Skip to main content

Tipp

Weitere Artikel dieser Ausgabe durch Wischen aufrufen

Erschienen in: European Surgery 5/2012

01.10.2012 | Original Scientific Paper

Regulation of tumor growth and angiogenesis in colorectal cancer

verfasst von: Dr. J. Nolde, Prof. Dr. C. deWit, Dr. E. Schloericke, Prof. Dr. H.-P. Bruch, Dr. T. Laubert

Erschienen in: European Surgery | Ausgabe 5/2012

Einloggen, um Zugang zu erhalten

Summary

Background

Hypoxia in malignant tissues is associated with poor prognosis and treatment options. It is obvious that the grade of malignancy is associated with dedifferentiation of a given tissue. Our aim was to assess the expression of proteins that act as cellular oxygen sensors, which directly regulate the hypoxia-inducible factor 1 (HIF-1) pathway, i.e., prolyl hydroxylase domain proteins (PHD) PHD-1, PHD-2, PHD-3, and its target gene vascular endothelial growth factor (VEGF) in colorectal cancer (CRC).

Methods

In this study, we cultured a human colon cancer cell line (SW480) and its correspondent lymph-node metastasis cell line (SW620) under normoxic or hypoxic conditions for different time periods. We then measured the HIF-1a expression using Western-Blot, the messenger RNA (mRNA)-expression of the PHDs with real-time polymerase chain reaction (PCR) and the amount of one of the target-genes using an VEGF-ELISA.

Results

SW620 shows a clearly elevated HIF-1a expression under normoxic and hypoxic states compared with SW480. Under hypoxic conditions, the amount of VEGF is elevated in both primary and secondary tumor-cell line, but the metastasis-cell line has a significant higher increase. PHD-1 shows no higher expression under hypoxic condition, PHD-2 expression is elevated but only in SW480. PHD-3 levels raised in both of the cell lines, with significant higher rates in SW480.

Conclusions

HIF-regulating proteins are highly expressed in CRCs and their metastases. These molecules play an important role in the control of hypoxia-induced genes and may also have a function in the regulation of cellular proliferation and differentiation during tumorigenesis and dedifferentiation of CRCs. Our results emphasize the important role of PHDs not only as an oxygen-sensor, but also as a control-unit for tumor growth, apoptosis, and angiogenesis through HIF-1 pathway.
Literatur
1.
Zurück zum Zitat Fandrey J. Regulation der Sauerstoffhomöostase durch Hypoxie-induzierbaren Faktor-1. BIOspektrum. 2007;13(7):26–8. Fandrey J. Regulation der Sauerstoffhomöostase durch Hypoxie-induzierbaren Faktor-1. BIOspektrum. 2007;13(7):26–8.
2.
Zurück zum Zitat Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107(1):43–54. PubMedCrossRef Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107(1):43–54. PubMedCrossRef
3.
Zurück zum Zitat Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–34. PubMedCrossRef Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29(5):625–34. PubMedCrossRef
4.
Zurück zum Zitat Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res. 2006;66(7):3688–98. PubMedCrossRef Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res. 2006;66(7):3688–98. PubMedCrossRef
5.
Zurück zum Zitat Krishnamachary B, Berg-Dixon S, Kelly B. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 2003;47(8):1138–43. Krishnamachary B, Berg-Dixon S, Kelly B. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 2003;47(8):1138–43.
6.
Zurück zum Zitat Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, et al. Over expression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res. 2008;14(20):6634–9. PubMedCrossRef Couvelard A, Deschamps L, Rebours V, Sauvanet A, Gatter K, Pezzella F, et al. Over expression of the oxygen sensors PHD-1, PHD-2, PHD-3, and FIH is associated with tumor aggressiveness in pancreatic endocrine tumors. Clin Cancer Res. 2008;14(20):6634–9. PubMedCrossRef
7.
Zurück zum Zitat Andersen S, Donnem T, Stenvold H, Al-Saad S, Al-Shibli K, Busund LT, et al. Over expression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival. PloS ONE. 2011;6(8):e23847. PubMedCrossRef Andersen S, Donnem T, Stenvold H, Al-Saad S, Al-Shibli K, Busund LT, et al. Over expression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival. PloS ONE. 2011;6(8):e23847. PubMedCrossRef
8.
Zurück zum Zitat Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14. PubMedCrossRef Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14. PubMedCrossRef
9.
Zurück zum Zitat Jokilehto T, Jaakkola PM. The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med. 2010;14(4):758–70. PubMedCrossRef Jokilehto T, Jaakkola PM. The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med. 2010;14(4):758–70. PubMedCrossRef
10.
Zurück zum Zitat Chan DA, Kawahara TL, Sutphin PD, Chang HY, Chi JT, Giaccia AJ. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell. 2009;15(6):527–38. PubMedCrossRef Chan DA, Kawahara TL, Sutphin PD, Chang HY, Chi JT, Giaccia AJ. Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Cancer Cell. 2009;15(6):527–38. PubMedCrossRef
11.
Zurück zum Zitat Ginouves A, Ilc K, Macias N, Pouyssegur J, Berra E. PHDs overactivation during chronic hypoxia “desensitizes” HIFalpha and protects cells from necrosis. Proc Natl Acad Sci U S A. 2008;105(12):4745–50. PubMedCrossRef Ginouves A, Ilc K, Macias N, Pouyssegur J, Berra E. PHDs overactivation during chronic hypoxia “desensitizes” HIFalpha and protects cells from necrosis. Proc Natl Acad Sci U S A. 2008;105(12):4745–50. PubMedCrossRef
12.
Zurück zum Zitat Wolff M, Fandrey J, Jelkmann W. Microelectrode measurements of pericellular PO2 in erythropoietin-producing human hepatoma cell cultures. Am J Physiol. 1993;265(5 Pt 1):C1266–70. PubMed Wolff M, Fandrey J, Jelkmann W. Microelectrode measurements of pericellular PO2 in erythropoietin-producing human hepatoma cell cultures. Am J Physiol. 1993;265(5 Pt 1):C1266–70. PubMed
13.
Zurück zum Zitat Metzen E, Wolff M, Fandrey J, Jelkmann W. Pericellular PO2 and O2 consumption in monolayer cell cultures. Respir Physiol. 1995;100(2):101–6. PubMedCrossRef Metzen E, Wolff M, Fandrey J, Jelkmann W. Pericellular PO2 and O2 consumption in monolayer cell cultures. Respir Physiol. 1995;100(2):101–6. PubMedCrossRef
14.
Zurück zum Zitat Soilleux EJ, Turley H, Tian YM, Pugh CW, Gatter KC, Harris AL. Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues. Histopathology. 2005;47(6):602–10. PubMedCrossRef Soilleux EJ, Turley H, Tian YM, Pugh CW, Gatter KC, Harris AL. Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues. Histopathology. 2005;47(6):602–10. PubMedCrossRef
15.
Zurück zum Zitat Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, et al. Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci. 2003;116(Pt 7):1319–26. PubMedCrossRef Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, et al. Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci. 2003;116(Pt 7):1319–26. PubMedCrossRef
16.
Zurück zum Zitat Moehler M. VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab. World J Gastroenterol. 2008;14(26):4156. PubMedCrossRef Moehler M. VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab. World J Gastroenterol. 2008;14(26):4156. PubMedCrossRef
17.
Zurück zum Zitat Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A. 2006;103(48):18154–9. PubMedCrossRef Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A. 2006;103(48):18154–9. PubMedCrossRef
18.
Zurück zum Zitat Niecknig H, Tug S, Reyes BD, Kirsch M, Fandrey J, Berchner-Pfannschmidt U. Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia. Free Radic Res. 2012;46(6):705–17. PubMedCrossRef Niecknig H, Tug S, Reyes BD, Kirsch M, Fandrey J, Berchner-Pfannschmidt U. Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia. Free Radic Res. 2012;46(6):705–17. PubMedCrossRef
19.
Zurück zum Zitat Xue J, Li X, Jiao S, Wei Y, Wu G, Fang J. Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity. Gastroenterology. 2010;138(2):606–15. PubMedCrossRef Xue J, Li X, Jiao S, Wei Y, Wu G, Fang J. Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity. Gastroenterology. 2010;138(2):606–15. PubMedCrossRef
20.
Zurück zum Zitat Henze AT, Riedel J, Diem T, Wenner J, Flamme I, Pouyseggur J, et al. Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors. Cancer Res. 2010;70(1):357–66. PubMedCrossRef Henze AT, Riedel J, Diem T, Wenner J, Flamme I, Pouyseggur J, et al. Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors. Cancer Res. 2010;70(1):357–66. PubMedCrossRef
21.
Zurück zum Zitat Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359(25):2685–92. PubMedCrossRef Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359(25):2685–92. PubMedCrossRef
22.
Zurück zum Zitat Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136(5):839–51. PubMedCrossRef Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136(5):839–51. PubMedCrossRef
23.
Zurück zum Zitat Minamishima YA, Moslehi J, Padera RF, Bronson RT, Liao R, Kaelin WG, Jr. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol. 2009;29(21):5729–41. PubMedCrossRef Minamishima YA, Moslehi J, Padera RF, Bronson RT, Liao R, Kaelin WG, Jr. A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo. Mol Cell Biol. 2009;29(21):5729–41. PubMedCrossRef
24.
Zurück zum Zitat Su Y, Loos M, Giese N, Hines OJ, Diebold I, Gorlach A, et al. PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer. Br J Cancer. 2010;103(10):1571–9. PubMedCrossRef Su Y, Loos M, Giese N, Hines OJ, Diebold I, Gorlach A, et al. PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer. Br J Cancer. 2010;103(10):1571–9. PubMedCrossRef
25.
26.
Metadaten
Titel
Regulation of tumor growth and angiogenesis in colorectal cancer
verfasst von
Dr. J. Nolde
Prof. Dr. C. deWit
Dr. E. Schloericke
Prof. Dr. H.-P. Bruch
Dr. T. Laubert
Publikationsdatum
01.10.2012
Verlag
Springer Vienna
Erschienen in
European Surgery / Ausgabe 5/2012
Print ISSN: 1682-8631
Elektronische ISSN: 1682-4016
DOI
https://doi.org/10.1007/s10353-012-0160-1

Weitere Artikel der Ausgabe 5/2012

European Surgery 5/2012 Zur Ausgabe