Skip to main content
SpringerLink
Log in

Iatrogenic Angiogenesis

  • Chapter
  • First Online:
Morphine and Metastasis

Abstract

The medicinal powers of opium poppy-derived extracts now called ‘opioids’ and the importance of vasculature in maintaining life were realized by ancient civilizations. However, the association of the two with each other has emerged in the last decade. Opioid receptors, including the mu opioid receptor (MOR) which mediates opioid analgesia, are present on the endothelium. Analgesic opioids such as morphine and its congeners stimulate growth- and survival promoting signaling directly via MOR and also by co-activating receptor tyrosine kinases for vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, etc. in the endothelial cells. Opioid signaling translates into increased tumor angiogenesis, tumor growth, metastases and reduced survival in mice. Additionally, opioids modulate the tumor microenvironment by acting on diverse cellular milieu of the tumor. Increased density of MOR in human tumors as compared to normal tissue, suggests a role for MOR in cancer. Based on experimental studies and MOR expression on human tumors it is critical to examine the role of opioids in cancer progression and survival in patients treated with opioids for severe pain.

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 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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

11C-CFN:

11C-carfentanil

11C-MeNTI:

11C-methylnaltrindole

cAMP:

cyclic adenosine monophosphate

COX:

Cyclooxygenase

DOR:

delta opioid receptor

GPCRs:

G-coupled protein receptors

GRK:

GPCR kinase

KOR:

kappa opioid receptor

MNTX:

methylnaltrexone

MAPK:

mitogen-activated protein kinase

MOR:

mu opioid receptor

NO:

nitric oxide

NOS:

NO synthase

NOP-R:

nociceptin/Orphanin FQ receptor

NSCLC:

non-small cell lung cancer

PDGF:

platelet-derived growth factor

PDGFR-b:

platelet-derived growth factor receptor-β

PET:

Positron emission tomography

POMC:

proopiomelanocortin

PGE2:

prostaglandin E2

Akt:

protein kinase B

RAVE:

Relative activity versus endocytosis

STAT-3:

signal transducer and activator of transcription-3

SCLC:

small cell lung cancer

S1P3R:

sphingosine-1 phosphate receptor

VEGF:

vascular endothelial growth factor

VEGFR2, Flk1:

VEGF receptor-2

References

  • Arerangaiah R, Chalasani N, Udager AM, Weber ML, Manivel JC, Griffin RJ, Song CW, Gupta K (2007) Opioids induce renal abnormalities in tumor-bearing mice. Nephron Exp Nephrol 105:e80–89. doi:10.1159/000098564

    Article  PubMed  CAS  Google Scholar 

  • Bartoli M, Platt D, Lemtalsi T, Gu X, Brooks SE, Marrero MB, Caldwell RB (2003) VEGF differentially activates STAT3 in microvascular endothelial cells. FASEB J 17:1562–1564. doi:10.1096/fj.02-1084fje

    PubMed  CAS  Google Scholar 

  • Birnbaum Y, Ye Y, Rosanio S, Tavackoli S, Hu ZY, Schwarz ER, Uretsky BF (2005) Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury. Cardiovasc Res 65:345–355. doi:10.1016/j.cardiores.2004.10.018

    Article  PubMed  CAS  Google Scholar 

  • Borner C, Kraus J, Schroder H, Ammer H, Hollt V (2004) Transcriptional regulation of the human mu-opioid receptor gene by interleukin-6. Mol Pharmacol 66:1719–1726. doi:10.1124/mol.104.003806

    Article  PubMed  Google Scholar 

  • Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC, Lane TF, Hla T (2004) Role of prostaglandin e2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci U S A 101:591–596. doi:10.1073/pnas.2535911100

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Farooqui M, Gupta K (2006) Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells. Curr Neurovasc Res 3:171–180

    Article  PubMed  CAS  Google Scholar 

  • Ecimovic P, Murray D, Doran P, McDonald J, Lambert DG, Buggy DJ (2011) Direct effect of morphine on breast cancer cell function in vitro: role of the net1 gene. Br J Anaesth 107:916–923. doi:10.1093/bja/aer259

    Article  PubMed  CAS  Google Scholar 

  • Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI (2006) Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105:660–664

    Article  PubMed  Google Scholar 

  • Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, Song CW, Gupta K (2007) COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer 97:1523–1531. doi:10.1038/sj.bjc.6604057

    Article  PubMed  CAS  Google Scholar 

  • Fichna J, Janecka A (2004) Opioid peptides in cancer. Cancer Metastasis Rev 23:351–366. doi:10.1023/B:CANC.0000031773.46458.63

    Article  PubMed  CAS  Google Scholar 

  • Fimiani C, Mattocks D, Cavani F, Salzet M, Deutsch DG, Pryor S, Bilfinger TV, Stefano GB (1999) Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal 11:189–193

    Article  PubMed  CAS  Google Scholar 

  • Fujioka N, Nguyen J, Chen C, Li Y, Pasrija T, Niehans G, Johnson KN, Gupta V, Kratzke RA, Gupta K (2011) Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer. Anesth Analg 113:1353–1364. doi:ANE.0b013e318232b35a [pii] 10.1213/ANE.0b013e318232b35a

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Vazquez ME, Hernandez-Salazar E, Novelo-Otanez JD, Cabrera-Pivaral CE, Davalos-Rodriguez IP, Salazar-Paramo M (2012) Effect of endovenous morphine vs. ketorolac on proinflammatory cytokines during postoperative analgesia in laparoscopic cholecystectomy. Cir Cir 80:56–62

    PubMed  Google Scholar 

  • Griffin RJ, Williams BW, Wild R, Cherrington JM, Park H, Song CW (2002) Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-derived growth factors suppresses tumor growth and enhances tumor radiation response. Cancer Res 62:1702–1706

    PubMed  CAS  Google Scholar 

  • Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP (2002) Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 62:4491–4498

    PubMed  CAS  Google Scholar 

  • Gupta M, Yunfang L, Gupta K (2007) Opioids as promoters and regulators of angiogenesis. In: Maragoudakis ME, Papadimitriou E (eds) Angiogenesis: basic science and clinical applications. Transworld Research Network, Kerala, pp 303–317

    Google Scholar 

  • Hood JD, Meininger CJ, Ziche M, Granger HJ (1998) VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol 274:H1054–H1058

    PubMed  CAS  Google Scholar 

  • Hou YN, Vlaskovska M, Cebers G, Kasakov L, Liljequist S, Terenius L (1996) A mu-receptor opioid agonist induces AP-1 and NF-kappa B transcription factor activity in primary cultures of rat cortical neurons. Neurosci Lett 212:159–162

    Article  PubMed  CAS  Google Scholar 

  • Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210. doi:10.1038/35093019

    Article  PubMed  CAS  Google Scholar 

  • Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL (2002) Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 62:625–631

    PubMed  CAS  Google Scholar 

  • Lennon FE, Mirzapoiazova T, Mambetsariev B, Salgia R, Moss J, Singleton PA (2012) Overexpression of the mu-opioid receptor in human non-small cell lung cancer promotes akt and mtor activation, tumor growth, and metastasis. Anesthesiology. doi:10.1097/ALN.0b013e31824babe2

  • Leo S, Nuydens R, Meert TF (2009) Opioid-induced proliferation of vascular endothelial cells. J Pain Res 2:59–66

    PubMed  CAS  Google Scholar 

  • Luk K, Boatman S, Johnson KN, Dudek OA, Ristau N, Vang D, Nguyen J, Gupta K (2012) Influence of morphine on pericyte-endothelial interaction: implications for antiangiogenic therapy. J Oncol 2012:458385. doi:10.1155/2012/458385

    Article  PubMed  Google Scholar 

  • Madar I, Bencherif B, Lever J, Heitmiller RF, Yang SC, Brock M, Brahmer J, Ravert H, Dannals R, Frost JJ (2007) Imaging delta- and mu-opioid receptors by pet in lung carcinoma patients. J Nucl Med 48:207–213

    Article  PubMed  CAS  Google Scholar 

  • Malmberg AB, Yaksh TL (1992) Hyperalgesia mediated by spinal glutamate or substance p receptor blocked by spinal cyclooxygenase inhibition. Science 257:1276–1279

    Article  PubMed  CAS  Google Scholar 

  • Manning BM, Hebbel RP, Gupta K, Haynes CL (2012) Carbon-fiber microelectrode amperometry reveals sickle-cell-induced inflammation and chronic morphine effects on single mast cells. ACS Chem Biol 7:543–551. doi:10.1021/cb200347q

    Article  PubMed  CAS  Google Scholar 

  • Mathew B, Lennon FE, Siegler J, Mirzapoiazova T, Mambetsariev N, Sammani S, Gerhold LM, LaRiviere PJ, Chen CT, Garcia JG, Salgia R, Moss J, Singleton PA (2011) The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg 112:558–567. doi:ANE.0b013e31820568af [pii] 10.1213/ANE.0b013e31820568af

    Article  PubMed  CAS  Google Scholar 

  • Merighi S, Gessi S, Varani K, Fazzi D, Mirandola P, Borea PA (2012) Cannabinoid CB(2) receptor attenuates morphine-induced inflammatory responses in activated microglial cells. Br J Pharmacol 166:2371–2385. doi:10.1111/j.1476-5381.2012.01948.x

    Article  PubMed  CAS  Google Scholar 

  • Nedelec E, Abid A, Cipolletta C, Presle N, Terlain B, Netter P, Jouzeau J (2001) Stimulation of cyclooxygenase-2-activity by nitric oxide-derived species in rat chondrocyte: lack of contribution to loss of cartilage anabolism. Biochem Pharmacol 61:965–978

    Article  PubMed  CAS  Google Scholar 

  • Nylund G, Pettersson A, Bengtsson C, Khorram-Manesh A, Nordgren S, Delbro DS (2008) Functional expression of mu-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon. Dig Dis Sci 53:461–466. doi:10.1007/s10620-007-9897-y

    Article  PubMed  CAS  Google Scholar 

  • Onoprishvili I, Simon EJ (2007) Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A. Brain Res 1177:9–18. doi:10.1016/j.brainres.2007.08.020

    Article  PubMed  CAS  Google Scholar 

  • Pol O (2007) The involvement of the nitric oxide in the effects and expression of opioid receptors during peripheral inflammation. Curr Med Chem 14:1945–1955

    Article  PubMed  CAS  Google Scholar 

  • Pol O, Sasaki M, Jimenez N, Dawson VL, Dawson TM, Puig MM (2005) The involvement of nitric oxide in the enhanced expression of mu-opioid receptors during intestinal inflammation in mice. Br J Pharmacol 145:758–766. doi:10.1038/sj.bjp. 0706227

    Article  PubMed  CAS  Google Scholar 

  • Poonawala T, Levay-Young BK, Hebbel RP, Gupta K (2005) Opioids heal ischemic wounds in the rat. Wound Repair Regen 13:165–174. doi:10.1111/j.1067-1927.2005.130207.x

    Article  PubMed  Google Scholar 

  • Prevot V, Rialas CM, Croix D, Salzet M, Dupouy JP, Poulain P, Beauvillain JC, Stefano GB (1998) Morphine and anandamide coupling to nitric oxide stimulates GnRH and CRF release from rat median eminence: neurovascular regulation. Brain Res 790:236–244

    Article  PubMed  CAS  Google Scholar 

  • Ribatti D, Crivellato E (2011) Mast cells, angiogenesis and cancer. In: Gilfillan AM, Metcalfe DD (eds). Mast Cell Biology: contemporary and emerging topics. Landes Bioscience and Springer Science + Business Media, Austin, pp 270–288

    Google Scholar 

  • Rittner HL, Labuz D, Richter JF, Brack A, Schafer M, Stein C, Mousa SA (2007) CXCR1/2 ligands induce p38 MAPK-dependent translocation and release of opioid peptides from primary granules in vitro and in vivo. Brain Behav Immun 21:1021–1032. doi:10.1016/j.bbi.2007.05.002

    Article  PubMed  CAS  Google Scholar 

  • Sacerdote P (2007) Immune cell-derived opioid peptides: back to the future. Brain Behav Immun 21:1019–1020. doi:10.1016/j.bbi.2007.06.006

    Article  PubMed  Google Scholar 

  • Salvemini D, Misko TP, Masferrer JL, Seibert K, Currie MG, Needleman P (1993) Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A 90:7240–7244

    Article  PubMed  CAS  Google Scholar 

  • Salvemini D, Seibert K, Masferrer JL, Misko TP, Currie MG, Needleman P (1994) Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation. J Clin Invest 93:1940–1947. doi:10.1172/JCI117185

    Article  PubMed  CAS  Google Scholar 

  • Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ (2001) Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410:471–475. doi:10.1038/35068566

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Simon FM, Ledo AS, Arevalo R, Rodriguez RE (2012) New insights into opioid regulatory pathways: influence of opioids on Wnt1 expression in zebrafish embryos. Neuroscience 200:237–247. doi:10.1016/j.neuroscience.2011.10.026

    Article  PubMed  CAS  Google Scholar 

  • Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J (2006) Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res 72:3–11. doi:10.1016/j.mvr.2006.04.004

    Article  PubMed  CAS  Google Scholar 

  • Singleton PA, Moreno-Vinasco L, Sammani S, Wanderling SL, Moss J, Garcia JG (2007) Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 37:222–231. doi:10.1165/rcmb.2006-0327OC

    Article  PubMed  CAS  Google Scholar 

  • Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, Casares F, Goligorsky MS (1995) Presence of the mu3 opiate receptor in endothelial cells: coupling to nitric oxide production and vasodilation. J Biol Chem 270:30290–30293

    Article  PubMed  CAS  Google Scholar 

  • Stefano GB, Salzet M, Magazine HI, Bilfinger TV (1998) Antagonism of LPS and IFN-gamma induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. J Cardiovasc Pharmacol 31:813–820

    Article  PubMed  CAS  Google Scholar 

  • Stein C, Schafer M, Machelska H (2003) Attacking pain at its source: new perspectives on opioids. Nat Med 9:1003–1008. doi:10.1038/nm908

    Article  PubMed  CAS  Google Scholar 

  • Stephenson EJ, Gupta K (2006) Existence and modus operandii of opioid receptors in endothelium. In: Aird W (ed) The endothelium: a comprehensive reference. Cambridge University Press, Cambridge, MA, pp 451–460

    Google Scholar 

  • Suzuki S, Chuang LF, Doi RH, Chuang RY (2003) Morphine suppresses lymphocyte apoptosis by blocking p53-mediated death signaling. Biochem Biophys Res Commun 308:802–808

    Article  PubMed  CAS  Google Scholar 

  • Ustun F, Durmus-Altun G, Altaner S, Tuncbilek N, Uzal C, Berkarda S (2011) Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC. Med Oncol 28:1264–1272. doi:10.1007/s12032-010-9573-5

    Article  PubMed  CAS  Google Scholar 

  • Weber ML, Vang D, Velho PE, Gupta P, Crosson JT, Hebbel RP, Gupta K (2012) Morphine promotes renal pathology in sickle mice. Int J Nephrol Renovasc Dis 5:109–118

    PubMed  CAS  Google Scholar 

  • Wen H, Lu Y, Yao H, Buch S (2011) Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability. PLoS One 6:e21707. doi:10.1371/journal.pone.0021707

    Article  PubMed  CAS  Google Scholar 

  • Westly HJ, Kleiss AJ, Kelley KW, Wong PK, Yuen PH (1986) Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene. J Exp Med 163:1589–1594

    Article  PubMed  CAS  Google Scholar 

  • Wong CS, Hsu MM, Chou R, Chou YY, Tung CS (2000) Intrathecal cyclooxygenase inhibitor administration attenuates morphine antinociceptive tolerance in rats. Br J Anaesth 85:747–751

    Article  PubMed  CAS  Google Scholar 

  • Yuen JW, So IY, Kam AY, Wong YH (2004) Regulation of STAT3 by mu-opioid receptors in human neuroblastoma SH-SY5Y cells. Neuroreport 15:1431–1435

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mihir Gupta and Hemant Kumar for assistance with figures and Ms Carol Taubert for the artwork and word processing. This work was funded by NIH grants, RO1 HL68802, HL103773, and CA109582.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Hematology, Oncology and Transplantation, Vascular Biology Center, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN, 55455, USA

    Kalpna Gupta Ph.D.

Authors
  1. Kalpna Gupta Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kalpna Gupta Ph.D. .

Editor information

Editors and Affiliations

  1. , School of Pharmacy, University of Queensland, Cornwall Street 20, Woolloongabba, QLD4102, Australia

    Marie-Odile Parat

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Gupta, K. (2013). Iatrogenic Angiogenesis. In: Parat, MO. (eds) Morphine and Metastasis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5678-6_5

Download citation

Publish with us

Policies and ethics

Search

Navigation