Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Breast cancer is the leading cause of death among women, and morphine is used to relieve the pain of patients with cancer. The data on the effects of morphine on tumour growth and angiogenesis are contradictory. We determined in mouse breast cancer model whether analgesic doses of morphine would affect tumour angiogenesis, and then the correlation between microvessel density (MVD), Doppler sonography (DS) and 99mTc-Tetrofosmin (TF) uptake. Ehrlich ascites tumour cell xenografts, Pgp-negative tumour were divided into two groups: (a) Morphine sulphate [0.714 mg/kg/day (equivalent to 50 mg per day for a 70 kg human)], (b) no-morphine. For the determination of angiogenesis in mice tumour tissue, TF scintigraphy, microvessel density and DS were done. MVD was significantly different between groups (49.4 ± 1.8 vs. 41.8 ± 1.9, morphine and no-morphine groups, respectively, P < 0.001). A strong correlation was found between late uptakes of mass at scintigraphy and degree of angiogenesis in histopathologic examination (r = 0.52, P < 0.01). There was statistically significant inverse correlation between degree of angiogenesis in histopathologic examination and washout ratio of TF (r = 0.40, P < 0.05). The higher values for angiogenesis are related to higher TF reuptake. There was no statistically significant correlation between DS and TF. A strong correlation was found between MVD and grade of DS (r = 0.51, P < 0.01). Our preclinical mice study indicates that morphine at clinically relevant doses stimulates angiogenesis, and angiogenesis triggered of morphine is demonstrated with MVD and DS, but not TF. However, uptake and washout of TF are compared with immunohistochemically assessed morphine-stimulated angiogenesis in tumour tissue.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Higley B, Smith FW, Smith T, Gemmell HG, Das Gupta P, et al. Technetium-99 m-1, 2-bis[bis(2-ethoxyethyl) phosphino]ethane: human biodistribution, dosimetry and safety of a new myocardial perfusion imaging agent. J Nucl Med. 1993;34:30–8.

    PubMed  CAS  Google Scholar 

  2. Rambaldi PF, Mansi L, Procaccini E, Di Gregorio F, Del Vecchio E. Breast cancer detection with Tc-99 m tetrofosmin. Clin Nucl Med. 1995;20:703–5.

    Article  PubMed  CAS  Google Scholar 

  3. Klain M, Maurea S, Lastoria S, Cuocolo A, Colao A, et al. Technetium-99 m-tetrofosmin imaging of differentiated mixed thyroid cancer. J Nucl Med. 1995;36:2248–51.

    PubMed  CAS  Google Scholar 

  4. Basoglu T, Sahin M, Coskun C, Koparan A, Bernay I, et al. Technetium-99 m-tetrofosmin uptake in malignant lung tumours. Eur J Nucl Med. 1995;22:687–9.

    Article  PubMed  CAS  Google Scholar 

  5. Rodrigues M, Chehne F, Kalinowska W, Berghammer P, Zielinski C, et al. Uptake of 99 mTc-MIBI and 99 mTc-tetrofosmin into malignant versus nonmalignant breast cell lines. J Nucl Med. 2000;41:1495–9.

    PubMed  CAS  Google Scholar 

  6. Liu TJ TJ, Shiau YC, Tsai SC, Wang JJ, Ho ST, et al. Predicting multidrug resistance-related protein and P-glycoprotein expression with technetium-99 m tetrofosmin mammoscintigraphy. Breast. 2003;12:58–62.

    Article  PubMed  Google Scholar 

  7. Fuster D, Viñolas N, Mallafré C, Pavia J, Martín F, et al. Tetrofosmin as predictors of tumour response. Q J Nucl Med. 2003;47:58–62.

    PubMed  CAS  Google Scholar 

  8. Yoon JH, Bom HS, Song HC, Lee JH, Jaegal YJ. Double-phase Tc-99m sestamibi scintimammography to assess angiogenesis and P-glycoprotein expression in patients with untreated breast cancer. Clin Nucl Med. 1999;24:314–8.

    Article  PubMed  CAS  Google Scholar 

  9. Lickiss JN. Approaching cancer pain relief. Eur J Pain. 2001;5(Suppl A):5–14.

    Article  PubMed  CAS  Google Scholar 

  10. Sueoka N, Sueoka E, Okabe S, Fujiki H. Anti-cancer effects of morphine through inhibition of tumour necrosis factor-alpha release and mRNA expression. Carcinogenesis. 1996;17:2337–41.

    Article  PubMed  CAS  Google Scholar 

  11. Maneckjee R, Minna JD. Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth Differ. 1994;5:1033–40.

    PubMed  CAS  Google Scholar 

  12. Maneckjee R, Minna JD. Opioid and nicotine receptors affect growth regulation of human lung cancer cell lines. Proc Natl Acad Sci USA. 1990;87:3294–8.

    Article  PubMed  CAS  Google Scholar 

  13. Pasi A, Qu BX, Steiner R, Senn HJ, Bär W, et al. Angiogenesis: modulation with opioids. Gen Pharmacol. 1991;22:1077–9.

    Article  PubMed  CAS  Google Scholar 

  14. Hatzoglou A, Ouafik L, Bakogeorgou E, Thermos K, Castanas E. Morphine cross-reacts with somatostatin receptor SSTR2 in the T47D human breast cancer cell line and decreases cell growth. Cancer Res. 1995;55:5632–6.

    PubMed  CAS  Google Scholar 

  15. Hatzoglou A, Bakogeorgou E, Castanas E. The antiproliferative effect of opioid receptor agonists on the T47D human breast cancer cell line, is partially mediated through opioid receptors. Eur J Pharmacol. 1996;296:199–207.

    Article  PubMed  CAS  Google Scholar 

  16. Maneckjee R, Biswas R, Vonderhaar BK. Binding of opioids to human MCF-7 breast cancer cells and their effects on growth. Cancer Res. 1990;50:2234–8.

    PubMed  CAS  Google Scholar 

  17. Kampa M, Bakogeorgou E, Hatzoglou A, Damianaki A, Martin PM, et al. Opioid alkaloids and casomorphin peptides decrease the proliferation of prostatic cancer cell lines (LNCaP, PC3 and DU145) through a partial interaction with opioid receptors. Eur J Pharmacol. 1997;335:255–65.

    Article  PubMed  CAS  Google Scholar 

  18. Tegeder I, Grösch S, Schmidtko A, Häussler A, Schmidt H, et al. G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res. 2003;63:1846–52.

    PubMed  CAS  Google Scholar 

  19. Yeager MP, Colacchio TA. Effect of morphine on growth of metastatic colon cancer in vivo. Arch Surg. 1991;126:454–6.

    PubMed  CAS  Google Scholar 

  20. Sasamura T, Nakamura S, Iida Y, Fujii H, Murata J, et al. Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation. Eur J Pharmacol. 2002;441:185–91.

    Article  PubMed  CAS  Google Scholar 

  21. Harimaya Y, Koizumi K, Andoh T, Nojima H, Kuraishi Y, et al. Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26–L5 carcinoma cells. Cancer Lett. 2002;187:121–7.

    Article  PubMed  CAS  Google Scholar 

  22. Simon RH, Arbo TE. Morphine increases metastatic tumor growth. Brain Res Bull. 1986;16:363–7.

    Article  PubMed  CAS  Google Scholar 

  23. Lewis JW, Shavit Y, Terman GW, Nelson LR, Gale RP, et al. Apparent involvement of opioid peptides in stress-induced enhancement of tumor growth. Peptides. 1983;4:635–8.

    Article  PubMed  CAS  Google Scholar 

  24. Sergeeva MG, Grishina ZV, Varfolomeyev SD. Morphine effect on proliferation of normal and tumor cells of immune origin. Immunol Lett. 1993;36:215–8.

    Article  PubMed  CAS  Google Scholar 

  25. Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 2002;62:4491–8.

    PubMed  CAS  Google Scholar 

  26. Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, et al. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer. 2007;97:1523–31.

    Article  PubMed  CAS  Google Scholar 

  27. Zhu X, Wu H, Xia J, Zhao M, Xianyu Z. The relationship between (99m)Tc-MIBI uptakes and tumor cell death/proliferation state under irradiation. Cancer Lett. 2002;182:217–22.

    Article  PubMed  CAS  Google Scholar 

  28. Ustun F, Durmus-Altun G, Cukur Z, Altaner S, Berkarda S. Glucose-induced alteration of accumulation of organotechnetium complexes accumulation in Pgp-negative tumor-bearing mice. Cancer Biother Radiopharm. 2009;24:333–8.

    Article  PubMed  CAS  Google Scholar 

  29. Benerjee SK, Zoubime MN, Mullick M, Weston AP, Cherian R, et al. Tumor angiogenesis in chronic pancreatitis and pancreatic adenocarcinoma: impact of K-ras mutations. Pankreas. 2000;20:248–55.

    Article  Google Scholar 

  30. Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res. 2006;72:3–11.

    Article  PubMed  CAS  Google Scholar 

  31. Arerangaiah R, Chalasani N, Udager AM, Weber ML, Manivel JC, et al. Opioids induce renal abnormalities in tumor-bearing mice. Nephron Exp Nephrol. 2007;105:e80–9.

    Article  PubMed  CAS  Google Scholar 

  32. Freier DO, Fuchs BA. A mechanism of action for morphine-induced immunosuppression: corticosterone mediates morphine-induced suppression of natural killer cell activity. J Pharmacol Exp Ther. 1994;270:1127–33.

    PubMed  CAS  Google Scholar 

  33. Glasel JA. The effects of morphine on cell proliferation. Prog Drug Res. 2000;55:33–80.

    Article  PubMed  CAS  Google Scholar 

  34. Peterson PK, Molitor TW, Chao CC. Mechanisms of morphine-induced immunomodulation. Biochem Pharmacol. 1993;46:343–8.

    Article  PubMed  CAS  Google Scholar 

  35. Ishikawa M, Tanno K, Kamo A, Takayanagi Y, Sasaki K. Enhancement of tumor growth by morphine and its possible mechanism in mice. Biol Pharm Bull. 1993;16:762–6.

    Article  PubMed  CAS  Google Scholar 

  36. Carr DJ, Serou M. Exogenous and endogenous opioids as biological response modifiers. Immunopharmacology. 1995;31:59–71.

    Article  PubMed  CAS  Google Scholar 

  37. Fecho K, Maslonek KA, Dykstra LA, Lysle DT. Evidence for sympathetic and adrenal involvement in the immunomodulatory effects of acute morphine treatment in rats. J Pharmacol Exp Ther. 1996;277:633–45.

    PubMed  CAS  Google Scholar 

  38. Stefano GB, Hartman A, Bilfinger TV, Magazine HI, Liu Y, et al. Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem. 1995;270:30290–3.

    Article  PubMed  CAS  Google Scholar 

  39. Fosslien E. Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci. 2000;37:431–502.

    Article  PubMed  CAS  Google Scholar 

  40. Locopo N, Fanelli M, Gasparini G. Clinical significance of angiogenic factors in breast cancer. Breast Cancer Res Treat. 1998;52:159–73.

    Article  PubMed  CAS  Google Scholar 

  41. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    Article  PubMed  CAS  Google Scholar 

  42. Kim SW, Park SS, Ahn SJ, Chung KW, Moon WK, et al. Identification of angiogenesis in primary breast carcinoma according to the image analysis. Breast Cancer Res Treat. 2002;74:121–9.

    Article  PubMed  CAS  Google Scholar 

  43. Adalet I, Demirkol MO, Müslümanoğlu M, Bozfakioğlu Y, Cantez S. 99Tcm-tetrofosmin scintigraphy in the evaluation of palpable breast masses. Nucl Med Commun. 1997;18:118–21.

    Article  PubMed  CAS  Google Scholar 

  44. Arbab AS, Koizumi K, Toyama K, Araki T. Uptake of technetium-99m-tetrofosmin, technetium-99m-MIBI and thallium-201 in tumor cell lines. J Nucl Med. 1996;37:1551–6.

    PubMed  CAS  Google Scholar 

  45. Taillefer R. The role of 99mTc-sestamibi and other conventional radiopharmaceuticals in breast cancer diagnosis. Semin Nucl Med. 1999;29:16–40.

    Article  PubMed  CAS  Google Scholar 

  46. Kim IJ, Kim SJ, Kim YK. Comparison of double phase Tc-99m MIBI and Tc-99m tetrofosmin scintimammography for characterization of breast lesions: Visual and quantitative analyses. Neoplasma. 2008;55:526–31.

    PubMed  CAS  Google Scholar 

  47. Ohira H, Kubota K, Ohuchi N, Harada Y, Fukuda H, et al. Comparison of intratumoral distribution of 99mTc-MIBI and deoxyglucose in mouse breast cancer models. J Nucl Med. 2000;41:1561–8.

    PubMed  CAS  Google Scholar 

  48. Ballinger JR. 99mTc-tetrofosmin for functional imaging of P-glycoprotein modulation in vivo. J Clin Pharmacol. 2001 Jul;Suppl:39S–47S.

  49. Chen WS, Luker KE, Dahlheimer JL, Pica CM, Luker GD, et al. Effects of MDR1 and MDR3 P-glycoproteins, MRP1, and BCRP/MXR/ABCP on the transport of (99m)Tc-tetrofosmin. Biochem Pharmacol. 2000;60:413–26.

    Article  PubMed  CAS  Google Scholar 

  50. Márián T, Szabó G, Goda K, Nagy H, Szincsák N, et al. In vivo and in vitro multitracer analyses of P-glycoprotein expression-related multidrug resistance. Eur J Nucl Med Mol Imaging. 2003;30:1147–54.

    Article  PubMed  Google Scholar 

  51. Fox SB, Generali DG, Harris AL. Breast tumour angiogenesis. Breast Cancer Res. 2007;9:216.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported by Trakya University Research Fund (TÜBAP) no. 615.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Çanakkale Onsekiz Mart University Faculty of Medicine, 17100, Canakkale, Turkey

    Funda Ustun

  2. Department of Nuclear Medicine, Trakya University Faculty of Medicine, Edirne, Turkey

    Gülay Durmus-Altun & Sakir Berkarda

  3. Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey

    Semsi Altaner

  4. Department of Radiology, Trakya University Faculty of Medicine, Edirne, Turkey

    Nermin Tuncbilek

  5. Department of Radiation Oncology, Trakya University Faculty of Medicine, Edirne, Turkey

    Cem Uzal

Authors
  1. Funda Ustun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gülay Durmus-Altun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Semsi Altaner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nermin Tuncbilek
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cem Uzal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sakir Berkarda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Funda Ustun.

Additional information

This work was presented in part at the Annual Congress of the European Association of Nuclear Medicine-EANM’2008, October 11-15, 2008, Munich, Germany.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ustun, F., Durmus-Altun, G., Altaner, S. et al. Evaluation of morphine effect on tumour angiogenesis in mouse breast tumour model, EATC. Med Oncol 28, 1264–1272 (2011). https://doi.org/10.1007/s12032-010-9573-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-010-9573-5

Keywords

Search

Navigation