Advertisement

Lung

, Volume 187, Issue 5, pp 321–329 | Cite as

Hypoxia Inducible Factor-1alpha and Vascular Endothelial Growth Factor in Biopsies of Small Cell Lung Carcinoma

  • M. Ioannou
  • R. Papamichali
  • E. Kouvaras
  • I. Mylonis
  • D. Vageli
  • T. Kerenidou
  • S. Barbanis
  • A. Daponte
  • G. Simos
  • K. Gourgoulianis
  • G. K. KoukoulisEmail author
Article

Abstract

Neoangiogenesis has been documented in small cell lung carcinoma (SCLC). In addition, antiangiogenic therapies are being tested in clinical trials that involve SCLC. However, study of the underlying mechanisms has been performed almost exclusively in cell lines. In the current study, we immunostained 30 biopsy samples of SCLC with antibodies to hypoxia inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), vascular endothelial growth factor-receptor 1 (VEGF-R1/flt-1) and vascular endothelial growth factor-receptor 2 (VEGF-R1/flk-1). The immunoreactivity was analyzed using a bivariate Spearman correlation test and linear regression analysis. We found significant correlation between HIF-1alpha nuclear staining and VEGF staining. Moreover HIF-1alpha+/VEGF+ cases were associated with poor survival. We also found a positive correlation between VEGF and VEGF-R2 expression. We suggest that a HIF-1alpha/VEGF angiogenic pathway may exist in vivo in SCLC, similar to that in non-SCLC. Our data also suggest a potential VEGF/VEGFR-2 autocrine pathway in SCLC. The inclusion of novel inhibitors to HIF-1alpha and other factors may optimize antiangiogenic interventions in SCLC.

Keywords

HIF1-alpha Vascular endothelial growth factor Vascular endothelial growth factor-receptor Hypoxia Lung Small cell carcinoma 

References

  1. 1.
    Elias D (1997) Small cell lung cancer: state-of-the-art therapy in 1996. Chest 112:251S–258SPubMedCrossRefGoogle Scholar
  2. 2.
    Rossi A, Maione G, Colantuoni C, Gridelli G (2004) The role of new targeted therapies in small-cell lung cancer. Clin Rev Oncol-Hematol 51:45–53CrossRefGoogle Scholar
  3. 3.
    Litz J, Krystal GW (2006) Imatinib inhibits c-kit-induced hypoxia-inducible factor-1alpha activity and vascular endothelial growth factor expression in small cell lung cancer cells. Mol Cancer Ther 5:1415–1422PubMedCrossRefGoogle Scholar
  4. 4.
    Lucchi M, Mussi A, Fontanini G, Faviana P, Ribechini A, Angeletti CA (2002) Small cell lung carcinoma: the angiogenic phenomenon. Eur J Cardiothorac Surg 21:1105–1110PubMedCrossRefGoogle Scholar
  5. 5.
    Ohta Y, Endo Y, Tanaka M, Shimuzu J, Oda M, Hayashi Y, Watanabe Y, Sasaki T (1996) Significance of vascular endothelial growth factor messenger RNA expression in primary lung cancer. Clin Cancer Res 2:1411–1416PubMedGoogle Scholar
  6. 6.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613PubMedGoogle Scholar
  7. 7.
    Ryan HE, Lo J, Johnson RS (1998) HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 17:3005–3015PubMedCrossRefGoogle Scholar
  8. 8.
    Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 12:149–162PubMedCrossRefGoogle Scholar
  9. 9.
    Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411–421PubMedGoogle Scholar
  10. 10.
    Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramowitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation, and tumor angiogenesis. Nature 394:485–490PubMedCrossRefGoogle Scholar
  11. 11.
    de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT (1992) The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255:989–991PubMedCrossRefGoogle Scholar
  12. 12.
    Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P (1992) Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun 187:1579–1586PubMedCrossRefGoogle Scholar
  13. 13.
    Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745PubMedCrossRefGoogle Scholar
  14. 14.
    Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH (1994) Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 269:26988–26995PubMedGoogle Scholar
  15. 15.
    Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D (1996) Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87:3336–3343PubMedGoogle Scholar
  16. 16.
    Clauss M, Weich H, Breier G, Knies U, Röckl W, Waltenberger J, Risau W (1996) The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 271:17629–17634PubMedCrossRefGoogle Scholar
  17. 17.
    Wang D, Donner DB, Warren RS (2000) Homeostatic modulation of cell surface KDR and Flt1 expression and expression of the vascular endothelial cell growth factor (VEGF) receptor mRNAs by VEGF. J Biol Chem 275:15905–15911PubMedCrossRefGoogle Scholar
  18. 18.
    Enholm B, Paavonen K, Ristimäki A, Kumar V, Gunji Y, Klefstrom J, Kivinen L, Laiho M, Olofsson B, Joukov V, Eriksson U, Alitalo K (1997) Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 14:2475–2483PubMedCrossRefGoogle Scholar
  19. 19.
    Okajima E, Thorgeirsson UP (2000) Different regulation of vascular endothelial growth factor expression by the ERK and p38 kinase pathways in v-ras, v-raf, and v-myc transformed cells. Biochem Biophys Res Commun 270:108–111PubMedCrossRefGoogle Scholar
  20. 20.
    Mukhopadhyay D, Tsiokas L, Sukhatme VP (1995) Wildtype p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res 55:6161–6165PubMedGoogle Scholar
  21. 21.
    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 375:577–581PubMedCrossRefGoogle Scholar
  22. 22.
    Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS (1995) Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55:4575–4580PubMedGoogle Scholar
  23. 23.
    Siemeister G, Weindel K, Mohrs K, Barleon B, Martiny-Baron G, Marme D (1996) Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein. Cancer Res 56:2299–2301PubMedGoogle Scholar
  24. 24.
    Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezella F, Gatter KC, Harris AL (2001) Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumors and survival. Br J Cancer 85:881–890PubMedCrossRefGoogle Scholar
  25. 25.
    Enatsu S, Iwasaki A, Shirakusa T, Hamasaki M, Nabeshima K, Iwasaki H, Kuroki M, Kuroki M (2006) Expression of hypoxia-inducible factor-1 alpha and its prognostic significance in non-small-sized adenocarcinomas of the lung. Eur J Cardiothorac Surg 29:891–895PubMedCrossRefGoogle Scholar
  26. 26.
    Pedersen MW, Holm S, Lund EL, Hojgaard L, Kristjansen PE (2001) Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer sublines in vivo and in vitro. Neoplasia 3:80–87PubMedCrossRefGoogle Scholar
  27. 27.
    Fan LF, Diao LM, Chen DJ, Liu MQ, Zhu LQ, Li HG, Tang ZJ, Xia D, Liu X, Chen HL (2002) Expression of HIF-1 alpha and its relationship to apoptosis and proliferation in lung cancer. Ai Zheng 21:254–258PubMedGoogle Scholar
  28. 28.
    Lyberopoulou A, Venieris E, Mylonis I, Chachami G, Pappas I, Simos G, Bonanou S, Georgatsou E (2007) MgcRacGAP interacts with HIF-1alpha and regulates its transcriptional activity. Cell Physiol Biochem 20:995–1006PubMedCrossRefGoogle Scholar
  29. 29.
    Wang GL, Semenza GL (1993) Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor-1 DNA binding activity; Implications for models of hypoxia signal transduction. Blood 82:3610–3615PubMedGoogle Scholar
  30. 30.
    Triantafyllou A, Liakos P, Tsakalof A, Georgatsou E, Simos G, Bonanou S (2006) Cobalt induces hypoxia-inducible factor-1α (HIF-1α) in HeLa cells by an iron-independent, but ROS-, PI-3 K- and MAPK-dependent mechanism. Free Radic Res 40:847–856PubMedCrossRefGoogle Scholar
  31. 31.
    Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G (2000) Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 60:4693–4696PubMedGoogle Scholar
  32. 32.
    Theodoropoulos V, Lazaris A, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I, Manikas K, Kastriotis I (2004) Hypoxia-inducible factor 1α expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol 46:200–208PubMedCrossRefGoogle Scholar
  33. 33.
    Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Smenza GL, Simmons JW (1999) Overexpression of hypoxia-inducible factor 1 alpha in common human cancers and their metastases. Cancer Res 59:5830–5835PubMedGoogle Scholar
  34. 34.
    Mabjeesh NJ, Amir S (2007) Hypoxia-inducible factor (HIF) in human tumorigenesis. Histol Histopathol 22:559–572PubMedGoogle Scholar
  35. 35.
    Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, Semenza GL (2001) Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 61:2911–2916PubMedGoogle Scholar
  36. 36.
    Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14:34–44PubMedGoogle Scholar
  37. 37.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275PubMedCrossRefGoogle Scholar
  38. 38.
    Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL (2000) Modulation of hypoxia-inducible factor 1 α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60:1541–1545PubMedGoogle Scholar
  39. 39.
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIF-a targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468PubMedCrossRefGoogle Scholar
  40. 40.
    Park JH, Kim TY, Jong HS, Kim TY, Chun YS, Park JW, Lee CT, Jung HC, Kim NK, Bang YJ (2003) Gastric epithelial reactive oxygen species prevent normoxic degradation of hypoxia-inducible factor-1alpha in gastric cancer cells. Clin Cancer Res 9:433–440PubMedGoogle Scholar
  41. 41.
    Maynard M, Ohh M (2007) The role of hypoxia-inducible factors in cancer. Cell Mol Life Sci 64:2170–2180PubMedCrossRefGoogle Scholar
  42. 42.
    Loureiro RMB, D’Amore PA (2005) Transcriptional regulation of vascular endothelial growth factor in cancer. Cytokine Growth Factor Rev 16:77–89PubMedCrossRefGoogle Scholar
  43. 43.
    Gaudin PB, Rosai J (1995) Florid vascular proliferation associated with neural and neuroendocrine neoplasms. A diagnostic clue and potential pitfall. Am J Surg Pathol 19:642–652PubMedCrossRefGoogle Scholar
  44. 44.
    Ustuner Z, Saip P, Yasasever V, Vural B, Yazar A, Bal C, Ozturk B, Ozbek U, Topuz (2008) Prognostic and predictive value of vascular endothelial growth factor and its soluble receptors, VEGFR-1 and VEGFR-2 levels in the sera of small cell lung cancer patients. Med Oncol 25:394–399PubMedCrossRefGoogle Scholar
  45. 45.
    Masood R, Cai J, Zheng T, Smith DL, Hinton DR, Gill PS (2001) Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor–positive human tumors. Blood 98:1904–1913PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • M. Ioannou
    • 1
  • R. Papamichali
    • 1
  • E. Kouvaras
    • 1
  • I. Mylonis
    • 2
  • D. Vageli
    • 1
  • T. Kerenidou
    • 4
  • S. Barbanis
    • 1
  • A. Daponte
    • 3
  • G. Simos
    • 2
  • K. Gourgoulianis
    • 4
  • G. K. Koukoulis
    • 1
    Email author
  1. 1.Department of Pathology, Medical SchoolUniversity of ThessalyLarissaGreece
  2. 2.Department of Biochemistry, Medical SchoolUniversity of ThessalyLarissaGreece
  3. 3.Department of Gynecology and Οbstetrics, Medical SchoolUniversity of ThessalyLarissaGreece
  4. 4.Department of Respiratory Medicine, Medical SchoolUniversity of ThessalyLarissaGreece

Personalised recommendations