Skip to main content
SpringerLink
Log in

Intercellular Communication, the Tumor Microenvironment, and Tumor Progression

  • Chapter
Intercellular Communication in Cancer

Abstract

Within a solid tumor, cancer cells interact with normal host cells as well as with insoluble and soluble factors, including extracellular matrix proteins and chemokines. Here, we survey the molecular mechanisms by which cancer cells interact with their surrounding microenvironment, with a particular focus on intercellular communication. This host-tumor crosstalk provides key signals that direct the growth, migration, and dissemination of cancer cells. Approaches that disrupt or coopt intercellular communication between the tumor and its host are exciting and potentially powerful anti-cancer therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CAF:

Cancer-associated fibroblast

CAR:

Coxsackie-adenovirus receptor

CC:

Chemokine

CCR:

Chemokine receptor

CSC:

Cancerstem cell

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EMT:

Epithelial-mesenchymal transition

GJ:

Gap junction

GJIC:

Gap junction intercellular communication

HCC:

Hepatocellular carcinoma

HGF:

Hepatocyte growth factor

ICAM:

Intercellular adhesion molecule

IL:

Interleukin

LN:

Lymph node

MSC:

Mesenchymal stem cell

MVB:

Multi-vesicular body

PDGF:

Platelet-derived growth factor

SLN:

Sentinel lymph node

TAK:

Transforming growth factor kinase

siRNA:

Short interfering RNA

TGF:

Transforming growth factor

TNF:

Tumor necrosis factor

VCAM:

Vascular cell adhesion molecule

VEGF:

Vascular endothelial growth factor

References

  1. Mueller MM, Fusenig NE (2004) Friends or foes – bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4(11):839–849

    Article  CAS  PubMed  Google Scholar 

  2. Korkaya H, Liu S, Wicha MS (2011) Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest 121(10):3804–3809

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Calorini L, Bianchini F (2010) Environmental control of invasiveness and metastatic dissemination of tumor cells: the role of tumor cell-host cell interactions. Cell Commun Signal 8:24

    PubMed Central  PubMed  Google Scholar 

  4. Polyak K, Haviv I, Campbell IG (2009) Co-evolution of tumor cells and their microenvironment. Trends Genet 25(1):30–38

    Article  CAS  PubMed  Google Scholar 

  5. Matter K, Aijaz S, Tsapara A, Balda MS (2005) Mammalian tight junctions in the regulation of epithelial differentiation and proliferation. Curr Opin Cell Biol 17(5):453–458

    Article  CAS  PubMed  Google Scholar 

  6. Evans WH, Martin PE (2002) Gap junctions: structure and function (review). Mol Membr Biol 19(2):121–136

    Article  CAS  PubMed  Google Scholar 

  7. Stains JP, Civitelli R (2005) Gap junctions regulate extracellular signal-regulated kinase signaling to affect gene transcription. Mol Biol Cell 16(1):64–72

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Yamasaki H (1990) Gap junctional intercellular communication and carcinogenesis. Carcinogenesis 11(7):1051–1058

    Article  CAS  PubMed  Google Scholar 

  9. Eghbali B, Kessler JA, Reid LM, Roy C, Spray DC (1991) Involvement of gap junctions in tumorigenesis: transfection of tumor cells with connexin 32 cdna retards growth in vivo. Proc Natl Acad Sci U S A 88(23):10701–10705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Imagawa W, Pedchenko VK, Helber J, Zhang H (2002) Hormone/growth factor interactions mediating epithelial/stromal communication in mammary gland development and carcinogenesis. J Steroid Biochem Mol Biol 80(2):213–230

    Article  CAS  PubMed  Google Scholar 

  11. O’Hayre M, Salanga CL, Handel TM, Allen SJ (2008) Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem J 409(3):635–649

    Article  PubMed  CAS  Google Scholar 

  12. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L (2010) Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int 78(9):838–848

    Article  CAS  PubMed  Google Scholar 

  13. Qu Y, Dahl G (2002) Function of the voltage gate of gap junction channels: selective exclusion of molecules. Proc Natl Acad Sci U S A 99(2):697–702

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Wolvetang EJ, Pera MF, Zuckerman KS (2007) Gap junction mediated transport of shRNA between human embryonic stem cells. Biochem Biophys Res Commun 363(3):610–615

    Article  CAS  PubMed  Google Scholar 

  15. Valiunas V, Polosina YY, Miller H, Potapova IA, Valiuniene L, Doronin S, Mathias RT, Robinson RB, Rosen MR, Cohen IS, Brink PR (2005) Connexin-specific cell-to-cell transfer of short interfering rna by gap junctions. J Physiol 568(Pt 2):459–468

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Chang Q, Tang W, Ahmad S, Zhou B, Lin X (2008) Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice. PLoS One 3(12), e4088

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Yamasaki H, Mesnil M, Omori Y, Mironov N, Krutovskikh V (1995) Intercellular communication and carcinogenesis. Mutat Res 333(1–2):181–188

    Article  CAS  PubMed  Google Scholar 

  18. Trosko JE, Ruch RJ (1998) Cell-cell communication in carcinogenesis. Front Biosci 3:d208–d236

    CAS  PubMed  Google Scholar 

  19. Djalilian AR, McGaughey D, Patel S, Seo EY, Yang C, Cheng J, Tomic M, Sinha S, Ishida-Yamamoto A, Segre JA (2006) Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response. J Clin Invest 116(5):1243–1253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Langlois S, Maher AC, Manias JL, Shao Q, Kidder GM, Laird DW (2007) Connexin levels regulate keratinocyte differentiation in the epidermis. J Biol Chem 282(41):30171–30180

    Article  CAS  PubMed  Google Scholar 

  21. Maass K, Ghanem A, Kim JS, Saathoff M, Urschel S, Kirfel G, Grummer R, Kretz M, Lewalter T, Tiemann K, Winterhager E, Herzog V, Willecke K (2004) Defective epidermal barrier in neonatal mice lacking the c-terminal region of connexin43. Mol Biol Cell 15(10):4597–4608

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Krutovskikh V, Mazzoleni G, Mironov N, Omori Y, Aguelon AM, Mesnil M, Berger F, Partensky C, Yamasaki H (1994) Altered homologous and heterologous gap-junctional intercellular communication in primary human liver tumors associated with aberrant protein localization but not gene mutation of connexin 32. Int J Cancer 56(1):87–94

    Article  CAS  PubMed  Google Scholar 

  23. Uchida Y, Matsuda K, Sasahara K, Kawabata H, Nishioka M (1995) Immunohistochemistry of gap junctions in normal and diseased gastric mucosa of humans. Gastroenterology 109(5):1492–1496

    Article  CAS  PubMed  Google Scholar 

  24. Tsai H, Werber J, Davia MO, Edelman M, Tanaka KE, Melman A, Christ GJ, Geliebter J (1996) Reduced connexin 43 expression in high grade, human prostatic adenocarcinoma cells. Biochem Biophys Res Commun 227(1):64–69

    Article  CAS  PubMed  Google Scholar 

  25. King TJ, Fukushima LH, Hieber AD, Shimabukuro KA, Sakr WA, Bertram JS (2000) Reduced levels of connexin43 in cervical dysplasia: inducible expression in a cervical carcinoma cell line decreases neoplastic potential with implications for tumor progression. Carcinogenesis 21(6):1097–1109

    Article  CAS  PubMed  Google Scholar 

  26. Loewenstein WR, Kanno Y (1966) Intercellular communication and the control of tissue growth: lack of communication between cancer cells. Nature 209(5029):1248–1249

    Article  CAS  PubMed  Google Scholar 

  27. Tada J, Hashimoto K (1997) Ultrastructural localization of gap junction protein connexin 43 in normal human skin, basal cell carcinoma, and squamous cell carcinoma. J Cutan Pathol 24(10):628–635

    Article  CAS  PubMed  Google Scholar 

  28. Temme A, Buchmann A, Gabriel HD, Nelles E, Schwarz M, Willecke K (1997) High incidence of spontaneous and chemically induced liver tumors in mice deficient for connexin32. Curr Biol 7(9):713–716

    Article  CAS  PubMed  Google Scholar 

  29. Avanzo JL, Mesnil M, Hernandez-Blazquez FJ, Mackowiak II, Mori CM, da Silva TC, Oloris SC, Garate AP, Massironi SM, Yamasaki H, Dagli ML (2004) Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43. Carcinogenesis 25(10):1973–1982

    Article  CAS  PubMed  Google Scholar 

  30. Saunders MM, Seraj MJ, Li Z, Zhou Z, Winter CR, Welch DR, Donahue HJ (2001) Breast cancer metastatic potential correlates with a breakdown in homospecific and heterospecific gap junctional intercellular communication. Cancer Res 61(5):1765–1767

    CAS  PubMed  Google Scholar 

  31. Yang J, Liu B, Wang Q, Yuan D, Hong X, Yang Y, Tao L (2011) Connexin 32 and its derived homotypic gap junctional intercellular communication inhibit the migration and invasion of transfected hela cells via enhancement of intercellular adhesion. Mol Med Rep 4(5):971–979

    CAS  PubMed  Google Scholar 

  32. McLachlan E, Shao Q, Laird DW (2007) Connexins and gap junctions in mammary gland development and breast cancer progression. J Membr Biol 218(1–3):107–121

    Article  CAS  PubMed  Google Scholar 

  33. Li Z, Zhou Z, Donahue HJ (2008) Alterations in cx43 and ob-cadherin affect breast cancer cell metastatic potential. Clin Exp Metastasis 25(3):265–272

    Article  CAS  PubMed  Google Scholar 

  34. Li Z, Zhou Z, Welch DR, Donahue HJ (2008) Expressing connexin 43 in breast cancer cells reduces their metastasis to lungs. Clin Exp Metastasis 25(8):893–901

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Rhee DY, Zhao XQ, Francis RJ, Huang GY, Mably JD, Lo CW (2009) Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development. Development 136(18):3185–3193

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Mehta PP, Bertram JS, Loewenstein WR (1986) Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell 44(1):187–196

    Article  CAS  PubMed  Google Scholar 

  37. Jara PI, Boric MP, Saez JC (1995) Leukocytes express connexin 43 after activation with lipopolysaccharide and appear to form gap junctions with endothelial cells after ischemia-reperfusion. Proc Natl Acad Sci U S A 92(15):7011–7015

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. El-Sabban ME, Pauli BU (1991) Cytoplasmic dye transfer between metastatic tumor cells and vascular endothelium. J Cell Biol 115(5):1375–1382

    Article  CAS  PubMed  Google Scholar 

  39. Pollmann MA, Shao Q, Laird DW, Sandig M (2005) Connexin 43 mediated gap junctional communication enhances breast tumor cell diapedesis in culture. Breast Cancer Res 7(4):R522–R534

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. El-Sabban ME, Pauli BU (1994) Adhesion-mediated gap junctional communication between lung-metastatic cancer cells and endothelium. Invasion Metastasis 14(1–6):164–176

    CAS  PubMed  Google Scholar 

  41. Elzarrad MK, Haroon A, Willecke K, Dobrowolski R, Gillespie MN, Al-Mehdi AB (2008) Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium. BMC Med 6:20

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Ito A, Katoh F, Kataoka TR, Okada M, Tsubota N, Asada H, Yoshikawa K, Maeda S, Kitamura Y, Yamasaki H, Nojima H (2000) A role for heterologous gap junctions between melanoma and endothelial cells in metastasis. J Clin Invest 105(9):1189–1197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Naoi Y, Miyoshi Y, Taguchi T, Kim SJ, Arai T, Maruyama N, Tamaki Y, Noguchi S (2008) Connexin26 expression is associated with aggressive phenotype in human papillary and follicular thyroid cancers. Cancer Lett 262(2):248–256

    Article  CAS  PubMed  Google Scholar 

  44. Ezumi K, Yamamoto H, Murata K, Higashiyama M, Damdinsuren B, Nakamura Y, Kyo N, Okami J, Ngan CY, Takemasa I, Ikeda M, Sekimoto M, Matsuura N, Nojima H, Monden M (2008) Aberrant expression of connexin 26 is associated with lung metastasis of colorectal cancer. Clin Cancer Res 14(3):677–684

    Article  CAS  PubMed  Google Scholar 

  45. Inose T, Kato H, Kimura H, Faried A, Tanaka N, Sakai M, Sano A, Sohda M, Nakajima M, Fukai Y, Miyazaki T, Masuda N, Fukuchi M, Kuwano H (2009) Correlation between connexin 26 expression and poor prognosis of esophageal squamous cell carcinoma. Ann Surg Oncol 16(6):1704–1710

    Article  PubMed  Google Scholar 

  46. Naoi Y, Miyoshi Y, Taguchi T, Kim SJ, Arai T, Tamaki Y, Noguchi S (2007) Connexin26 expression is associated with lymphatic vessel invasion and poor prognosis in human breast cancer. Breast Cancer Res Treat 106(1):11–17

    Article  CAS  PubMed  Google Scholar 

  47. Lim PK, Bliss SA, Patel SA, Taborga M, Dave MA, Gregory LA, Greco SJ, Bryan M, Patel PS, Rameshwar P (2011) Gap junction-mediated import of microrna from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res 71(5):1550–1560

    Article  CAS  PubMed  Google Scholar 

  48. Ao M, Franco OE, Park D, Raman D, Williams K, Hayward SW (2007) Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium. Cancer Res 67(9):4244–4253

    Article  CAS  PubMed  Google Scholar 

  49. Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9(8):581–593

    Article  CAS  PubMed  Google Scholar 

  50. Simons M, Raposo G (2009) Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol 21(4):575–581

    Article  CAS  PubMed  Google Scholar 

  51. Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH (2009) Exosomal microrna: a diagnostic marker for lung cancer. Clin Lung Cancer 10(1):42–46

    Article  CAS  PubMed  Google Scholar 

  52. Suetsugu A, Honma K, Saji S, Moriwaki H, Ochiya T, Hoffman RM (2013) Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. Adv Drug Deliv Rev 65(3):383–390

    Article  CAS  PubMed  Google Scholar 

  53. Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, Skog J (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2:180

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mrnas and micrornas is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659

    Article  CAS  PubMed  Google Scholar 

  55. Xiao D, Ohlendorf J, Chen Y, Taylor DD, Rai SN, Waigel S, Zacharias W, Hao H, McMasters KM (2012) Identifying mrna, microrna and protein profiles of melanoma exosomes. PLoS One 7(10), e46874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Kogure T, Lin WL, Yan IK, Braconi C, Patel T (2011) Intercellular nanovesicle-mediated microrna transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 54(4):1237–1248

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Staubach S, Razawi H, Hanisch FG (2009) Proteomics of muc1-containing lipid rafts from plasma membranes and exosomes of human breast carcinoma cells mcf-7. Proteomics 9(10):2820–2835

    Article  CAS  PubMed  Google Scholar 

  58. Hood JL, Pan H, Lanza GM, Wickline SA, Consortium for Translational Research in Advanced I, Nanomedicine (2009) Paracrine induction of endothelium by tumor exosomes. Lab Invest 89(11):1317–1328

    Article  PubMed Central  PubMed  Google Scholar 

  59. Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH (2013) Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem 288(48):34343–34351

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through met. Nat Med 18(6):883–891

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, Yan Y, Mao F, Zhao C, Shi Y, Xu W (2012) Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through tgf-beta/smad pathway. PLoS One 7(12), e52465

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL (2012) Exosomes mediate stromal mobilization of autocrine wnt-pcp signaling in breast cancer cell migration. Cell 151(7):1542–1556

    Article  CAS  PubMed  Google Scholar 

  63. Abusamra AJ, Zhong Z, Zheng X, Li M, Ichim TE, Chin JL, Min WP (2005) Tumor exosomes expressing fas ligand mediate cd8+ t-cell apoptosis. Blood Cells Mol Dis 35(2):169–173

    Article  CAS  PubMed  Google Scholar 

  64. Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, Tang JH (2014) Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of micrornas. PLoS One 9(4), e95240

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Taylor DD, Gercel-Taylor C (2008) Microrna signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110(1):13–21

    Article  CAS  PubMed  Google Scholar 

  66. Rosell R, Wei J, Taron M (2009) Circulating microrna signatures of tumor-derived exosomes for early diagnosis of non-small-cell lung cancer. Clin Lung Cancer 10(1):8–9

    Article  CAS  PubMed  Google Scholar 

  67. Silva J, Garcia V, Rodriguez M, Compte M, Cisneros E, Veguillas P, Garcia JM, Dominguez G, Campos-Martin Y, Cuevas J, Pena C, Herrera M, Diaz R, Mohammed N, Bonilla F (2012) Analysis of exosome release and its prognostic value in human colorectal cancer. Genes Chromosomes Cancer 51(4):409–418

    Article  CAS  PubMed  Google Scholar 

  68. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S (2009) Microenvironmental ph is a key factor for exosome traffic in tumor cells. J Biol Chem 284(49):34211–34222

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated kras and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289(7):3869–3875

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, Zheng Y, Hoshino A, Brazier H, Xiang J, Williams C, Rodriguez-Barrueco R, Silva JM, Zhang W, Hearn S, Elemento O, Paknejad N, Manova-Todorova K, Welte K, Bromberg J, Peinado H, Lyden D (2014) Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res 24:766–769. doi:10.1038/cr.2014.44

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Bettermann K, Vucur M, Haybaeck J, Koppe C, Janssen J, Heymann F, Weber A, Weiskirchen R, Liedtke C, Gassler N, Muller M, de Vos R, Wolf MJ, Boege Y, Seleznik GM, Zeller N, Erny D, Fuchs T, Zoller S, Cairo S, Buendia MA, Prinz M, Akira S, Tacke F, Heikenwalder M, Trautwein C, Luedde T (2010) Tak1 suppresses a nemo-dependent but nf-kappab-independent pathway to liver cancer. Cancer Cell 17(5):481–496

    Article  CAS  PubMed  Google Scholar 

  72. Rana S, Malinowska K, Zoller M (2013) Exosomal tumor microrna modulates premetastatic organ cells. Neoplasia 15(3):281–295

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71(11):3792–3801

    Article  CAS  PubMed  Google Scholar 

  74. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  75. Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, Morelli D, Villa A, Della Mina P, Menard S, Filipazzi P, Rivoltini L, Tagliabue E, Pupa SM (2012) Potential role of her2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol 227(2):658–667

    Article  CAS  PubMed  Google Scholar 

  76. Rasanen K, Vaheri A (2010) Activation of fibroblasts in cancer stroma. Exp Cell Res 316(17):2713–2722

    Article  PubMed  CAS  Google Scholar 

  77. Xu J, Lamouille S, Derynck R (2009) Tgf-beta-induced epithelial to mesenchymal transition. Cell Res 19(2):156–172

    Article  CAS  PubMed  Google Scholar 

  78. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, Abbruzzese JL, Hortobagyi GN, Hung MC (2007) Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of twist gene expression. Cancer Res 67(19):9066–9076

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Elliott BE, Hung WL, Boag AH, Tuck AB (2002) The role of hepatocyte growth factor (scatter factor) in epithelial-mesenchymal transition and breast cancer. Can J Physiol Pharmacol 80(2):91–102

    Article  CAS  PubMed  Google Scholar 

  80. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, Oberyszyn TM, Hall BM (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28(33):2940–2947

    Article  CAS  PubMed  Google Scholar 

  81. Fernando RI, Castillo MD, Litzinger M, Hamilton DH, Palena C (2011) Il-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res 71(15):5296–5306

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Nieto MA, Cano A (2012) The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin Cancer Biol 22(5–6):361–368

    Article  CAS  PubMed  Google Scholar 

  83. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    Article  CAS  PubMed  Google Scholar 

  84. Fuxe J, Vincent T, Garcia de Herreros A (2010) Transcriptional crosstalk between tgf-beta and stem cell pathways in tumor cell invasion: role of emt promoting smad complexes. Cell Cycle 9(12):2363–2374

    Article  CAS  PubMed  Google Scholar 

  85. Radisky DC (2005) Epithelial-mesenchymal transition. J Cell Sci 118(Pt 19):4325–4326

    Article  CAS  PubMed  Google Scholar 

  86. Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. De Craene B, Berx G (2013) Regulatory networks defining emt during cancer initiation and progression. Nat Rev Cancer 13(2):97–110

    Article  PubMed  CAS  Google Scholar 

  88. Akhurst RJ, Derynck R (2001) Tgf-beta signaling in cancer–a double-edged sword. Trends Cell Biol 11(11):S44–S51

    Article  CAS  PubMed  Google Scholar 

  89. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8(2):98–101

    CAS  PubMed  Google Scholar 

  91. Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4(7):540–550

    Article  CAS  PubMed  Google Scholar 

  92. Zlotnik A, Yoshie O (2012) The chemokine superfamily revisited. Immunity 36(5):705–716

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, Lipp M (1999) Ccr7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99(1):23–33

    Article  CAS  PubMed  Google Scholar 

  94. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56

    Article  CAS  PubMed  Google Scholar 

  95. Zlotnik A (2006) Involvement of chemokine receptors in organ-specific metastasis. Contrib Microbiol 13:191–199

    Article  CAS  PubMed  Google Scholar 

  96. Constantin G, Majeed M, Giagulli C, Piccio L, Kim JY, Butcher EC, Laudanna C (2000) Chemokines trigger immediate beta2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. Immunity 13(6):759–769

    Article  CAS  PubMed  Google Scholar 

  97. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695

    Article  CAS  PubMed  Google Scholar 

  98. Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3(6):453–458

    Article  CAS  PubMed  Google Scholar 

  99. Witz IP (2008) The selectin-selectin ligand axis in tumor progression. Cancer Metastasis Rev 27(1):19–30

    Article  CAS  PubMed  Google Scholar 

  100. Laubli H, Spanaus KS, Borsig L (2009) Selectin-mediated activation of endothelial cells induces expression of ccl5 and promotes metastasis through recruitment of monocytes. Blood 114(20):4583–4591

    Article  CAS  PubMed  Google Scholar 

  101. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563

    Article  CAS  PubMed  Google Scholar 

  102. Velasco-Velazquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG (2012) Ccr5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res 72(15):3839–3850

    Article  CAS  PubMed  Google Scholar 

  103. Keeley EC, Mehrad B, Strieter RM (2011) Chemokines as mediators of tumor angiogenesis and neovascularization. Exp Cell Res 317(5):685–690

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY, Buechi L, Walz A, Richmond A, Strieter RM (2000) The cxc chemokine receptor 2, cxcr2, is the putative receptor for elr + cxc chemokine-induced angiogenic activity. J Immunol 165(9):5269–5277

    Article  CAS  PubMed  Google Scholar 

  105. Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ, Murphy WJ (2000) Human endothelial cells express ccr2 and respond to mcp-1: direct role of mcp-1 in angiogenesis and tumor progression. Blood 96(1):34–40

    CAS  PubMed  Google Scholar 

  106. Li X, Loberg R, Liao J, Ying C, Snyder LA, Pienta KJ, McCauley LK (2009) A destructive cascade mediated by ccl2 facilitates prostate cancer growth in bone. Cancer Res 69(4):1685–1692

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Singh S, Varney M, Singh RK (2009) Host cxcr2-dependent regulation of melanoma growth, angiogenesis, and experimental lung metastasis. Cancer Res 69(2):411–415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Nathanson SD (2003) Insights into the mechanisms of lymph node metastasis. Cancer 98(2):413–423

    Article  PubMed  Google Scholar 

  109. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001) Induction of tumor lymphangiogenesis by vegf-c promotes breast cancer metastasis. Nat Med 7(2):192–198

    Article  CAS  PubMed  Google Scholar 

  110. Oh SJ, Jeltsch MM, Birkenhager R, McCarthy JE, Weich HA, Christ B, Alitalo K, Wilting J (1997) Vegf and vegf-c: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188(1):96–109

    Article  CAS  PubMed  Google Scholar 

  111. Saeki H, Moore AM, Brown MJ, Hwang ST (1999) Cutting edge: secondary lymphoid-tissue chemokine (slc) and cc chemokine receptor 7 (ccr7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol 162(5):2472–2475

    CAS  PubMed  Google Scholar 

  112. Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, Butz S, Vestweber D, Corada M, Molendini C, Dejana E, McDonald DM (2007) Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med 204(10):2349–2362

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Hopken UE, Foss HD, Meyer D, Hinz M, Leder K, Stein H, Lipp M (2002) Up-regulation of the chemokine receptor ccr7 in classical but not in lymphocyte-predominant hodgkin disease correlates with distinct dissemination of neoplastic cells in lymphoid organs. Blood 99(4):1109–1116

    Article  CAS  PubMed  Google Scholar 

  114. Liu F, Lang R, Wei J, Fan Y, Cui L, Gu F, Guo X, Pringle GA, Zhang X, Fu L (2009) Increased expression of sdf-1/cxcr4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast. Histopathology 54(6):741–750

    Article  PubMed  Google Scholar 

  115. Ding Y, Shimada Y, Maeda M, Kawabe A, Kaganoi J, Komoto I, Hashimoto Y, Miyake M, Hashida H, Imamura M (2003) Association of cc chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma. Clin Cancer Res 9(9):3406–3412

    CAS  PubMed  Google Scholar 

  116. Manzo A, Bugatti S, Caporali R, Prevo R, Jackson DG, Uguccioni M, Buckley CD, Montecucco C, Pitzalis C (2007) Ccl21 expression pattern of human secondary lymphoid organ stroma is conserved in inflammatory lesions with lymphoid neogenesis. Am J Pathol 171(5):1549–1562

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA (2007) Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine ccr7 signaling. Cancer Cell 11(6):526–538

    Article  CAS  PubMed  Google Scholar 

  118. Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST (2001) Expression of cc chemokine receptor-7 and regional lymph node metastasis of b16 murine melanoma. J Natl Cancer Inst 93(21):1638–1643

    Article  CAS  PubMed  Google Scholar 

  119. Uchida D, Onoue T, Begum NM, Kuribayashi N, Tomizuka Y, Tamatani T, Nagai H, Miyamoto Y (2009) Vesnarinone downregulates cxcr4 expression via upregulation of kruppel-like factor 2 in oral cancer cells. Mol Cancer 8:62

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  120. Mirisola V, Zuccarino A, Bachmeier BE, Sormani MP, Falter J, Nerlich A, Pfeffer U (2009) Cxcl12/sdf1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival. Eur J Cancer 45(14):2579–2587

    Article  CAS  PubMed  Google Scholar 

  121. Salmaggi A, Maderna E, Calatozzolo C, Gaviani P, Canazza A, Milanesi I, Silvani A, DiMeco F, Carbone A, Pollo B (2009) Cxcl12, cxcr4 and cxcr7 expression in brain metastases. Cancer Biol Ther 8(17):1608–1614

    Article  CAS  PubMed  Google Scholar 

  122. Salogni L, Musso T, Bosisio D, Mirolo M, Jala VR, Haribabu B, Locati M, Sozzani S (2009) Activin a induces dendritic cell migration through the polarized release of cxc chemokine ligands 12 and 14. Blood 113(23):5848–5856

    Article  CAS  PubMed  Google Scholar 

  123. Sozzani S, Allavena P, D’Amico G, Luini W, Bianchi G, Kataura M, Imai T, Yoshie O, Bonecchi R, Mantovani A (1998) Differential regulation of chemokine receptors during dendritic cell maturation: a model for their trafficking properties. J Immunol 161(3):1083–1086

    CAS  PubMed  Google Scholar 

  124. Xu Q, Yuan X, Xu M, McLafferty F, Hu J, Lee BS, Liu G, Zeng Z, Black KL, Yu JS (2009) Chemokine cxc receptor 4--mediated glioma tumor tracking by bone marrow--derived neural progenitor/stem cells. Mol Cancer Ther 8(9):2746–2753

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Sugiyama T, Kohara H, Noda M, Nagasawa T (2006) Maintenance of the hematopoietic stem cell pool by cxcl12-cxcr4 chemokine signaling in bone marrow stromal cell niches. Immunity 25(6):977–988

    Article  CAS  PubMed  Google Scholar 

  126. Cardones AR, Murakami T, Hwang ST (2003) Cxcr4 enhances adhesion of b16 tumor cells to endothelial cells in vitro and in vivo via beta (1) integrin. Cancer Res 63(20):6751–6757

    CAS  PubMed  Google Scholar 

  127. Kim M, Koh YJ, Kim KE, Koh BI, Nam DH, Alitalo K, Kim I, Koh GY (2010) Cxcr4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res 70(24):10411–10421

    Article  CAS  PubMed  Google Scholar 

  128. Arigami T, Natsugoe S, Uenosono Y, Yanagita S, Arima H, Hirata M, Ishigami S, Aikou T (2009) Ccr7 and cxcr4 expression predicts lymph node status including micrometastasis in gastric cancer. Int J Oncol 35(1):19–24

    Article  CAS  PubMed  Google Scholar 

  129. Tanaka M, Grossman HB (2001) Connexin 26 gene therapy of human bladder cancer: induction of growth suppression, apoptosis, and synergy with cisplatin. Hum Gene Ther 12(18):2225–2236

    Article  CAS  PubMed  Google Scholar 

  130. Shishido SN, Nguyen TA (2012) Gap junction enhancer increases efficacy of cisplatin to attenuate mammary tumor growth. PLoS One 7(9), e44963

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  131. Li Z, Zhao R, Wu X, Sun Y, Yao M, Li J, Xu Y, Gu J (2005) Identification and characterization of a novel peptide ligand of epidermal growth factor receptor for targeted delivery of therapeutics. FASEB J 19(14):1978–1985

    Article  CAS  PubMed  Google Scholar 

  132. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M (2013) Systemically injected exosomes targeted to egfr deliver antitumor microrna to breast cancer cells. Mol Ther 21(1):185–191

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, Wei J, Nie G (2014) A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 35(7):2383–2390

    Article  CAS  PubMed  Google Scholar 

  134. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11(3):259–273

    Article  CAS  PubMed  Google Scholar 

  135. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M, Stanford J, Cook RS, Arteaga CL (2013) Tgf-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest 123(3):1348–1358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Domanska UM, Timmer-Bosscha H, Nagengast WB, Oude Munnink TH, Kruizinga RC, Ananias HJ, Kliphuis NM, Huls G, De Vries EG, de Jong IJ, Walenkamp AM (2012) Cxcr4 inhibition with amd3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia 14(8):709–718

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Chemical and Biological Engineering, Princeton University, Princeton, NJ, 08544, USA

    Mei-Fong Pang & Celeste M. Nelson

  2. Departments of Molecular Biology, Princeton University, 303 Hoyt Laboratory, William Street, Princeton, NJ, 08544, USA

    Mei-Fong Pang & Celeste M. Nelson

Authors
  1. Mei-Fong Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Celeste M. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Celeste M. Nelson .

Editor information

Editors and Affiliations

  1. Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA

    Mustapha Kandouz

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Pang, MF., Nelson, C.M. (2015). Intercellular Communication, the Tumor Microenvironment, and Tumor Progression. In: Kandouz, M. (eds) Intercellular Communication in Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7380-5_13

Download citation

Publish with us

Policies and ethics

Search

Navigation