Skip to main content
SpringerLink
Log in

Impact of Tumor Hypoxia, Src, and Met Signaling in the Dissemination of Tumor Cells

  • Chapter
  • First Online:
Signaling Pathways and Molecular Mediators in Metastasis

  • 1328 Accesses

Abstract

Metastasis is the major cause of therapeutic failure and high mortality in cancer patients. The metastatic cascade consists of a series of cellular processes including migration, invasion and survival. Hypoxia has been identified as a key contributor to critical functions associated with tumor cell dissemination. Hypoxia-induced alterations are primarily mediated by the transcription factor hypoxia-inducible factor 1 (HIF-1), a factor that induces the expression of an array of genes associated with cell aggressiveness. In addition, altered intracellular signaling pathways, such as c-Src and c-Met, aid tumor cells to progress towards a metastatic phenotype and strongly correlates with poor prognosis. Given the pivotal role of hypoxia/HIF-1, c-Src and c-Met in the metastatic process, the potential for developing therapeutic strategies targeting these pathways is significant. Although the effects of HIF-1 inhibitors require further investigation, small molecule kinase inhibitors targeting Src or Met already have been shown to have considerable efficacy in metastatic diseases. Overall, the fact that cancer cell dissemination can be driven by both external (hypoxia) and internal features (c-Src, c-Met) suggests that the combined targeting of tumor microenvironment and intracellular signaling pathways may have particular utility in impeding cancer metastasis.

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

References

  1. Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300

    PubMed  Google Scholar 

  2. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM (2006) Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 244:254–9

    PubMed  Google Scholar 

  3. Talmadge JE, Fidler IJ (2010) AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 70:5649–69

    PubMed  CAS  Google Scholar 

  4. Ljungkvist AS, Bussink J, Kaanders JH, Wiedenmann NE, Vlasman R, van der Kogel AJ (2006) Dynamics of hypoxia, proliferation and apoptosis after irradiation in a murine tumor model. Radiat Res 165:326–36

    PubMed  CAS  Google Scholar 

  5. Bristow RG, Hill RP (2008) Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8:180–92

    PubMed  CAS  Google Scholar 

  6. Chan DA, Giaccia AJ (2007) Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev 26:333–9

    PubMed  CAS  Google Scholar 

  7. Chaudary N, Hill RP (2007) Hypoxia and metastasis. Clin Cancer Res 13:1947–9

    PubMed  CAS  Google Scholar 

  8. Vergis R, Corbishley CM, Norman AR et al (2008) Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 9:342–51

    PubMed  Google Scholar 

  9. Gort EH, Groot AJ, van der Wall E, van Diest PJ, Vooijs MA (2008) Hypoxic regulation of metastasis via hypoxia-inducible factors. Curr Mol Med 8:60–7

    PubMed  CAS  Google Scholar 

  10. Fyles A, Milosevic M, Pintilie M et al (2006) Long-term performance of interstitial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 80:132–7

    PubMed  Google Scholar 

  11. Zhang L, Hill RP (2007) Hypoxia enhances metastatic efficiency in HT1080 fibrosarcoma cells by increasing cell survival in lungs, not cell adhesion and invasion. Cancer Res 67:7789–97

    PubMed  CAS  Google Scholar 

  12. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–32

    PubMed  CAS  Google Scholar 

  13. Sullivan R, Graham CH (2007) Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 26:319–31

    PubMed  CAS  Google Scholar 

  14. Mak P, Leav I, Pursell B et al (2010) ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell 17:319–32

    PubMed  CAS  Google Scholar 

  15. Dvorak HF, Nagy JA, Feng D, Brown LF, Dvorak AM (1999) Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis. Curr Top Microbiol Immunol 237:97–132

    PubMed  CAS  Google Scholar 

  16. Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–47

    PubMed  CAS  Google Scholar 

  17. Fukumura D, Jain RK (2007) Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 101:937–49

    PubMed  CAS  Google Scholar 

  18. Kimura H, Braun RD, Ong ET et al (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56:5522–8

    PubMed  CAS  Google Scholar 

  19. Rofstad EK, Galappathi K, Mathiesen B, Ruud EB (2007) Fluctuating and diffusion-limited hypoxia in hypoxia-induced metastasis. Clin Cancer Res 13:1971–8

    PubMed  CAS  Google Scholar 

  20. Thews O, Wolloscheck T, Dillenburg W et al (2004) Microenvironmental adaptation of experimental tumours to chronic vs. acute hypoxia. Br J Cancer 91:1181–9

    PubMed  CAS  Google Scholar 

  21. Alqawi O, Wang HP, Espiritu M, Singh G (2007) Chronic hypoxia promotes an aggressive phenotype in rat prostate cancer cells. Free Radic Res 41:788–97

    PubMed  CAS  Google Scholar 

  22. Cairns RA, Kalliomaki T, Hill RP (2001) Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 61:8903–8

    PubMed  CAS  Google Scholar 

  23. Cairns RA, Hill RP (2004) Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res 64:2054–61

    PubMed  CAS  Google Scholar 

  24. Hill RP, De Jaeger K, Jang A, Cairns R (2001) pH, hypoxia and metastasis. Novartis Found Symp 240:154–65; discussion 65–8

    PubMed  CAS  Google Scholar 

  25. Ackerstaff E, Artemov D, Gillies RJ, Bhujwalla ZM (2007) Hypoxia and the presence of human vascular endothelial cells affect prostate cancer cell invasion and metabolism. Neoplasia 9:1138–51

    PubMed  CAS  Google Scholar 

  26. McKenzie S, Sakamoto S, Kyprianou N (2008) Maspin modulates prostate cancer cell apoptotic and angiogenic response to hypoxia via targeting AKT. Oncogene 27:7171–9

    PubMed  CAS  Google Scholar 

  27. Giaccia A, Siim BG, Johnson RS (2003) HIF-1 as a target for drug development. Nat Rev Drug Discov 2:803–11

    PubMed  CAS  Google Scholar 

  28. Zhong H, De Marzo AM, Laughner E et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5

    PubMed  CAS  Google Scholar 

  29. Liao D, Corle C, Seagroves TN, Johnson RS (2007) Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 67:563–72

    PubMed  CAS  Google Scholar 

  30. Hiraga T, Kizaka-Kondoh S, Hirota K, Hiraoka M, Yoneda T (2007) Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer. Cancer Res 67:4157–63

    PubMed  CAS  Google Scholar 

  31. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–34

    PubMed  CAS  Google Scholar 

  32. Kopetz S, Shah AN, Gallick GE (2007) Src continues aging: current and future clinical directions. Clin Cancer Res 13:7232–6

    PubMed  CAS  Google Scholar 

  33. Trevino JG, Summy JM, Lesslie DP et al (2006) Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol 168:962–72

    PubMed  CAS  Google Scholar 

  34. Verbeek BS, Vroom TM, Adriaansen-Slot SS et al (1996) c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J Pathol 180:383–8

    PubMed  CAS  Google Scholar 

  35. Tatarov O, Mitchell TJ, Seywright M, Leung HY, Brunton VG, Edwards J (2009) SRC family kinase activity is up-regulated in hormone-refractory prostate cancer. Clin Cancer Res 15:3540–9

    PubMed  CAS  Google Scholar 

  36. Bolen JB, Veillette A, Schwartz AM, DeSeau V, Rosen N (1987) Activation of pp 60c-src protein kinase activity in human colon carcinoma. Proc Natl Acad Sci U S A 84:2251–5

    PubMed  CAS  Google Scholar 

  37. Fizazi K (2007) The role of Src in prostate cancer. Ann Oncol 18:1765–73

    PubMed  CAS  Google Scholar 

  38. Finn RS (2008) Targeting Src in breast cancer. Ann Oncol 19:1379–86

    PubMed  CAS  Google Scholar 

  39. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–72

    PubMed  CAS  Google Scholar 

  40. Kim LC, Song L, Haura EB (2009) Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 6:587–95

    PubMed  Google Scholar 

  41. Irby RB, Yeatman TJ (2002) Increased Src activity disrupts cadherin/catenin-mediated homotypic adhesion in human colon cancer and transformed rodent cells. Cancer Res 62:2669–74

    PubMed  CAS  Google Scholar 

  42. Frame MC (2002) Src in cancer: deregulation and consequences for cell behaviour. Biochim Biophys Acta 1602:114–30

    PubMed  CAS  Google Scholar 

  43. Allgayer H, Wang H, Gallick GE et al (1999) Transcriptional induction of the urokinase receptor gene by a constitutively active Src. Requirement of an upstream motif (-152/-135) bound with Sp1. J Biol Chem 274:18428–37

    PubMed  CAS  Google Scholar 

  44. Criscuoli ML, Nguyen M, Eliceiri BP (2005) Tumor metastasis but not tumor growth is dependent on Src-mediated vascular permeability. Blood 105:1508–14

    PubMed  CAS  Google Scholar 

  45. Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R (2004) Src kinase activity is essential for osteoclast function. J Biol Chem 279:17660–6

    PubMed  CAS  Google Scholar 

  46. Sanjay A, Houghton A, Neff L et al (2001) Cbl associates with Pyk2 and Src to regulate Src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion, and osteoclast motility. J Cell Biol 152:181–95

    PubMed  CAS  Google Scholar 

  47. Myoui A, Nishimura R, Williams PJ et al (2003) C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 63:5028–33

    PubMed  CAS  Google Scholar 

  48. Ishizawar R, Parsons SJ (2004) c-Src and cooperating partners in human cancer. Cancer Cell 6:209–14

    PubMed  CAS  Google Scholar 

  49. Schlaepfer DD, Mitra SK (2004) Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev 14:92–101

    PubMed  CAS  Google Scholar 

  50. Mitra SK, Schlaepfer DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18:516–23

    PubMed  CAS  Google Scholar 

  51. Wheeler DL, Iida M, Dunn EF (2009) The role of Src in solid tumors. Oncologist 14:667–78

    PubMed  CAS  Google Scholar 

  52. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–25

    PubMed  CAS  Google Scholar 

  53. Trusolino L, Bertotti A, Comoglio PM (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11:834–48

    PubMed  CAS  Google Scholar 

  54. Lesko E, Majka M (2008) The biological role of HGF-MET axis in tumor growth and development of metastasis. Front Biosci 13:1271–80

    PubMed  CAS  Google Scholar 

  55. Siegfried JM, Weissfeld LA, Singh-Kaw P, Weyant RJ, Testa JR, Landreneau RJ (1997) Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer. Cancer Res 57:433–9

    PubMed  CAS  Google Scholar 

  56. Gupta A, Karakiewicz PI, Roehrborn CG, Lotan Y, Zlotta AR, Shariat SF (2008) Predictive value of plasma hepatocyte growth factor/scatter factor levels in patients with clinically localized prostate cancer. Clin Cancer Res 14:7385–90

    PubMed  CAS  Google Scholar 

  57. Russo AL, Jedlicka K, Wernick M et al (2009) Urine analysis and protein networking identify met as a marker of metastatic prostate cancer. Clin Cancer Res 15:4292–8

    PubMed  CAS  Google Scholar 

  58. Knudsen BS, Gmyrek GA, Inra J et al (2002) High expression of the Met receptor in prostate cancer metastasis to bone. Urology 60:1113–7

    PubMed  Google Scholar 

  59. Liu X, Newton RC, Scherle PA (2010) Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med 16:37–45

    PubMed  CAS  Google Scholar 

  60. Comoglio PM, Giordano S, Trusolino L (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov 7:504–16

    PubMed  CAS  Google Scholar 

  61. Danilkovitch-Miagkova A, Zbar B (2002) Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest 109:863–7

    PubMed  CAS  Google Scholar 

  62. Schmidt L, Duh FM, Chen F et al (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16:68–73

    PubMed  CAS  Google Scholar 

  63. Di Renzo MF, Olivero M, Martone T et al (2000) Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19:1547–55

    PubMed  Google Scholar 

  64. Houldsworth J, Cordon-Cardo C, Ladanyi M, Kelsen DP, Chaganti RS (1990) Gene amplification in gastric and esophageal adenocarcinomas. Cancer Res 50:6417–22

    PubMed  CAS  Google Scholar 

  65. Di Renzo MF, Olivero M, Giacomini A et al (1995) Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1:147–54

    PubMed  Google Scholar 

  66. Tuck AB, Park M, Sterns EE, Boag A, Elliott BE (1996) Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am J Pathol 148:225–32

    PubMed  CAS  Google Scholar 

  67. Koochekpour S, Jeffers M, Rulong S et al (1997) Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res 57:5391–8

    PubMed  CAS  Google Scholar 

  68. Ferracini R, Di Renzo MF, Scotlandi K et al (1995) The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene 10:739–49

    PubMed  CAS  Google Scholar 

  69. Benvenuti S, Comoglio PM (2007) The MET receptor tyrosine kinase in invasion and metastasis. J Cell Physiol 213:316–25

    PubMed  CAS  Google Scholar 

  70. Dong G, Lee TL, Yeh NT, Geoghegan J, Van Waes C, Chen Z (2004) Metastatic squamous cell carcinoma cells that overexpress c-Met exhibit enhanced angiogenesis factor expression, scattering and metastasis in response to hepatocyte growth factor. Oncogene 23:6199–208

    PubMed  CAS  Google Scholar 

  71. Mineo R, Costantino A, Frasca F et al (2004) Activation of the hepatocyte growth factor (HGF)-Met system in papillary thyroid cancer: biological effects of HGF in thyroid cancer cells depend on Met expression levels. Endocrinology 145:4355–65

    PubMed  CAS  Google Scholar 

  72. Xie Q, Liu KD, Hu MY, Zhou K (2001) SF/HGF-c-Met autocrine and paracrine promote metastasis of hepatocellular carcinoma. World J Gastroenterol 7:816–20

    PubMed  CAS  Google Scholar 

  73. Dai Y, Siemann DW (2010) BMS-777607, a small-molecule met kinase inhibitor, suppresses hepatocyte growth factor-stimulated prostate cancer metastatic phenotype in vitro. Mol Cancer Ther 9:1554–61

    PubMed  CAS  Google Scholar 

  74. Navab R, Liu J, Seiden-Long I et al (2009) Co-overexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells. Neoplasia 11:1292–300

    PubMed  CAS  Google Scholar 

  75. Otsuka T, Takayama H, Sharp R et al (1998) c-Met autocrine activation induces development of malignant melanoma and acquisition of the metastatic phenotype. Cancer Res 58:5157–67

    PubMed  CAS  Google Scholar 

  76. Zeng ZS, Weiser MR, Kuntz E et al (2008) c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett 265:258–69

    PubMed  CAS  Google Scholar 

  77. Lorenzato A, Olivero M, Patane S et al (2002) Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res 62:7025–30

    PubMed  CAS  Google Scholar 

  78. Ghadjar P, Blank-Liss W, Simcock M et al (2009) MET Y1253D-activating point mutation and development of distant metastasis in advanced head and neck cancers. Clin Exp Metastasis 26:809–15

    PubMed  CAS  Google Scholar 

  79. Puri N, Salgia R (2008) Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer. J Carcinog 7:9

    PubMed  Google Scholar 

  80. Tuck AB, Elliott BE, Hota C, Tremblay E, Chambers AF (2000) Osteopontin-induced, integrin-dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factor receptor (Met). J Cell Biochem 78:465–75

    PubMed  CAS  Google Scholar 

  81. Fujita S, Sugano K (1997) Expression of c-met proto-oncogene in primary colorectal cancer and liver metastases. Jpn J Clin Oncol 27:378–83

    PubMed  CAS  Google Scholar 

  82. Yu Y, Merlino G (2002) Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model. Cancer Res 62:2951–6

    PubMed  CAS  Google Scholar 

  83. Boccaccio C, Comoglio PM (2006) Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 6:637–45

    PubMed  CAS  Google Scholar 

  84. Eder JP, Vande Woude GF, Boerner SA, LoRusso PM (2009) Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 15:2207–14

    PubMed  CAS  Google Scholar 

  85. Migliore C, Giordano S (2008) Molecular cancer therapy: can our expectation be MET? Eur J Cancer 44:641–51

    PubMed  CAS  Google Scholar 

  86. Humphrey PA, Zhu X, Zarnegar R et al (1995) Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147:386–96

    PubMed  CAS  Google Scholar 

  87. Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R (2002) Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 13:41–59

    PubMed  CAS  Google Scholar 

  88. Savagner P, Yamada KM, Thiery JP (1997) The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol 137:1403–19

    PubMed  CAS  Google Scholar 

  89. Rosen EM, Lamszus K, Laterra J, Polverini PJ, Rubin JS, Goldberg ID (1997) HGF/SF in angiogenesis. Ciba Found Symp 212:215–26; discussion 27–9

    PubMed  CAS  Google Scholar 

  90. Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC, Van Waes C (2001) Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res 61:5911–8

    PubMed  CAS  Google Scholar 

  91. Tang MK, Zhou HY, Yam JW, Wong AS (2010) c-Met overexpression contributes to the acquired apoptotic resistance of nonadherent ovarian cancer cells through a cross talk mediated by phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2. Neoplasia 12:128–38

    PubMed  CAS  Google Scholar 

  92. Simpson CD, Anyiwe K, Schimmer AD (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272:177–85

    PubMed  CAS  Google Scholar 

  93. Wells CM, Ahmed T, Masters JR, Jones GE (2005) Rho family GTPases are activated during HGF-stimulated prostate cancer-cell scattering. Cell Motil Cytoskeleton 62:180–94

    PubMed  CAS  Google Scholar 

  94. Ridley AJ, Comoglio PM, Hall A (1995) Regulation of scatter factor/hepatocyte growth factor responses by Ras, Rac, and Rho in MDCK cells. Mol Cell Biol 15:1110–22

    PubMed  CAS  Google Scholar 

  95. Zhu H, Naujokas MA, Fixman ED, Torossian K, Park M (1994) Tyrosine 1356 in the carboxyl-terminal tail of the HGF/SF receptor is essential for the transduction of signals for cell motility and morphogenesis. J Biol Chem 269:29943–8

    PubMed  CAS  Google Scholar 

  96. Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC (2000) Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem 275:8806–11

    PubMed  CAS  Google Scholar 

  97. Reznik TE, Sang Y, Ma Y et al (2008) Transcription-dependent epidermal growth factor receptor activation by hepatocyte growth factor. Mol Cancer Res 6:139–50

    PubMed  CAS  Google Scholar 

  98. Khoury H, Naujokas MA, Zuo D et al (2005) HGF converts ErbB2/Neu epithelial morphogenesis to cell invasion. Mol Biol Cell 16:550–61

    PubMed  CAS  Google Scholar 

  99. Maggiora P, Lorenzato A, Fracchioli S et al (2003) The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness. Exp Cell Res 288:382–9

    PubMed  CAS  Google Scholar 

  100. Lau CK, Yang ZF, Ho DW et al (2009) An Akt/hypoxia-inducible factor-1alpha/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells. Clin Cancer Res 15:3462–71

    PubMed  CAS  Google Scholar 

  101. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–61

    PubMed  Google Scholar 

  102. Lluis JM, Buricchi F, Chiarugi P, Morales A, Fernandez-Checa JC (2007) Dual role of mitochondrial reactive oxygen species in hypoxia signaling: activation of nuclear factor-{kappa}B via c-SRC and oxidant-dependent cell death. Cancer Res 67:7368–77

    PubMed  CAS  Google Scholar 

  103. Pham NA, Magalhaes JM, Do T et al (2009) Activation of Src and Src-associated signaling pathways in relation to hypoxia in human cancer xenograft models. Int J Cancer 124:280–6

    PubMed  CAS  Google Scholar 

  104. Karni R, Dor Y, Keshet E, Meyuhas O, Levitzki A (2002) Activated pp 60c-Src leads to elevated hypoxia-inducible factor (HIF)-1alpha expression under normoxia. J Biol Chem 277:42919–25

    PubMed  CAS  Google Scholar 

  105. Jiang BH, Agani F, Passaniti A, Semenza GL (1997) V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res 57:5328–35

    PubMed  CAS  Google Scholar 

  106. Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP (1995) Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375:577–81

    PubMed  CAS  Google Scholar 

  107. Gray MJ, Zhang J, Ellis LM et al (2005) HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24:3110–20

    PubMed  CAS  Google Scholar 

  108. Hara S, Nakashiro K, Klosek SK, Ishikawa T, Shintani S, Hamakawa H (2006) Hypoxia enhances c-Met/HGF receptor expression and signaling by activating HIF-1alpha in human salivary gland cancer cells. Oral Oncol 42:593–8

    PubMed  CAS  Google Scholar 

  109. Knudsen BS, Vande Woude G (2008) Showering c-MET-dependent cancers with drugs. Curr Opin Genet Dev 18:87–96

    PubMed  CAS  Google Scholar 

  110. Toda S, Yamada S, Aoki S, Inokuchi A, Sugihara H (2005) Air-liquid interface promotes invasive growth of laryngeal squamous cell carcinoma with or without hypoxia. Biochem Biophys Res Commun 326:866–72

    PubMed  CAS  Google Scholar 

  111. Eckerich C, Zapf S, Fillbrandt R, Loges S, Westphal M, Lamszus K (2007) Hypoxia can induce c-Met expression in glioma cells and enhance SF/HGF-induced cell migration. Int J Cancer 121:276–83

    PubMed  CAS  Google Scholar 

  112. Wang T, Niki T, Goto A et al (2007) Hypoxia increases the motility of lung adenocarcinoma cell line A549 via activation of the epidermal growth factor receptor pathway. Cancer Sci 98:506–11

    PubMed  CAS  Google Scholar 

  113. Chen HH, Su WC, Lin PW, Guo HR, Lee WY (2007) Hypoxia-inducible factor-1alpha correlates with MET and metastasis in node-negative breast cancer. Breast Cancer Res Treat 103:167–75

    PubMed  CAS  Google Scholar 

  114. Ide T, Kitajima Y, Miyoshi A et al (2006) Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. Int J Cancer 119:2750–9

    PubMed  CAS  Google Scholar 

  115. Scarpino S, Cancellario d’Alena F, Di Napoli A, Pasquini A, Marzullo A, Ruco LP (2004) Increased expression of Met protein is associated with up-regulation of hypoxia inducible factor-1 (HIF-1) in tumour cells in papillary carcinoma of the thyroid. J Pathol 202:352–8

    PubMed  CAS  Google Scholar 

  116. Koochekpour S, Jeffers M, Wang PH et al (1999) The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol 19:5902–12

    PubMed  CAS  Google Scholar 

  117. Hung W, Elliott B (2001) Co-operative effect of c-Src tyrosine kinase and Stat3 in activation of hepatocyte growth factor expression in mammary carcinoma cells. J Biol Chem 276:12395–403

    PubMed  CAS  Google Scholar 

  118. Rahimi N, Hung W, Tremblay E, Saulnier R, Elliott B (1998) c-Src kinase activity is required for hepatocyte growth factor-induced motility and anchorage-independent growth of mammary carcinoma cells. J Biol Chem 273:33714–21

    PubMed  CAS  Google Scholar 

  119. Fan S, Meng Q, Laterra JJ, Rosen EM (2009) Role of Src signal transduction pathways in scatter factor-mediated cellular protection. J Biol Chem 284:7561–77

    PubMed  CAS  Google Scholar 

  120. Herynk MH, Zhang J, Parikh NU, Gallick GE (2007) Activation of Src by c-Met overexpression mediates metastatic properties of colorectal carcinoma cells. J Exp Ther Oncol 6:205–17

    PubMed  CAS  Google Scholar 

  121. Emaduddin M, Bicknell DC, Bodmer WF, Feller SM (2008) Cell growth, global phosphotyrosine elevation, and c-Met phosphorylation through Src family kinases in colorectal cancer cells. Proc Natl Acad Sci U S A 105:2358–62

    PubMed  CAS  Google Scholar 

  122. Rohwer N, Lobitz S, Daskalow K et al (2009) HIF-1alpha determines the metastatic potential of gastric cancer cells. Br J Cancer 100:772–81

    PubMed  CAS  Google Scholar 

  123. Shin DH, Kim JH, Jung YJ et al (2007) Preclinical evaluation of YC-1, a HIF inhibitor, for the prevention of tumor spreading. Cancer Lett 255:107–16

    PubMed  CAS  Google Scholar 

  124. Choi HJ, Eun JS, Kim BG, Kim SY, Jeon H, Soh Y (2006) Vitexin, an HIF-1alpha inhibitor, has anti-metastatic potential in PC12 cells. Mol Cells 22:291–9

    PubMed  CAS  Google Scholar 

  125. Morton JP, Karim SA, Graham K et al (2010) Dasatinib inhibits the development of metastases in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 139:292–303

    PubMed  CAS  Google Scholar 

  126. Fraser CK, Lousberg EL, Guerin LR et al (2010) Dasatinib alters the metastatic phenotype of B16-OVA melanoma in vivo. Cancer Biol Ther 10:715–27

    PubMed  CAS  Google Scholar 

  127. Koreckij T, Nguyen H, Brown LG, Yu EY, Vessella RL, Corey E (2009) Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer 101:263–8

    PubMed  CAS  Google Scholar 

  128. Park SI, Zhang J, Phillips KA et al (2008) Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res 68:3323–33

    PubMed  CAS  Google Scholar 

  129. Green TP, Fennell M, Whittaker R et al (2009) Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol Oncol 3:248–61

    PubMed  CAS  Google Scholar 

  130. Dong M, Rice L, Lepler S, Pampo C, Siemann DW (2010) Impact of the Src inhibitor saracatinib on the metastatic phenotype of a fibrosarcoma (KHT) tumor model. Anticancer Res 30:4405–13

    Google Scholar 

  131. Yang JC, Bai L, Yap S, Gao AC, Kung HJ, Evans CP (2010) Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol Cancer Ther 9:1629–37

    PubMed  CAS  Google Scholar 

  132. Chang YM, Bai L, Liu S, Yang JC, Kung HJ, Evans CP (2008) Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530. Oncogene 27:6365–75

    PubMed  CAS  Google Scholar 

  133. Ammer AG, Kelley LC, Hayes KE et al (2009) Saracatinib impairs head and neck squamous cell carcinoma invasion by disrupting invadopodia function. J Cancer Sci Ther 1:52–61

    PubMed  CAS  Google Scholar 

  134. Nautiyal J, Majumder P, Patel BB, Lee FY, Majumdar AP (2009) Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling. Cancer Lett 283:143–51

    PubMed  CAS  Google Scholar 

  135. Rabbani SA, Valentino ML, Arakelian A, Ali S, Boschelli F (2010) SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol Cancer Ther 9:1147–57

    PubMed  CAS  Google Scholar 

  136. Vultur A, Buettner R, Kowolik C et al (2008) SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther 7:1185–94

    PubMed  CAS  Google Scholar 

  137. Jallal H, Valentino ML, Chen G, Boschelli F, Ali S, Rabbani SA (2007) A Src/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo. Cancer Res 67:1580–8

    PubMed  CAS  Google Scholar 

  138. Weis S, Cui J, Barnes L, Cheresh D (2004) Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis. J Cell Biol 167:223–9

    PubMed  CAS  Google Scholar 

  139. Kenessey I, Keszthelyi M, Kramer Z et al (2010) Inhibition of c-Met with the specific small molecule tyrosine kinase inhibitor SU11274 decreases growth and metastasis formation of experimental human melanoma. Curr Cancer Drug Targets 10:332–42

    PubMed  CAS  Google Scholar 

  140. Wang X, Le P, Liang C et al (2003) Potent and selective inhibitors of the Met [hepatocyte growth factor/scatter factor (HGF/SF) receptor] tyrosine kinase block HGF/SF-induced tumor cell growth and invasion. Mol Cancer Ther 2:1085–92

    PubMed  CAS  Google Scholar 

  141. Koon EC, Ma PC, Salgia R et al (2008) Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion. Int J Gynecol Cancer 18:976–84

    PubMed  CAS  Google Scholar 

  142. Christensen JG, Schreck R, Burrows J et al (2003) A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 63:7345–55

    PubMed  CAS  Google Scholar 

  143. Zou HY, Li Q, Lee JH et al (2007) An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res 67:4408–17

    PubMed  CAS  Google Scholar 

  144. Munshi N, Jeay S, Hill J, et al. ARQ 197, a highly selective small molecule inhibitor of c-Met, inhibits invasive and metastatic growth of cancer cells [abstract 2367]. Proceedings of the American Association for Cancer Research Annual Meeting, Los Angeles, CA 2007

    Google Scholar 

  145. Li Y, Zhou W, Chen D, et al. Anti-metastatic activity of ARQ 197, a highly selective oral small molecule inhibitor of c-Met, in experimental metastatic models of colon cancer [abstract 2191]. Proceedings of the American Association for Cancer Research Annual Meeting, Los Angeles, CA 2007

    Google Scholar 

  146. Onnis B, Rapisarda A, Melillo G (2009) Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med 13:2780–6

    PubMed  CAS  Google Scholar 

  147. Rapisarda A, Melillo G (2011) HIF-1 inhibitors for cancer therapy. In: Siemann DW (ed) Tumor Microenvironment, 1st edn. Wiley-Blackwell, UK

    Google Scholar 

  148. Golas JM, Lucas J, Etienne C et al (2005) SKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models. Cancer Res 65:5358–64

    PubMed  CAS  Google Scholar 

  149. Rucci N, Recchia I, Angelucci A et al (2006) Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. J Pharmacol Exp Ther 318:161–72

    PubMed  CAS  Google Scholar 

  150. Nam JS, Ino Y, Sakamoto M, Hirohashi S (2002) Src family kinase inhibitor PP2 restores the E-cadherin/catenin cell adhesion system in human cancer cells and reduces cancer metastasis. Clin Cancer Res 8:2430–6

    PubMed  CAS  Google Scholar 

  151. Nam S, Kim D, Cheng JQ et al (2005) Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 65:9185–9

    PubMed  CAS  Google Scholar 

  152. Cecchi F, Rabe DC, Bottaro DP (2010) Targeting the HGF/Met signalling pathway in cancer. Eur J Cancer 46:1260–70

    PubMed  CAS  Google Scholar 

  153. Qian F, Engst S, Yamaguchi K et al (2009) Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res 69:8009–16

    PubMed  CAS  Google Scholar 

  154. Accornero P, Lattanzio G, Mangano T et al (2008) An in vivo model of Met-driven lymphoma as a tool to explore the therapeutic potential of Met inhibitors. Clin Cancer Res 14:2220–6

    PubMed  CAS  Google Scholar 

  155. Hov H, Holt RU, Ro TB et al (2004) A selective c-met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin Cancer Res 10:6686–94

    PubMed  CAS  Google Scholar 

  156. Schroeder GM, An Y, Cai ZW et al (2009) Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluor ophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily. J Med Chem 52:1251–4

    PubMed  CAS  Google Scholar 

  157. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127:679–95

    PubMed  CAS  Google Scholar 

  158. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M, Foekens JA, Massagué J (2009) Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16:67–78

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville, FL, 32610, USA

    Yao Dai, Nikolett Molnar & Dietmar Siemann

  2. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Wenyin Shi

  3. Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA

    Nikolett Molnar

Authors
  1. Yao Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenyin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nikolett Molnar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dietmar Siemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dietmar Siemann .

Editor information

Editors and Affiliations

  1. Drexel University College of Medicine, N. 15th Street 245, Philadelphia, 19102, Pennsylvania, USA

    Alessandro Fatatis

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Dai, Y., Shi, W., Molnar, N., Siemann, D. (2011). Impact of Tumor Hypoxia, Src, and Met Signaling in the Dissemination of Tumor Cells. In: Fatatis, A. (eds) Signaling Pathways and Molecular Mediators in Metastasis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2558-4_7

Download citation

Publish with us

Policies and ethics

Search

Navigation