can realize their malignant and metastatic potential. Here, we describe some fundamental aspects that underlie contact normalization, and how this information can be used to develop innovative ways to detect and treat many forms of cancer.


Cancer Intercellular junctions Cadherins Connexins Integrins Contact normalization Podoplanin 


  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2013) GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11.
  2. 2.
    Bray F, Guerra Yi M, Parkin DM (2003) The comprehensive cancer monitoring programme in Europe. Eur J Public Health 13(3 Suppl):61–66PubMedCrossRefGoogle Scholar
  3. 3.
    Klein CA (2011) Framework models of tumor dormancy from patient-derived observations. Curr Opin Genet Dev 21(1):42–49. doi: 10.1016/j.gde.2010.10.011 PubMedCrossRefGoogle Scholar
  4. 4.
    Bray F, Ren JS, Masuyer E, Ferlay J (2013) Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132(5):1133–1145. doi: 10.1002/ijc.27711 PubMedCrossRefGoogle Scholar
  5. 5.
    Keleg S, Buchler P, Ludwig R, Buchler MW, Friess H (2003) Invasion and metastasis in pancreatic cancer. Mol Cancer 2:14PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi: 10.1016/j.cell.2011.02.013 PubMedCrossRefGoogle Scholar
  7. 7.
    Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE (2002) Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer 94(2):344–351. doi: 10.1002/cncr.10221 PubMedCrossRefGoogle Scholar
  8. 8.
    Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R, Yeatman TJ (1999) Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet 21(2):187–190. doi: 10.1038/5971 PubMedCrossRefGoogle Scholar
  9. 9.
    Irby RB, Yeatman TJ (2000) Role of Src expression and activation in human cancer. Oncogene 19(49):5636–5642PubMedCrossRefGoogle Scholar
  10. 10.
    Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35. doi: 10.1016/j.cell.2012.03.003 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Singhi AD, Cimino-Mathews A, Jenkins RB, Lan F, Fink SR, Nassar H, Vang R, Fetting JH, Hicks J, Sukumar S, De Marzo AM, Argani P (2012) MYC gene amplification is often acquired in lethal distant breast cancer metastases of unamplified primary tumors. Mod Pathol 25(3):378–387. doi: 10.1038/modpathol.2011.171 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Vita M, Henriksson M (2006) The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 16(4):318–330. doi: 10.1016/j.semcancer.2006.07.015 PubMedCrossRefGoogle Scholar
  13. 13.
    Fernandez-Medarde A, Santos E (2011) Ras in cancer and developmental diseases. Genes Cancer 2(3):344–358. doi: 10.1177/1947601911411084 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Prior IA, Lewis PD, Mattos C (2012) A comprehensive survey of Ras mutations in cancer. Cancer Res 72(10):2457–2467. doi: 10.1158/0008-5472.CAN-11-2612 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Shen Y, Chen CS, Ichikawa H, Goldberg GS (2010) SRC induces podoplanin expression to promote cell migration. J Biol Chem 285(13):9649–9656. doi: 10.1074/jbc.M109.047696 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954. doi: 10.1038/nature00766 PubMedCrossRefGoogle Scholar
  17. 17.
    Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63(7):1454–1457PubMedGoogle Scholar
  18. 18.
    Krishnan H, Ochoa-Alvarez JA, Shen Y, Nevel E, Lakshminarayanan M, Williams MC, Ramirez MI, Miller WT, Goldberg GS (2013) Serines in the intracellular tail of podoplanin (PDPN) regulate cell motility. J Biol Chem 288(17):12215–12221. doi: 10.1074/jbc.C112.446823 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kumar R, Angelini S, Czene K, Sauroja I, Hahka-Kemppinen M, Pyrhonen S, Hemminki K (2003) BRAF mutations in metastatic melanoma: a possible association with clinical outcome. Clin Cancer Res 9(9):3362–3368PubMedGoogle Scholar
  20. 20.
    Maria Pérez-Caro IS-G (2007) BCR-ABL and human cancer. In: Srivastava R (ed) Apoptosis, cell signaling, and human diseases, vol I. Humana Press, pp 3–34. doi: 10.1007/978-1-59745-200-7_1
  21. 21.
    Grande E, Bolos MV, Arriola E (2011) Targeting oncogenic ALK: a promising strategy for cancer treatment. Mol Cancer Ther 10(4):569–579. doi: 10.1158/1535-7163.MCT-10-0615 PubMedCrossRefGoogle Scholar
  22. 22.
    Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24(50):7455–7464. doi: 10.1038/sj.onc.1209085 PubMedCrossRefGoogle Scholar
  23. 23.
    Krishnan H, Miller WT, Goldberg GS (2012) SRC points the way to biomarkers and chemotherapeutic targets. Genes Cancer 3(5–6):426–435. doi: 10.1177/1947601912458583 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Lennartsson J, Ronnstrand L (2012) Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev 92(4):1619–1649. doi: 10.1152/physrev.00046.2011 PubMedCrossRefGoogle Scholar
  25. 25.
    Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94(4):455–459. doi: 10.1038/sj.bjc.6602970 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27(41):5497–5510. doi: 10.1038/onc.2008.245 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Anastas JN, Moon RT (2013) WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13(1):11–26. doi: 10.1038/nrc3419 PubMedCrossRefGoogle Scholar
  28. 28.
    Benhaj K, Akcali KC, Ozturk M (2006) Redundant expression of canonical Wnt ligands in human breast cancer cell lines. Oncol Rep 15(3):701–707PubMedGoogle Scholar
  29. 29.
    Park JK, Song JH, He TC, Nam SW, Lee JY, Park WS (2009) Overexpression of Wnt-2 in colorectal cancers. Neoplasma 56(2):119–123PubMedCrossRefGoogle Scholar
  30. 30.
    Morin PJ (1999) beta-catenin signaling and cancer. Bioessays 21(12):1021–1030, doi:10.1002/(SICI)1521-1878(199912)22:1<1021::AID-BIES6>3.0.CO;2-PPubMedCrossRefGoogle Scholar
  31. 31.
    Polakis P (2000) Wnt signaling and cancer. Genes Dev 14(15):1837–1851PubMedGoogle Scholar
  32. 32.
    Polakis P (2012) Wnt signaling in cancer. Cold Spring Harb Perspect Biol 4(5). doi: 10.1101/cshperspect.a008052
  33. 33.
    Diehl JA (2002) Cycling to cancer with cyclin D1. Cancer Biol Ther 1(3):226–231PubMedCrossRefGoogle Scholar
  34. 34.
    Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11(8):558–572. doi: 10.1038/nrc3090 PubMedCrossRefGoogle Scholar
  35. 35.
    Tai W, Mahato R, Cheng K (2010) The role of HER2 in cancer therapy and targeted drug delivery. J Control Release 146(3):264–275. doi: 10.1016/j.jconrel.2010.04.009 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Iqbal J, Neppalli VT, Wright G, Dave BJ, Horsman DE, Rosenwald A, Lynch J, Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Campo E, Ott G, Muller-Hermelink HK, Delabie J, Jaffe ES, Grogan TM, Connors JM, Vose JM, Armitage JO, Staudt LM, Chan WC (2006) BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol 24(6):961–968. doi: 10.1200/JCO.2005.03.4264 PubMedCrossRefGoogle Scholar
  37. 37.
    Kirkin V, Joos S, Zornig M (2004) The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta 1644(2–3):229–249. doi: 10.1016/j.bbamcr.2003.08.009 PubMedCrossRefGoogle Scholar
  38. 38.
    Koch U, Radtke F (2010) Notch signaling in solid tumors. Curr Top Dev Biol 92:411–455. doi: 10.1016/S0070-2153(10)92013-9 PubMedCrossRefGoogle Scholar
  39. 39.
    Palomero T, Ferrando A (2008) Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-cell acute lymphoblastic leukemias and lymphomas. Clin Cancer Res 14(17):5314–5317. doi: 10.1158/1078-0432.CCR-07-4864 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Gordon GM, Du W (2011) Targeting Rb inactivation in cancers by synthetic lethality. Am J Cancer Res 1(6):773–786PubMedPubMedCentralGoogle Scholar
  41. 41.
    Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE (2010) The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 120(12):4478–4492. doi: 10.1172/JCI44239 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, Han JH, Lowstuter K, Longmate J, Sommer SS, Weitzel JN (2009) Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27(8):1250–1256. doi: 10.1200/JCO.2008.16.6959 PubMedCrossRefGoogle Scholar
  43. 43.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L (2013) Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333–339. doi: 10.1038/nature12634 PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Muller PA, Vousden KH (2014) Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25(3):304–317. doi: 10.1016/j.ccr.2014.01.021 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Georgescu MM (2010) PTEN tumor suppressor network in PI3K-Akt pathway control. Genes Cancer 1(12):1170–1177. doi: 10.1177/1947601911407325 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Petrucelli N, Daly MB, Feldman GL (1993) BRCA1 and BRCA2 hereditary breast and ovarian cancer. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews. University of Washington, SeattleGoogle Scholar
  47. 47.
    Fearnhead NS, Britton MP, Bodmer WF (2001) The ABC of APC. Hum Mol Genet 10(7):721–733PubMedCrossRefGoogle Scholar
  48. 48.
    Fodde R (2002) The APC gene in colorectal cancer. Eur J Cancer 38(7):867–871PubMedCrossRefGoogle Scholar
  49. 49.
    Cremona CA, Behrens A (2014) ATM signalling and cancer. Oncogene 33(26):3351–3360. doi: 10.1038/onc.2013.275 PubMedCrossRefGoogle Scholar
  50. 50.
    Banham AH, Beasley N, Campo E, Fernandez PL, Fidler C, Gatter K, Jones M, Mason DY, Prime JE, Trougouboff P, Wood K, Cordell JL (2001) The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res 61(24):8820–8829PubMedGoogle Scholar
  51. 51.
    Koon HB, Ippolito GC, Banham AH, Tucker PW (2007) FOXP1: a potential therapeutic target in cancer. Expert Opin Ther Targets 11(7):955–965. doi: 10.1517/14728222.11.7.955 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Krohn A, Seidel A, Burkhardt L, Bachmann F, Mader M, Grupp K, Eichenauer T, Becker A, Adam M, Graefen M, Huland H, Kurtz S, Steurer S, Tsourlakis MC, Minner S, Michl U, Schlomm T, Sauter G, Simon R, Sirma H (2013) Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers. J Pathol 231(1):130–141. doi: 10.1002/path.4223 PubMedCrossRefGoogle Scholar
  53. 53.
    Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW (2011) Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 43(9):828–829. doi: 10.1038/ng.903 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Wang X, Haswell JR, Roberts CW (2014) Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer – mechanisms and potential therapeutic insights. Clin Cancer Res 20(1):21–27. doi: 10.1158/1078-0432.CCR-13-0280 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, Zeng T, Senz J, McConechy MK, Anglesio MS, Kalloger SE, Yang W, Heravi-Moussavi A, Giuliany R, Chow C, Fee J, Zayed A, Prentice L, Melnyk N, Turashvili G, Delaney AD, Madore J, Yip S, McPherson AW, Ha G, Bell L, Fereday S, Tam A, Galletta L, Tonin PN, Provencher D, Miller D, Jones SJ, Moore RA, Morin GB, Oloumi A, Boyd N, Aparicio SA, Shih IM, Mes-Masson AM, Bowtell DD, Hirst M, Gilks B, Marra MA, Huntsman DG (2010) ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 363(16):1532–1543. doi: 10.1056/NEJMoa1008433 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Goldstein AM, Tucker MA (2001) Genetic epidemiology of cutaneous melanoma: a global perspective. Arch Dermatol 137(11):1493–1496PubMedCrossRefGoogle Scholar
  57. 57.
    McWilliams RR, Wieben ED, Rabe KG, Pedersen KS, Wu Y, Sicotte H, Petersen GM (2011) Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur J Hum Genet 19(4):472–478. doi: 10.1038/ejhg.2010.198 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kaelin WG Jr (2004) The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 10(18 Pt 2):6290S–6295S. doi: 10.1158/1078-0432.CCR-sup-040025 PubMedCrossRefGoogle Scholar
  59. 59.
    Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22(24):4991–5004. doi: 10.1200/JCO.2004.05.061 PubMedCrossRefGoogle Scholar
  60. 60.
    Goodman RH, Smolik S (2000) CBP/p300 in cell growth, transformation, and development. Genes Dev 14(13):1553–1577PubMedGoogle Scholar
  61. 61.
    Iyer NG, Ozdag H, Caldas C (2004) p300/CBP and cancer. Oncogene 23(24):4225–4231. doi: 10.1038/sj.onc.1207118 PubMedCrossRefGoogle Scholar
  62. 62.
    Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA, Heatley SL, Holmfeldt L, Collins-Underwood JR, Ma J, Buetow KH, Pui CH, Baker SD, Brindle PK, Downing JR (2011) CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471(7337):235–239. doi: 10.1038/nature09727 PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Korsse SE, Peppelenbosch MP, van Veelen W (2013) Targeting LKB1 signaling in cancer. Biochim Biophys Acta 1835(2):194–210. doi: 10.1016/j.bbcan.2012.12.006 PubMedGoogle Scholar
  64. 64.
    Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS, Shaw RJ (2013) LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23(2):143–158. doi: 10.1016/j.ccr.2012.12.008 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Holzel M, Huang S, Koster J, Ora I, Lakeman A, Caron H, Nijkamp W, Xie J, Callens T, Asgharzadeh S, Seeger RC, Messiaen L, Versteeg R, Bernards R (2010) NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome. Cell 142(2):218–229. doi: 10.1016/j.cell.2010.06.004 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Korf BR (2000) Malignancy in neurofibromatosis type 1. Oncologist 5(6):477–485PubMedCrossRefGoogle Scholar
  67. 67.
    Gutmann DH, Sherman L, Seftor L, Haipek C, Hoang Lu K, Hendrix M (1999) Increased expression of the NF2 tumor suppressor gene product, merlin, impairs cell motility, adhesion and spreading. Hum Mol Genet 8(2):267–275PubMedCrossRefGoogle Scholar
  68. 68.
    Xiao GH, Gallagher R, Shetler J, Skele K, Altomare DA, Pestell RG, Jhanwar S, Testa JR (2005) The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression. Mol Cell Biol 25(6):2384–2394. doi: 10.1128/MCB.25.6.2384-2394.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I, Devgan V, Lieb J, Raffoul W, Hohl D, Neel V, Garlick J, Chiorino G, Dotto GP (2007) Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev 21(5):562–577. doi: 10.1101/gad.1484707 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Lobry C, Oh P, Aifantis I (2011) Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think. J Exp Med 208(10):1931–1935. doi: 10.1084/jem.20111855 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Wade M, Wahl GM (2006) c-Myc, genome instability, and tumorigenesis: the devil is in the details. Curr Top Microbiol Immunol 302:169–203PubMedGoogle Scholar
  72. 72.
    Kwon MJ, Shin YK (2011) Epigenetic regulation of cancer-associated genes in ovarian cancer. Int J Mol Sci 12(2):983–1008. doi: 10.3390/ijms12020983 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Han NM, Curley SA, Gallick GE (1996) Differential activation of pp 60(c-src) and pp62(c-yes) in human colorectal carcinoma liver metastases. Clin Cancer Res 2(8):1397–1404PubMedGoogle Scholar
  74. 74.
    Suzuki K, Oneyama C, Kimura H, Tajima S, Okada M (2011) Down-regulation of the tumor suppressor C-terminal Src kinase (Csk)-binding protein (Cbp)/PAG1 is mediated by epigenetic histone modifications via the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K) pathway. J Biol Chem 286(18):15698–15706. doi: 10.1074/jbc.M110.195362 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Herschkowitz JI, He X, Fan C, Perou CM (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 10(5):R75. doi: 10.1186/bcr2142 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2(1):a001008. doi: 10.1101/cshperspect.a001008
  77. 77.
    Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13(1):58–68. doi: 10.1016/j.ccr.2007.12.003 PubMedCrossRefGoogle Scholar
  78. 78.
    Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C, Polzer B, Petronio M, Eils R, Klein CA (2005) Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8(3):227–239. doi: 10.1016/j.ccr.2005.08.003 PubMedCrossRefGoogle Scholar
  79. 79.
    Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3(6):453–458. doi: 10.1038/nrc1098 PubMedCrossRefGoogle Scholar
  80. 80.
    Giugliano FM, Alberti D, Guida G, Palma GD, Iadanza L, Mormile M, Cammarota F, Montanino A, Fulciniti F, Ravo V, Muto P (2013) Non small-cell lung cancer with metastasis to thigh muscle and mandible: two case reports. J Med Case Rep 7(1):98. doi: 10.1186/1752-1947-7-98 PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lee YT, Geer DA (1987) Primary liver cancer: pattern of metastasis. J Surg Oncol 36(1):26–31PubMedCrossRefGoogle Scholar
  82. 82.
    Leong SP, Cady B, Jablons DM, Garcia-Aguilar J, Reintgen D, Jakub J, Pendas S, Duhaime L, Cassell R, Gardner M, Giuliano R, Archie V, Calvin D, Mensha L, Shivers S, Cox C, Werner JA, Kitagawa Y, Kitajima M (2006) Clinical patterns of metastasis. Cancer Metastasis Rev 25(2):221–232. doi: 10.1007/s10555-006-8502-8 PubMedCrossRefGoogle Scholar
  83. 83.
    Berman AT, Thukral AD, Hwang WT, Solin LJ, Vapiwala N (2013) Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment. Clin Breast Cancer 13(2):88–94. doi: 10.1016/j.clbc.2012.11.001 PubMedCrossRefGoogle Scholar
  84. 84.
    Betka J (2001) Distant metastases from lip and oral cavity cancer. ORL J Otorhinolaryngol Relat Spec 63(4):217–221. doi: 10.1159/000055744
  85. 85.
    Noguti J, De Moura CF, De Jesus GP, Da Silva VH, Hossaka TA, Oshima CT, Ribeiro DA (2012) Metastasis from oral cancer: an overview. Cancer Genomics Proteomics 9(5):329–335PubMedGoogle Scholar
  86. 86.
    Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C, Sessa C (2013) Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24(Suppl 6):vi33–vi38. doi: 10.1093/annonc/mdt353
  87. 87.
    Yachida S, Iacobuzio-Donahue CA (2009) The pathology and genetics of metastatic pancreatic cancer. Arch Pathol Lab Med 133(3):413–422. doi: 10.1043/1543-2165-133.3.413 PubMedGoogle Scholar
  88. 88.
    Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, Gasser TC, Mihatsch MJ (2000) Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31(5):578–583PubMedCrossRefGoogle Scholar
  89. 89.
    Viadana E, Bross ID, Pickren JW (1978) An autopsy study of the metastatic patterns of human leukemias. Oncology (Williston Park) 35(2):87–96CrossRefGoogle Scholar
  90. 90.
    Shinagare AB, Ramaiya NH, Jagannathan JP, Fennessy FM, Taplin ME, Van den Abbeele AD (2011) Metastatic pattern of bladder cancer: correlation with the characteristics of the primary tumor. AJR Am J Roentgenol 196(1):117–122. doi: 10.2214/AJR.10.5036 PubMedCrossRefGoogle Scholar
  91. 91.
    Lengyel E (2010) Ovarian cancer development and metastasis. Am J Pathol 177(3):1053–1064. doi: 10.2353/ajpath.2010.100105 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Ramadan S, Ugas MA, Berwick RJ, Notay M, Cho H, Jerjes W, Giannoudis PV (2012) Spinal metastasis in thyroid cancer. Head Neck Oncol 4:39. doi: 10.1186/1758-3284-4-39 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Bhatia S, Tykodi SS, Thompson JA (2009) Treatment of metastatic melanoma: an overview. Oncology (Williston Park) 23(6):488–496Google Scholar
  94. 94.
    Thompson Coon J, Hoyle M, Green C, Liu Z, Welch K, Moxham T, Stein K (2010) Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation. Health Technol Assess 14(2):1–184, iii-iv. doi: 10.3310/hta14020 PubMedCrossRefGoogle Scholar
  95. 95.
    Brooks SA, Lomax-Browne HJ, Carter TM, Kinch CE, Hall DM (2010) Molecular interactions in cancer cell metastasis. Acta Histochem 112(1):3–25. doi: 10.1016/j.acthis.2008.11.022 PubMedCrossRefGoogle Scholar
  96. 96.
    Bockhorn M, Jain RK, Munn LL (2007) Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed? Lancet Oncol 8(5):444–448. doi: 10.1016/S1470-2045(07)70140-7 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Takagi S, Sato S, Oh-hara T, Takami M, Koike S, Mishima Y, Hatake K, Fujita N (2013) Platelets promote tumor growth and metastasis via direct interaction between Aggrus/podoplanin and CLEC-2. PLoS One 8(8), e73609. doi: 10.1371/journal.pone.0073609 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Gout S, Tremblay PL, Huot J (2008) Selectins and selectin ligands in extravasation of cancer cells and organ selectivity of metastasis. Clin Exp Metastasis 25(4):335–344. doi: 10.1007/s10585-007-9096-4 PubMedCrossRefGoogle Scholar
  99. 99.
    Krishnan H, Miller WT, Goldberg GS (2012) SRC points the way to biomarkers and chemotherapeutic targets. Genes Cancer 3(5–6):426–435PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Jhon Alberto Ochoa-Alvarez CG, Krishnan H, Xiaoxuan Wu, Goldberg GS (2011) Contact normalization: mechanisms and pathways to biomarkers and chemotherapeutic targets. In: Extracellular and intracellular signaling. RSC Publishing, Cambridge. doi: 10.1039/9781849733434-00105 Google Scholar
  101. 101.
    Rubin H (2006) What keeps cells in tissues behaving normally in the face of myriad mutations? Bioessays 28(5):515–524. doi: 10.1002/bies.20403 PubMedCrossRefGoogle Scholar
  102. 102.
    Rubin H (2008) Contact interactions between cells that suppress neoplastic development: can they also explain metastatic dormancy? Adv Cancer Res 100:159–202. doi: 10.1016/S0065-230X(08)00006-7 PubMedCrossRefGoogle Scholar
  103. 103.
    Albertsen PC (2007) Commentary: occult prostate cancer – imposter or the real deal? Int J Epidemiol 36(2):281–282. doi: 10.1093/ije/dym051 PubMedCrossRefGoogle Scholar
  104. 104.
    Nielsen M, Thomsen JL, Primdahl S, Dyreborg U, Andersen JA (1987) Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br J Cancer 56(6):814–819PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Klein G (2012) Tumor resistance. Oncoimmunology 1(8):1355–1359. doi: 10.4161/onci.22194 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7(11):834–846. doi: 10.1038/nrc2256 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Barkan D, Chambers AF (2011) beta1-integrin: a potential therapeutic target in the battle against cancer recurrence. Clin Cancer Res 17(23):7219–7223. doi: 10.1158/1078-0432.CCR-11-0642 PubMedCrossRefGoogle Scholar
  108. 108.
    Aguirre-Ghiso JA, Liu D, Mignatti A, Kovalski K, Ossowski L (2001) Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 12(4):863–879PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Allgayer H, Aguirre-Ghiso JA (2008) The urokinase receptor (u-PAR)--a link between tumor cell dormancy and minimal residual disease in bone marrow? APMIS 116(7–8):602–614. doi: 10.1111/j.1600-0463.2008.00997.x PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Giancotti FG (2013) Mechanisms governing metastatic dormancy and reactivation. Cell 155(4):750–764. doi: 10.1016/j.cell.2013.10.029 PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Naumov GN, Bender E, Zurakowski D, Kang SY, Sampson D, Flynn E, Watnick RS, Straume O, Akslen LA, Folkman J, Almog N (2006) A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 98(5):316–325. doi: 10.1093/jnci/djj068 PubMedCrossRefGoogle Scholar
  112. 112.
    Paez D, Labonte MJ, Bohanes P, Zhang W, Benhanim L, Ning Y, Wakatsuki T, Loupakis F, Lenz HJ (2012) Cancer dormancy: a model of early dissemination and late cancer recurrence. Clin Cancer Res 18(3):645–653. doi: 10.1158/1078-0432.CCR-11-2186 PubMedCrossRefGoogle Scholar
  113. 113.
    Swann JB, Smyth MJ (2007) Immune surveillance of tumors. J Clin Invest 117(5):1137–1146. doi: 10.1172/JCI31405 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Kleffel S, Schatton T (2013) Tumor dormancy and cancer stem cells: two sides of the same coin? Adv Exp Med Biol 734:145–179. doi: 10.1007/978-1-4614-1445-2_8 PubMedCrossRefGoogle Scholar
  115. 115.
    Horak CE, Lee JH, Marshall JC, Shreeve SM, Steeg PS (2008) The role of metastasis suppressor genes in metastatic dormancy. APMIS 116(7–8):586–601. doi: 10.1111/j.1600-0463.2008.01213.x PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Nash KT, Phadke PA, Navenot JM, Hurst DR, Accavitti-Loper MA, Sztul E, Vaidya KS, Frost AR, Kappes JC, Peiper SC, Welch DR (2007) Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. J Natl Cancer Inst 99(4):309–321. doi: 10.1093/jnci/djk053 PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Schewe DM, Aguirre-Ghiso JA (2009) Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer Res 69(4):1545–1552. doi: 10.1158/0008-5472.CAN-08-3858 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Hogan C (2012) Impact of interactions between normal and transformed epithelial cells and the relevance to cancer. Cell Mol Life Sci 69(2):203–213. doi: 10.1007/s00018-011-0806-3 PubMedCrossRefGoogle Scholar
  119. 119.
    Alt-Holland A, Zhang W, Margulis A, Garlick JA (2005) Microenvironmental control of premalignant disease: the role of intercellular adhesion in the progression of squamous cell carcinoma. Semin Cancer Biol 15(2):84–96. doi: 10.1016/j.semcancer.2004.08.007 PubMedCrossRefGoogle Scholar
  120. 120.
    Bissell MJ, Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17(3):320–329. doi: 10.1038/nm.2328 PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Soto AM, Sonnenschein C (2011) The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays 33(5):332–340. doi: 10.1002/bies.201100025 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Hennings H, Robinson VA, Michael DM, Pettit GR, Jung R, Yuspa SH (1990) Development of an in vitro analogue of initiated mouse epidermis to study tumor promoters and antipromoters. Cancer Res 50(15):4794–4800PubMedGoogle Scholar
  123. 123.
    Mehta PP, Bertram JS, Loewenstein WR (1986) Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell 44(1):187–196PubMedCrossRefGoogle Scholar
  124. 124.
    Booth BW, Boulanger CA, Anderson LH, Smith GH (2011) The normal mammary microenvironment suppresses the tumorigenic phenotype of mouse mammary tumor virus-neu-transformed mammary tumor cells. Oncogene 30(6):679–689. doi: 10.1038/onc.2010.439 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Stoker MG (1967) Transfer of growth inhibition between normal and virus-transformed cells: autoradiographic studies using marked cells. J Cell Sci 2(3):293–304PubMedGoogle Scholar
  126. 126.
    Alexander DB, Ichikawa H, Bechberger JF, Valiunas V, Ohki M, Naus CC, Kunimoto T, Tsuda H, Miller WT, Goldberg GS (2004) Normal cells control the growth of neighboring transformed cells independent of gap junctional communication and SRC activity. Cancer Res 64(4):1347–1358PubMedCrossRefGoogle Scholar
  127. 127.
    Martin W, Zempel G, Hulser D, Willecke K (1991) Growth inhibition of oncogene-transformed rat fibroblasts by cocultured normal cells: relevance of metabolic cooperation mediated by gap junctions. Cancer Res 51(19):5348–5351PubMedGoogle Scholar
  128. 128.
    Rubin H (1960) The suppression of morphological alterations in cells infected with Rous sarcoma virus. Virology 12:14–31PubMedCrossRefGoogle Scholar
  129. 129.
    Stoker M (1964) Regulation of growth and orientation in hamster cells transformed by polyoma virus. Virology 24:165–174PubMedCrossRefGoogle Scholar
  130. 130.
    Stoker MG, Shearer M, O’Neill C (1966) Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J Cell Sci 1(3):297–310PubMedGoogle Scholar
  131. 131.
    Hogan C, Kajita M, Lawrenson K, Fujita Y (2011) Interactions between normal and transformed epithelial cells: their contributions to tumourigenesis. Int J Biochem Cell Biol 43(4):496–503. doi: 10.1016/j.biocel.2010.12.019 PubMedCrossRefGoogle Scholar
  132. 132.
    Moreno E (2008) Is cell competition relevant to cancer? Nat Rev Cancer 8(2):141–147. doi: 10.1038/nrc2252 PubMedCrossRefGoogle Scholar
  133. 133.
    Hogan C, Dupre-Crochet S, Norman M, Kajita M, Zimmermann C, Pelling AE, Piddini E, Baena-Lopez LA, Vincent JP, Itoh Y, Hosoya H, Pichaud F, Fujita Y (2009) Characterization of the interface between normal and transformed epithelial cells. Nat Cell Biol 11(4):460–467. doi: 10.1038/ncb1853 PubMedCrossRefGoogle Scholar
  134. 134.
    Kajita M, Hogan C, Harris AR, Dupre-Crochet S, Itasaki N, Kawakami K, Charras G, Tada M, Fujita Y (2010) Interaction with surrounding normal epithelial cells influences signalling pathways and behaviour of Src-transformed cells. J Cell Sci 123(Pt 2):171–180. doi: 10.1242/jcs.057976 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Vidal M, Larson DE, Cagan RL (2006) Csk-deficient boundary cells are eliminated from normal Drosophila epithelia by exclusion, migration, and apoptosis. Dev Cell 10(1):33–44. doi: 10.1016/j.devcel.2005.11.007 PubMedCrossRefGoogle Scholar
  136. 136.
    Brinster RL (1974) The effect of cells transferred into the mouse blastocyst on subsequent development. J Exp Med 140(4):1049–1056PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci U S A 72(9):3585–3589PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Gumbiner BM (2005) Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6(8):622–634. doi: 10.1038/nrm1699 PubMedCrossRefGoogle Scholar
  139. 139.
    Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8(1):9–22PubMedCrossRefGoogle Scholar
  140. 140.
    Grazia Lampugnani M, Zanetti A, Corada M, Takahashi T, Balconi G, Breviario F, Orsenigo F, Cattelino A, Kemler R, Daniel TO, Dejana E (2003) Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148. J Cell Biol 161(4):793–804. doi: 10.1083/jcb.200209019 PubMedCrossRefGoogle Scholar
  141. 141.
    Jeanes A, Gottardi CJ, Yap AS (2008) Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene 27(55):6920–6929. doi: 10.1038/onc.2008.343 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Dejana E, Orsenigo F, Lampugnani MG (2008) The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121(Pt 13):2115–2122. doi: 10.1242/jcs.017897 PubMedCrossRefGoogle Scholar
  143. 143.
    Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437(2):169–183. doi: 10.1042/BJ20110301 PubMedCrossRefGoogle Scholar
  144. 144.
    Simoneau B, Houle F, Huot J (2012) Regulation of endothelial permeability and transendothelial migration of cancer cells by tropomyosin-1 phosphorylation. Vasc Cell 4(1):18. doi: 10.1186/2045-824X-4-18 PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Goodenough DA, Goliger JA, Paul DL (1996) Connexins, connexons, and intercellular communication. Annu Rev Biochem 65:475–502PubMedCrossRefGoogle Scholar
  146. 146.
    Hirschi KK, Xu CE, Tsukamoto T, Sager R (1996) Gap junction genes Cx26 and Cx43 individually suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential. Cell Growth Differ 7(7):861–870PubMedGoogle Scholar
  147. 147.
    Huang RP, Fan Y, Hossain MZ, Peng A, Zeng ZL, Boynton AL (1998) Reversion of the neoplastic phenotype of human glioblastoma cells by connexin 43 (cx43). Cancer Res 58(22):5089–5096PubMedGoogle Scholar
  148. 148.
    Goldberg GS, Martyn KD, Lau AF (1994) A connexin 43 antisense vector reduces the ability of normal cells to inhibit the foci formation of transformed cells. Mol Carcinog 11(2):106–114PubMedCrossRefGoogle Scholar
  149. 149.
    Zhu D, Kidder GM, Caveney S, Naus CC (1992) Growth retardation in glioma cells cocultured with cells overexpressing a gap junction protein. Proc Natl Acad Sci U S A 89(21):10218–10221PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Pahujaa M, Anikin M, Goldberg GS (2007) Phosphorylation of connexin43 induced by Src: regulation of gap junctional communication between transformed cells. Exp Cell Res 313(20):4083–4090. doi: 10.1016/j.yexcr.2007.09.010 PubMedCrossRefGoogle Scholar
  151. 151.
    Shen Y, Khusial PR, Li X, Ichikawa H, Moreno AP, Goldberg GS (2007) SRC utilizes Cas to block gap junctional communication mediated by connexin43. J Biol Chem 282(26):18914–18921. doi: 10.1074/jbc.M608980200 PubMedCrossRefGoogle Scholar
  152. 152.
    Zhou L, Kasperek EM, Nicholson BJ (1999) Dissection of the molecular basis of pp60(v-src) induced gating of connexin 43 gap junction channels. J Cell Biol 144(5):1033–1045Google Scholar
  153. 153.
    Kamei J, Toyofuku T, Hori M (2003) Negative regulation of p21 by beta-catenin/TCF signaling: a novel mechanism by which cell adhesion molecules regulate cell proliferation. Biochem Biophys Res Commun 312(2):380–387PubMedCrossRefGoogle Scholar
  154. 154.
    Aleshin A, Finn RS (2010) SRC: a century of science brought to the clinic. Neoplasia 12(8):599–607PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Goldberg GS, Moreno AP, Lampe PD (2002) Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. J Biol Chem 277(39):36725–36730. doi: 10.1074/jbc.M109797200 PubMedCrossRefGoogle Scholar
  156. 156.
    Ding L, Niu C, Zheng Y, Xiong Z, Liu Y, Lin J, Sun H, Huang K, Yang W, Li X, Ye Q (2011) FHL1 interacts with oestrogen receptors and regulates breast cancer cell growth. J Cell Mol Med 15(1):72–85. doi: 10.1111/j.1582-4934.2009.00938.x PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Li X, Jia Z, Shen Y, Ichikawa H, Jarvik J, Nagele RG, Goldberg GS (2008) Coordinate suppression of Sdpr and Fhl1 expression in tumors of the breast, kidney, and prostate. Cancer Sci 99(7):1326–1333. doi: 10.1111/j.1349-7006.2008.00816.x PubMedCrossRefGoogle Scholar
  158. 158.
    Niu C, Liang C, Guo J, Cheng L, Zhang H, Qin X, Zhang Q, Ding L, Yuan B, Xu X, Li J, Lin J, Ye Q (2012) Downregulation and growth inhibitory role of FHL1 in lung cancer. Int J Cancer 130(11):2549–2556. doi: 10.1002/ijc.26259 PubMedCrossRefGoogle Scholar
  159. 159.
    Bai L, Deng X, Li Q, Wang M, An W, Deli A, Gao Z, Xie Y, Dai Y, Cong YS (2012) Down-regulation of the cavin family proteins in breast cancer. J Cell Biochem 113(1):322–328. doi: 10.1002/jcb.23358 PubMedCrossRefGoogle Scholar
  160. 160.
    Shioi K, Komiya A, Hattori K, Huang Y, Sano F, Murakami T, Nakaigawa N, Kishida T, Kubota Y, Nagashima Y, Yao M (2006) Vascular cell adhesion molecule 1 predicts cancer-free survival in clear cell renal carcinoma patients. Clin Cancer Res 12(24):7339–7346. doi: 10.1158/1078-0432.CCR-06-1737 PubMedCrossRefGoogle Scholar
  161. 161.
    Gustavsson E, Sernbo S, Andersson E, Brennan DJ, Dictor M, Jerkeman M, Borrebaeck CA, Ek S (2010) SOX11 expression correlates to promoter methylation and regulates tumor growth in hematopoietic malignancies. Mol Cancer 9:187. doi: 10.1186/1476-4598-9-187 PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Sernbo S, Gustavsson E, Brennan DJ, Gallagher WM, Rexhepaj E, Rydnert F, Jirstrom K, Borrebaeck CA, Ek S (2011) The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation. BMC Cancer 11:405. doi: 10.1186/1471-2407-11-405 PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, Bradley A, Gerstein R, Jurecic R, Jones SN (2003) Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4(5):349–360PubMedCrossRefGoogle Scholar
  164. 164.
    Ying J, Li H, Yu J, Ng KM, Poon FF, Wong SC, Chan AT, Sung JJ, Tao Q (2008) WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res 14(1):55–61. doi: 10.1158/1078-0432.CCR-07-1644 PubMedCrossRefGoogle Scholar
  165. 165.
    Chatterjee S, Heukamp LC, Siobal M, Schottle J, Wieczorek C, Peifer M, Frasca D, Koker M, Konig K, Meder L, Rauh D, Buettner R, Wolf J, Brekken RA, Neumaier B, Christofori G, Thomas RK, Ullrich RT (2013) Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest 123(4):1732–1740. doi: 10.1172/JCI65385 PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Liang Y, Brekken RA, Hyder SM (2006) Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 13(3):905–919. doi: 10.1677/erc.1.01221 PubMedCrossRefGoogle Scholar
  167. 167.
    Smith NR, Baker D, James NH, Ratcliffe K, Jenkins M, Ashton SE, Sproat G, Swann R, Gray N, Ryan A, Jurgensmeier JM, Womack C (2010) Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res 16(14):3548–3561. doi: 10.1158/1078-0432.CCR-09-2797 PubMedCrossRefGoogle Scholar
  168. 168.
    Tanno S, Ohsaki Y, Nakanishi K, Toyoshima E, Kikuchi K (2004) Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3. Lung Cancer 46(1):11–19. doi: 10.1016/j.lungcan.2004.03.006 PubMedCrossRefGoogle Scholar
  169. 169.
    Huttenlocher S, Seibold ND, Gebhard MP, Noack F, Thorns C, Hasselbacher K, Wollenberg B, Schild SE, Rades D (2014) Evaluation of the prognostic role of tumor cell podoplanin expression in locally advanced squamous cell carcinoma of the head and neck. Strahlenther Onkol. doi: 10.1007/s00066-014-0694-1 PubMedGoogle Scholar
  170. 170.
    Kimura N, Kimura I (2005) Podoplanin as a marker for mesothelioma. Pathol Int 55(2):83–86. doi: 10.1111/j.1440-1827.2005.01791.x PubMedCrossRefGoogle Scholar
  171. 171.
    Ochoa-Alvarez JA, Krishnan H, Shen Y, Acharya NK, Han M, McNulty DE, Hasegawa H, Hyodo T, Senga T, Geng JG, Kosciuk M, Shin SS, Goydos JS, Temiakov D, Nagele RG, Goldberg GS (2012) Plant lectin can target receptors containing sialic acid, exemplified by podoplanin, to inhibit transformed cell growth and migration. PLoS One 7(7), e41845. doi: 10.1371/journal.pone.0041845 PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Raica M, Cimpean AM, Ribatti D (2008) The role of podoplanin in tumor progression and metastasis. Anticancer Res 28(5B):2997–3006PubMedGoogle Scholar
  173. 173.
    Shibahara J, Kashima T, Kikuchi Y, Kunita A, Fukayama M (2006) Podoplanin is expressed in subsets of tumors of the central nervous system. Virchows Arch 448(4):493–499. doi: 10.1007/s00428-005-0133-x PubMedCrossRefGoogle Scholar
  174. 174.
    Brune V, Tiacci E, Pfeil I, Doring C, Eckerle S, van Noesel CJ, Klapper W, Falini B, von Heydebreck A, Metzler D, Brauninger A, Hansmann ML, Kuppers R (2008) Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med 205(10):2251–2268. doi: 10.1084/jem.20080809 PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Li AM, Tian AX, Zhang RX, Ge J, Sun X, Cao XC (2013) Protocadherin-7 induces bone metastasis of breast cancer. Biochem Biophys Res Commun 436(3):486–490. doi: 10.1016/j.bbrc.2013.05.131 PubMedCrossRefGoogle Scholar
  176. 176.
    Shen Y, Jia Z, Nagele RG, Ichikawa H, Goldberg GS (2006) SRC uses Cas to suppress Fhl1 in order to promote nonanchored growth and migration of tumor cells. Cancer Res 66(3):1543–1552PubMedCrossRefGoogle Scholar
  177. 177.
    Ding L, Wang Z, Yan J, Yang X, Liu A, Qiu W, Zhu J, Han J, Zhang H, Lin J, Cheng L, Qin X, Niu C, Yuan B, Wang X, Zhu C, Zhou Y, Li J, Song H, Huang C, Ye Q (2009) Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. J Clin Invest 119(2):349–361. doi: 10.1172/JCI35930 PubMedPubMedCentralGoogle Scholar
  178. 178.
    Lin J, Ding L, Jin R, Zhang H, Cheng L, Qin X, Chai J, Ye Q (2009) Four and a half LIM domains 1 (FHL1) and receptor interacting protein of 140 kDa (RIP140) interact and cooperate in estrogen signaling. Int J Biochem Cell Biol 41(7):1613–1618. doi: 10.1016/j.biocel.2009.02.007 PubMedCrossRefGoogle Scholar
  179. 179.
    Sakashita K, Mimori K, Tanaka F, Kamohara Y, Inoue H, Sawada T, Hirakawa K, Mori M (2008) Clinical significance of loss of Fhl1 expression in human gastric cancer. Ann Surg Oncol 15(8):2293–2300. doi: 10.1245/s10434-008-9904-3 PubMedCrossRefGoogle Scholar
  180. 180.
    Li X, Jia Z, Shen Y, Ichikawa H, Jarvik J, Nagele RG, Goldberg GS (2008) Coordinate suppression of Sdpr and Fhl1 expression in tumors of the breast, kidney, and prostate. Cancer Sci 99(7):1326–1333PubMedCrossRefGoogle Scholar
  181. 181.
    Shen Y, Chen CS, Ichikawa H, Goldberg GS (2010) SRC induces podoplanin expression to promote cell migration. J Biol Chem 285(13):9649–9656PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Burgener R, Wolf M, Ganz T, Baggiolini M (1990) Purification and characterization of a major phosphatidylserine-binding phosphoprotein from human platelets. Biochem J 269(3):729–734PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Hansen CG, Bright NA, Howard G, Nichols BJ (2009) SDPR induces membrane curvature and functions in the formation of caveolae. Nat Cell Biol 11(7):807–814. doi: 10.1038/ncb1887 PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Gustincich S, Schneider C (1993) Serum deprivation response gene is induced by serum starvation but not by contact inhibition. Cell Growth Differ 4(9):753–760PubMedGoogle Scholar
  185. 185.
    Holmes K, Roberts OL, Thomas AM, Cross MJ (2007) Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 19(10):2003–2012. doi: 10.1016/j.cellsig.2007.05.013 PubMedCrossRefGoogle Scholar
  186. 186.
    Takahashi T, Shibuya M (1997) The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene 14(17):2079–2089. doi: 10.1038/sj.onc.1201047 PubMedCrossRefGoogle Scholar
  187. 187.
    Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56(4):549–580. doi: 10.1124/pr.56.4.3 PubMedCrossRefGoogle Scholar
  188. 188.
    Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling – in control of vascular function. Nat Rev Mol Cell Biol 7(5):359–371. doi: 10.1038/nrm1911 PubMedCrossRefGoogle Scholar
  189. 189.
    Yao X, Ping Y, Liu Y, Chen K, Yoshimura T, Liu M, Gong W, Chen C, Niu Q, Guo D, Zhang X, Wang JM, Bian X (2013) Vascular endothelial growth factor receptor 2 (VEGFR-2) plays a key role in vasculogenic mimicry formation, neovascularization and tumor initiation by Glioma stem-like cells. PLoS One 8(3), e57188. doi: 10.1371/journal.pone.0057188 PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Watanabe M, Okochi E, Sugimoto Y, Tsuruo T (1988) Identification of a platelet-aggregating factor of murine colon adenocarcinoma 26: Mr 44,000 membrane protein as determined by monoclonal antibodies. Cancer Res 48(22):6411–6416PubMedGoogle Scholar
  191. 191.
    Watanabe M, Sugimoto Y, Tsuruo T (1990) Expression of a Mr 41,000 glycoprotein associated with thrombin-independent platelet aggregation in high metastatic variants of murine B16 melanoma. Cancer Res 50(20):6657–6662PubMedGoogle Scholar
  192. 192.
    Nose K, Saito H, Kuroki T (1990) Isolation of a gene sequence induced later by tumor-promoting 12-O-tetradecanoylphorbol-13-acetate in mouse osteoblastic cells (MC3T3-E1) and expressed constitutively in ras-transformed cells. Cell Growth Differ 1(11):511–518PubMedGoogle Scholar
  193. 193.
    Kaneko MK, Kato Y, Kitano T, Osawa M (2006) Conservation of a platelet activating domain of Aggrus/podoplanin as a platelet aggregation-inducing factor. Gene 378:52–57PubMedCrossRefGoogle Scholar
  194. 194.
    Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester-Christensen MB, Schjoldager KT, Lavrsen K, Dabelsteen S, Pedersen NB, Marcos-Silva L, Gupta R, Bennett EP, Mandel U, Brunak S, Wandall HH, Levery SB, Clausen H (2013) Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J 32(10):1478–1488. doi: 10.1038/emboj.2013.79 PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Fernandez-Munoz B, Yurrita MM, Martin-Villar E, Carrasco-Ramirez P, Megias D, Renart J, Quintanilla M (2011) The transmembrane domain of podoplanin is required for its association with lipid rafts and the induction of epithelial-mesenchymal transition. Int J Biochem Cell Biol 43(6):886–896. doi: 10.1016/j.biocel.2011.02.010 PubMedCrossRefGoogle Scholar
  196. 196.
    Martin-Villar E, Megias D, Castel S, Yurrita MM, Vilaro S, Quintanilla M (2006) Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J Cell Sci 119(Pt 21):4541–4553PubMedCrossRefGoogle Scholar
  197. 197.
    Kaneko MK, Kato Y, Kameyama A, Ito H, Kuno A, Hirabayashi J, Kubota T, Amano K, Chiba Y, Hasegawa Y, Sasagawa I, Mishima K, Narimatsu H (2007) Functional glycosylation of human podoplanin: glycan structure of platelet aggregation-inducing factor. FEBS Lett 581(2):331–336. doi: 10.1016/j.febslet.2006.12.044 PubMedCrossRefGoogle Scholar
  198. 198.
    Kato Y, Fujita N, Kunita A, Sato S, Kaneko M, Osawa M, Tsuruo T (2003) Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors. J Biol Chem 278(51):51599–51605. doi: 10.1074/jbc.M309935200 PubMedCrossRefGoogle Scholar
  199. 199.
    Kunita A, Kashima TG, Morishita Y, Fukayama M, Kato Y, Tsuruo T, Fujita N (2007) The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis. Am J Pathol 170(4):1337–1347. doi: 10.2353/ajpath.2007.060790 PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Barth K, Blasche R, Kasper M (2010) T1alpha/podoplanin shows raft-associated distribution in mouse lung alveolar epithelial E10 cells. Cell Physiol Biochem 25(1):103–112. doi: 10.1159/000272065 PubMedCrossRefGoogle Scholar
  201. 201.
    Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G (2006) Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9(4):261–272. doi: 10.1016/j.ccr.2006.03.010 PubMedCrossRefGoogle Scholar
  202. 202.
    Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, Williams M, Dvorak AM, Dvorak HF, Oliver G, Detmar M (2003) T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 22(14):3546–3556. doi: 10.1093/emboj/cdg342 PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140(4):460–476. doi: 10.1016/j.cell.2010.01.045 PubMedCrossRefGoogle Scholar
  204. 204.
    Uhrin P, Zaujec J, Breuss JM, Olcaydu D, Chrenek P, Stockinger H, Fuertbauer E, Moser M, Haiko P, Fassler R, Alitalo K, Binder BR, Kerjaschki D (2010) Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 115(19):3997–4005. doi: 10.1182/blood-2009-04-216069 PubMedCrossRefGoogle Scholar
  205. 205.
    Navarro A, Perez RE, Rezaiekhaligh MH, Mabry SM, Ekekezie II (2011) Polarized migration of lymphatic endothelial cells is critically dependent on podoplanin regulation of Cdc42. Am J Physiol Lung Cell Mol Physiol 300(1):L32–L42. doi: 10.1152/ajplung.00171.2010 PubMedCrossRefGoogle Scholar
  206. 206.
    Williams MC, Cao Y, Hinds A, Rishi AK, Wetterwald A (1996) T1 alpha protein is developmentally regulated and expressed by alveolar type I cells, choroid plexus, and ciliary epithelia of adult rats. Am J Respir Cell Mol Biol 14(6):577–585. doi: 10.1165/ajrcmb.14.6.8652186 PubMedCrossRefGoogle Scholar
  207. 207.
    Ramirez MI, Millien G, Hinds A, Cao Y, Seldin DC, Williams MC (2003) T1alpha, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev Biol 256(1):61–72PubMedCrossRefGoogle Scholar
  208. 208.
    Breiteneder-Geleff S, Matsui K, Soleiman A, Meraner P, Poczewski H, Kalt R, Schaffner G, Kerjaschki D (1997) Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. Am J Pathol 151(4):1141–1152PubMedPubMedCentralGoogle Scholar
  209. 209.
    Matsui K, Breitender-Geleff S, Soleiman A, Kowalski H, Kerjaschki D (1999) Podoplanin, a novel 43-kDa membrane protein, controls the shape of podocytes. Nephrol Dial Transplant 14(Suppl 1):9–11PubMedCrossRefGoogle Scholar
  210. 210.
    Astarita JL, Acton SE, Turley SJ (2012) Podoplanin: emerging functions in development, the immune system, and cancer. Front Immunol 3:283. doi: 10.3389/fimmu.2012.00283 PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Tomooka M, Kaji C, Kojima H, Sawa Y (2013) Distribution of podoplanin-expressing cells in the mouse nervous systems. Acta Histochem Cytochem 46(6):171–177. doi: 10.1267/ahc.13035 PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, Yamazaki Y, Narimatsu H, Ozaki Y (2007) Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 282(36):25993–26001. doi: 10.1074/jbc.M702327200 PubMedCrossRefGoogle Scholar
  213. 213.
    Acton SE, Astarita JL, Malhotra D, Lukacs-Kornek V, Franz B, Hess PR, Jakus Z, Kuligowski M, Fletcher AL, Elpek KG, Bellemare-Pelletier A, Sceats L, Reynoso ED, Gonzalez SF, Graham DB, Chang J, Peters A, Woodruff M, Kim YA, Swat W, Morita T, Kuchroo V, Carroll MC, Kahn ML, Wucherpfennig KW, Turley SJ (2012) Podoplanin-rich stromal networks induce dendritic cell motility via activation of the C-type lectin receptor CLEC-2. Immunity 37(2):276–289. doi: 10.1016/j.immuni.2012.05.022 PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Herzog BH, Fu J, Wilson SJ, Hess PR, Sen A, McDaniel JM, Pan Y, Sheng M, Yago T, Silasi-Mansat R, McGee S, May F, Nieswandt B, Morris AJ, Lupu F, Coughlin SR, McEver RP, Chen H, Kahn ML, Xia L (2013) Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502(7469):105–109. doi: 10.1038/nature12501 PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Cueni LN, Detmar M (2009) Galectin-8 interacts with podoplanin and modulates lymphatic endothelial cell functions. Exp Cell Res 315(10):1715–1723PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Nakazawa Y, Sato S, Naito M, Kato Y, Mishima K, Arai H, Tsuruo T, Fujita N (2008) Tetraspanin family member CD9 inhibits Aggrus/podoplanin-induced platelet aggregation and suppresses pulmonary metastasis. Blood 112(5):1730–1739. doi: 10.1182/blood-2007-11-124693 PubMedCrossRefGoogle Scholar
  217. 217.
    Martin-Villar E, Fernandez-Munoz B, Parsons M, Yurrita MM, Megias D, Perez-Gomez E, Jones GE, Quintanilla M (2010) Podoplanin associates with CD44 to promote directional cell migration. Mol Biol Cell 21(24):4387–4399. doi: 10.1091/mbc.E10-06-0489 PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Tsuneki M, Yamazaki M, Maruyama S, Cheng J, Saku T (2013) Podoplanin-mediated cell adhesion through extracellular matrix in oral squamous cell carcinoma. Lab Invest 93(8):921–932. doi: 10.1038/labinvest.2013.86 PubMedCrossRefGoogle Scholar
  219. 219.
    Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, Birner P, Krieger S, Hovorka A, Silberhumer G, Laakkonen P, Petrova T, Langer B, Raab I (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15(3):603–612PubMedCrossRefGoogle Scholar
  220. 220.
    Tsuneki M, Maruyama S, Yamazaki M, Xu B, Essa A, Abe T, Babkair H, Cheng J, Yamamoto T, Saku T (2013) Extracellular heat shock protein A9 is a novel interaction partner of podoplanin in oral squamous cell carcinoma cells. Biochem Biophys Res Commun 434(1):124–130. doi: 10.1016/j.bbrc.2013.03.057 PubMedCrossRefGoogle Scholar
  221. 221.
    Navarro A, Perez RE, Rezaiekhaligh M, Mabry SM, Ekekezie II (2008) T1alpha/podoplanin is essential for capillary morphogenesis in lymphatic endothelial cells. Am J Physiol Lung Cell Mol Physiol 295(4):L543–L551. doi: 10.1152/ajplung.90262.2008 PubMedCrossRefGoogle Scholar
  222. 222.
    Wicki A, Christofori G (2007) The potential role of podoplanin in tumour invasion. Br J Cancer 96(1):1–5. doi: 10.1038/sj.bjc.6603518 PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Martin-Villar E, Scholl FG, Gamallo C, Yurrita MM, Munoz-Guerra M, Cruces J, Quintanilla M (2005) Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int J Cancer 113(6):899–910. doi: 10.1002/ijc.20656 PubMedCrossRefGoogle Scholar
  224. 224.
    Hantusch B, Kalt R, Krieger S, Puri C, Kerjaschki D (2007) Sp1/Sp3 and DNA-methylation contribute to basal transcriptional activation of human podoplanin in MG63 versus Saos-2 osteoblastic cells. BMC Mol Biol 8:20. doi: 10.1186/1471-2199-8-20 PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Pan Y, Wang WD, Yago T (2014) Transcriptional regulation of podoplanin expression by Prox1 in lymphatic endothelial cells. Microvasc Res 94C:96–102. doi: 10.1016/j.mvr.2014.05.006 CrossRefGoogle Scholar
  226. 226.
    Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225(3):351–357. doi: 10.1002/dvdy.10163 PubMedCrossRefGoogle Scholar
  227. 227.
    Kulkarni RM, Greenberg JM, Akeson AL (2009) NFATc1 regulates lymphatic endothelial development. Mech Dev 126(5-6):350–365. doi: 10.1016/j.mod.2009.02.003 PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Durchdewald M, Guinea-Viniegra J, Haag D, Riehl A, Lichter P, Hahn M, Wagner EF, Angel P, Hess J (2008) Podoplanin is a novel fos target gene in skin carcinogenesis. Cancer Res 68(17):6877–6883. doi: 10.1158/0008-5472.CAN-08-0299 PubMedCrossRefGoogle Scholar
  229. 229.
    Ekwall AK, Eisler T, Anderberg C, Jin C, Karlsson N, Brisslert M, Bokarewa MI (2011) The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis. Arthritis Res Ther 13(2):R40. doi: 10.1186/ar3274 PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Honma M, Minami-Hori M, Takahashi H, Iizuka H (2012) Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-beta and STAT-3 activating cytokines, IFN-gamma, IL-6, and IL-22. J Dermatol Sci 65(2):134–140. doi: 10.1016/j.jdermsci.2011.11.011 PubMedCrossRefGoogle Scholar
  231. 231.
    Hwang YS, Xianglan Z, Park KK, Chung WY (2012) Functional invadopodia formation through stabilization of the PDPN transcript by IMP-3 and cancer-stromal crosstalk for PDPN expression. Carcinogenesis 33(11):2135–2146. doi: 10.1093/carcin/bgs258 PubMedCrossRefGoogle Scholar
  232. 232.
    Peterziel H, Muller J, Danner A, Barbus S, Liu HK, Radlwimmer B, Pietsch T, Lichter P, Schutz G, Hess J, Angel P (2012) Expression of podoplanin in human astrocytic brain tumors is controlled by the PI3K-AKT-AP-1 signaling pathway and promoter methylation. Neuro Oncol 14(4):426–439. doi: 10.1093/neuonc/nos055 PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Cortez MA, Nicoloso MS, Shimizu M, Rossi S, Gopisetty G, Molina JR, Carlotti C Jr, Tirapelli D, Neder L, Brassesco MS, Scrideli CA, Tone LG, Georgescu MM, Zhang W, Puduvalli V, Calin GA (2010) miR-29b and miR-125a regulate podoplanin and suppress invasion in glioblastoma. Genes Chromosomes Cancer 49(11):981–990. doi: 10.1002/gcc.20808 PubMedCrossRefGoogle Scholar
  234. 234.
    Martin-Villar E, Yurrita MM, Fernandez-Munoz B, Quintanilla M, Renart J (2009) Regulation of podoplanin/PA2.26 antigen expression in tumour cells. Involvement of calpain-mediated proteolysis. Int J Biochem Cell Biol 41(6):1421–1429. doi: 10.1016/j.biocel.2008.12.010 PubMedCrossRefGoogle Scholar
  235. 235.
    Yurrita MM, Fernandez-Munoz B, Del Castillo G, Martin-Villar E, Renart J, Quintanilla M (2014) Podoplanin is a substrate of presenilin-1/gamma-secretase. Int J Biochem Cell Biol 46:68–75. doi: 10.1016/j.biocel.2013.11.016 PubMedCrossRefGoogle Scholar
  236. 236.
    Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154(2):385–394. doi: 10.1016/S0002-9440(10)65285-6 PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Kono T, Shimoda M, Takahashi M, Matsumoto K, Yoshimoto T, Mizutani M, Tabata C, Okoshi K, Wada H, Kubo H (2007) Immunohistochemical detection of the lymphatic marker podoplanin in diverse types of human cancer cells using a novel antibody. Int J Oncol 31(3):501–508PubMedGoogle Scholar
  238. 238.
    Niemiec JA, Adamczyk A, Ambicka A, Mucha-Malecka A, W MW, Rys J (2014) Triple-negative, basal marker-expressing, and high-grade breast carcinomas are characterized by high lymphatic vessel density and the expression of podoplanin in stromal fibroblasts. Appl Immunohistochem Mol Morphol 22(1):10–16. doi: 10.1097/PAI.0b013e318286030d
  239. 239.
    Pula B, Wojnar A, Werynska B, Ambicka A, Kruczak A, Witkiewicz W, Ugorski M, Podhorska-Okolow M, Dziegiel P (2013) Impact of different tumour stroma assessment methods regarding podoplanin expression on clinical outcome in patients with invasive ductal breast carcinoma. Anticancer Res 33(4):1447–1455PubMedGoogle Scholar
  240. 240.
    Schoppmann SF, Berghoff A, Dinhof C, Jakesz R, Gnant M, Dubsky P, Jesch B, Heinzl H, Birner P (2012) Podoplanin-expressing cancer-associated fibroblasts are associated with poor prognosis in invasive breast cancer. Breast Cancer Res Treat 134(1):237–244. doi: 10.1007/s10549-012-1984-x PubMedCrossRefGoogle Scholar
  241. 241.
    Cortez MA, Nicoloso MS, Shimizu M, Rossi S, Gopisetty G, Molina JR, Carlotti C Jr, Tirapelli D, Neder L, Brassesco MS, Scrideli CA, Tone LG, Georgescu MM, Zhang W, Puduvalli V, Calin GA (2010) miR-29b and miR-125a regulate podoplanin and suppress invasion in glioblastoma. Genes Chromosomes Cancer 49:981–990PubMedCrossRefGoogle Scholar
  242. 242.
    Kan S, Konishi E, Arita T, Ikemoto C, Takenaka H, Yanagisawa A, Katoh N, Asai J (2014) Podoplanin expression in cancer-associated fibroblasts predicts aggressive behavior in melanoma. J Cutan Pathol 41(7):561–567. doi: 10.1111/cup.12322 PubMedCrossRefGoogle Scholar
  243. 243.
    Kawaguchi H, El Naggar AK, Papadimitrakopoulou V, Ren H, Fan YH, Feng L, Lee JJ, Kim E, Hong WK, Lippman SM, Mao L (2008) Podoplanin: a novel marker for oral cancer risk in patients with oral premalignancy. J Clin Oncol 26(3):354–360PubMedCrossRefGoogle Scholar
  244. 244.
    Yuan P, Temam S, El Naggar A, Zhou X, Liu DD, Lee JJ, Mao L (2006) Overexpression of podoplanin in oral cancer and its association with poor clinical outcome. Cancer 107(3):563–569PubMedCrossRefGoogle Scholar
  245. 245.
    Shindo K, Aishima S, Ohuchida K, Fujiwara K, Fujino M, Mizuuchi Y, Hattori M, Mizumoto K, Tanaka M, Oda Y (2013) Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas. Mol Cancer 12(1):168. doi: 10.1186/1476-4598-12-168 PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Ito M, Ishii G, Nagai K, Maeda R, Nakano Y, Ochiai A (2012) Prognostic impact of cancer-associated stromal cells in patients with stage I lung adenocarcinoma. Chest 142(1):151–158. doi: 10.1378/chest.11-2458 PubMedCrossRefGoogle Scholar
  247. 247.
    Ono S, Ishii G, Nagai K, Takuwa T, Yoshida J, Nishimura M, Hishida T, Aokage K, Fujii S, Ikeda N, Ochiai A (2013) Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer-associated fibroblast phenotype. Chest 143(4):963–970. doi: 10.1378/chest.12-0913 PubMedCrossRefGoogle Scholar
  248. 248.
    Schoppmann SF, Jesch B, Riegler MF, Maroske F, Schwameis K, Jomrich G, Birner P (2013) Podoplanin expressing cancer associated fibroblasts are associated with unfavourable prognosis in adenocarcinoma of the esophagus. Clin Exp Metastasis 30(4):441–446. doi: 10.1007/s10585-012-9549-2 PubMedCrossRefGoogle Scholar
  249. 249.
    Cirligeriu L, Cimpean AM, Raica M, Doros CI (2014) Dual role of podoplanin in oral cancer development. In Vivo 28(3):341–347Google Scholar
  250. 250.
    de Vicente JC, Rodrigo JP, Rodriguez-Santamarta T, Lequerica-Fernandez P, Allonca E, Garcia-Pedrero JM (2013) Podoplanin expression in oral leukoplakia: tumorigenic role. Oral Oncol 49(6):598–603. doi: 10.1016/j.oraloncology.2013.02.008 PubMedCrossRefGoogle Scholar
  251. 251.
    Cueni LN, Hegyi I, Shin JW, Albinger-Hegyi A, Gruber S, Kunstfeld R, Moch H, Detmar M (2010) Tumor lymphangiogenesis and metastasis to lymph nodes induced by cancer cell expression of podoplanin. Am J Pathol 177(2):1004–1016PubMedPubMedCentralCrossRefGoogle Scholar
  252. 252.
    Funayama A, Cheng J, Maruyama S, Yamazaki M, Kobayashi T, Syafriadi M, Kundu S, Shingaki S, Saito C, Saku T (2011) Enhanced expression of podoplanin in oral carcinomas in situ and squamous cell carcinomas. Pathobiology 78(3):171–180PubMedCrossRefGoogle Scholar
  253. 253.
    Huber GF, Fritzsche FR, Zullig L, Storz M, Graf N, Haerle K, Jochum W, Stoeckli SJ, Moch H (2011) Podoplanin expression correlates with sentinel lymph node metastasis in early squamous cell carcinomas of the oral cavity and oropharynx. Int J Cancer 129(6):1404–1409PubMedCrossRefGoogle Scholar
  254. 254.
    Inoue H, Miyazaki Y, Kikuchi K, Yoshida N, Ide F, Ohmori Y, Tomomura A, Sakashita H, Kusama K (2012) Podoplanin promotes cell migration via the EGF-Src-Cas pathway in oral squamous cell carcinoma cell lines. J Oral Sci 54(3):241–250PubMedCrossRefGoogle Scholar
  255. 255.
    Kreppel M, Drebber U, Wedemeyer I, Eich HT, Backhaus T, Zoller JE, Scheer M (2011) Podoplanin expression predicts prognosis in patients with oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy. Oral Oncol 47(9):873–878PubMedCrossRefGoogle Scholar
  256. 256.
    dos Santos Almeida A, Oliveira DT, Pereira MC, Faustino SE, Nonogaki S, Carvalho AL, Kowalski LP (2013) Podoplanin and VEGF-C immunoexpression in oral squamous cell carcinomas: prognostic significance. Anticancer Res 33(9):3969–3976PubMedGoogle Scholar
  257. 257.
    Nakashima Y, Yoshinaga K, Kitao H, Ando K, Kimura Y, Saeki H, Oki E, Morita M, Kakeji Y, Hirahashi M, Oda Y, Maehara Y (2013) Podoplanin is expressed at the invasive front of esophageal squamous cell carcinomas and is involved in collective cell invasion. Cancer Sci 104(12):1718–1725. doi: 10.1111/cas.12286 PubMedCrossRefGoogle Scholar
  258. 258.
    Pula B, Witkiewicz W, Dziegiel P, Podhorska-Okolow M (2013) Significance of podoplanin expression in cancer-associated fibroblasts: a comprehensive review. Int J Oncol 42(6):1849–1857. doi: 10.3892/ijo.2013.1887 PubMedGoogle Scholar
  259. 259.
    Sugimoto Y, Watanabe M, Oh-hara T, Sato S, Isoe T, Tsuruo T (1991) Suppression of experimental lung colonization of a metastatic variant of murine colon adenocarcinoma 26 by a monoclonal antibody 8F11 inhibiting tumor cell-induced platelet aggregation. Cancer Res 51(3):921–925PubMedGoogle Scholar
  260. 260.
    Chandramohan V, Bao X, Kato Kaneko M, Kato Y, Keir ST, Szafranski SE, Kuan CT, Pastan IH, Bigner DD (2013) Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors. Int J Cancer 132(10):2339–2348. doi: 10.1002/ijc.27919 PubMedCrossRefGoogle Scholar
  261. 261.
    Kato Y, Kaneko MK, Kuno A, Uchiyama N, Amano K, Chiba Y, Hasegawa Y, Hirabayashi J, Narimatsu H, Mishima K, Osawa M (2006) Inhibition of tumor cell-induced platelet aggregation using a novel anti-podoplanin antibody reacting with its platelet-aggregation-stimulating domain. Biochem Biophys Res Commun 349(4):1301–1307. doi: 10.1016/j.bbrc.2006.08.171 PubMedCrossRefGoogle Scholar
  262. 262.
    Kato Y, Vaidyanathan G, Kaneko MK, Mishima K, Srivastava N, Chandramohan V, Pegram C, Keir ST, Kuan CT, Bigner DD, Zalutsky MR (2010) Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas. Nucl Med Biol 37(7):785–794. doi: 10.1016/j.nucmedbio.2010.03.010 PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Abe S, Morita Y, Kaneko MK, Hanibuchi M, Tsujimoto Y, Goto H, Kakiuchi S, Aono Y, Huang J, Sato S, Kishuku M, Taniguchi Y, Azuma M, Kawazoe K, Sekido Y, Yano S, Akiyama S, Sone S, Minakuchi K, Kato Y, Nishioka Y (2013) A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody. J Immunol 190(12):6239–6249. doi: 10.4049/jimmunol.1300448 PubMedCrossRefGoogle Scholar
  264. 264.
    Kaneko MK, Kunita A, Abe S, Tsujimoto Y, Fukayama M, Goto K, Sawa Y, Nishioka Y, Kato Y (2012) Chimeric anti-podoplanin antibody suppresses tumor metastasis through neutralization and antibody-dependent cellular cytotoxicity. Cancer Sci 103(11):1913–1919. doi: 10.1111/j.1349-7006.2012.02385.x PubMedCrossRefGoogle Scholar
  265. 265.
    Cheriyan VT, Wang Y, Muthu M, Jamal S, Chen D, Yang H, Polin LA, Tarca AL, Pass HI, Dou QP, Sharma S, Wali A, Rishi AK (2014) Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis. PLoS One 9(4), e93711. doi: 10.1371/journal.pone.0093711 PubMedPubMedCentralCrossRefGoogle Scholar
  266. 266.
    Jamal S, Cheriyan VT, Muthu M, Munie S, Levi E, Ashour AE, Pass HI, Wali A, Singh M, Rishi AK (2014) CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells. PLoS One 9(3), e89146. doi: 10.1371/journal.pone.0089146 PubMedPubMedCentralCrossRefGoogle Scholar
  267. 267.
    Chang CH, Chung CH, Hsu CC, Peng HC, Huang TF (2014) Inhibitory effects of polypeptides derived from a snake venom C-type lectin, aggretin, on tumor cell-induced platelet aggregation. J Thromb Haemost 12(4):540–549. doi: 10.1111/jth.12519 PubMedCrossRefGoogle Scholar
  268. 268.
    Ochoa-Alvarez JA, Krishnan H, Pastorino JG, Nevel E, Kephart D, Lee JJ, Retzbach EP, Shen Y, Fatahzadeh M, Baredes S, Kalyoussef E, Honma M, Adelson ME, Kaneko MK, Kato Y, Young MA, Deluca-Rapone L, Shienbaum AJ, Yin K, Jensen LD, Goldberg GS (2015) Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms. Oncotarget 6(11):9045–9060Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Graduate School of Biomedical Sciences and Department of Molecular Biology, School of Osteopathic MedicineRowan UniversityStratfordUSA

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