Molecular Bio-Imaging Probe for Non-Invasive Differentiation Between Human Leiomyoma Versus Leiomyosarcoma


Leiomyosarcoma is the most frequent subtype of the deadly uterine sarcoma and shares many common clinical grounds with leiomyoma, which is in turn the most common solid benign uterine neoplasm. With the recent progress in minimally invasive techniques for managing leiomyomas, accurate preoperative diagnosis of uterine masses has become the most important selection criterion for the safest therapeutic option. Therefore, different imaging modalities would be playing a key role in management of uterine masses. Testing for a sarcoma-specific promoter that expresses its downstream reporter gene only in leiomyosarcoma and not in leiomyoma or healthy uterine tissue. Adenoviral vectors were utilized both in vitro and in vivo to test the specificity of the promoters. Quantitative studies of downstream gene expression of these promoters was carried out both in vitro and in vivo. Our data indicated that human leiomyosarcoma cells highly expressed the reporter gene downstream to survivin promoter (Ad-SUR-LUC) when compared with benign leiomyoma or normal cells (p value of 0.05). Our study suggested that survivin is the unique promoter capable of distinguishing between the deadly sarcoma and the benign counterparts.

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

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Perri T, Korach J, Sadetzki S, Oberman B, Fridman E, Ben-Baruch G. Uterine leiomyosarcoma: does the surgical procedure matter? Int J Gynecol Cancer. 2009;19(2):257–60.

  2. 2.

    Pritts EA, Parker WH, Brown J, Olive DL. Outcome of occult uterine leiomyosarcoma after surgery for presumed uterine fibroids: a systematic review. J Minim Invasive Gynecol. 2015;22(1):26–33.

  3. 3.

    Ottarsdottir H, Cohen SL, Cox M, Vitonis A, Einarsson JI. Trends in mode of hysterectomy after the US Food and Drug Administration power morcellation advisory. Obstet Gynecol. 2017;129(6):1014–21.

  4. 4.

    Schatz F, et al. The role of decidual cells in uterine hemostasis, menstruation, inflammation, adverse pregnancy outcomes and abnormal uterine bleeding. Hum Reprod Update. 2016;22(4):497–515.

  5. 5.

    Wright JD, et al. Economic and survival implications of use of electric power morcellation for hysterectomy for presumed benign gynecologic disease. J Natl Cancer Inst. 2015;107(11):djv251.

  6. 6.

    Mao J, et al. Population-based estimates of the prevalence of uterine sarcoma among patients with leiomyomata undergoing surgical treatment. JAMA Surgery. 2015;150(4):368–70.

  7. 7.

    Hayashi T, et al. A novel diagnostic biomarker for human uterine leiomyosarcoma: PSMB9/β1i. Chin Clin Oncol. 2017;6(2).

  8. 8.

    Jitsumori M, et al. Hyperphosphatasemia in leiomyosarcoma of the uterus: two case reports and a literature review. J Obstet Gynaecol Res. 2017;43(9):1498–503.

  9. 9.

    Wu TI, et al. Prognostic factors and impact of adjuvant chemotherapy for uterine leiomyosarcoma. Gynecol Oncol. 2006;100(1):166–72.

  10. 10.

    White M. Uterine smooth muscle tumors of uncertain malignant potential (stump): review of pathophysiology, classification, diagnosis, treatment, and surveillance. J Health Commun. 2017;2:4.

  11. 11.

    Goto A, Takeuchi S, Sugimura K, Maruo T. Usefulness of Gd-DTPA contrast-enhanced dynamic MRI and serum determination of LDH and its isozymes in the differential diagnosis of leiomyosarcoma from degenerated leiomyoma of the uterus. Int J Gynecol Cancer. 2002;12(4):354–61.

  12. 12.

    Cui RR, Wright JD. Risk of occult uterine sarcoma in presumed uterine fibroids. Clin Obstet Gynecol. 2016;59(1):103–18.

  13. 13.

    Peters A, Sadecky AM, Winger DG, Guido RS, Lee TTM, Mansuria SM, et al. Characterization and preoperative risk analysis of leiomyosarcomas at a high-volume tertiary care center. Int J Gynecol Cancer. 2017;27(6):1183–90.

  14. 14.

    Hyoeun CB, et al. Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression. Nat Med. 2011;17(1):123–9.

  15. 15.

    Mohan K, et al. Sub-nanomolar detection of prostate-specific membrane antigen in synthetic urine by synergistic, dual-ligand phage. J Am Chem Soc. 2013;135(20):7761–7.

  16. 16.

    Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997;3(8):917–21.

  17. 17.

    Gianani R, Jarboe E, Orlicky D, Frost M, Bobak J, Lehner R, et al. Expression of survivin in normal, hyperplastic, and neoplastic colonic mucosa. Hum Pathol. 2001;32(1):119–25.

  18. 18.

    Kami K, Doi R, Koizumi M, Toyoda E, Mori T, Ito D, et al. Survivin expression is a prognostic marker in pancreatic cancer patients. Surgery. 2004;136(2):443–8.

  19. 19.

    Shariat SF, Lotan Y, Saboorian H, Khoddami SM, Roehrborn CG, Slawin KM, et al. Survivin expression is associated with features of biologically aggressive prostate carcinoma. Cancer. 2004;100(4):751–7.

  20. 20.

    Tanaka K, et al. Expression of survivin and its relationship to loss of apoptosis in breast carcinomas. Clin Cancer Res. 2000;6(1):127–34.

  21. 21.

    Ansell S, Arendt BK, Grote DM, Jelinek DF, Novak AJ, Wellik LE, et al. Inhibition of survivin expression suppresses the growth of aggressive non-Hodgkin's lymphoma. Leukemia. 2004;18(3):616–23.

  22. 22.

    Mita AC, et al. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14(16):5000–5.

  23. 23.

    Zhu ZB, et al. Transcriptional targeting of tumors with a novel tumor-specific survivin promoter. Cancer Gene Ther. 2004;11(4):256–62.

  24. 24.

    Bao R, Connolly DC, Murphy M, Green J, Weinstein JK, Pisarcik DA, et al. Activation of cancer-specific gene expression by the survivin promoter. J Natl Cancer Inst. 2002;94(7):522–8.

  25. 25.

    Monzó M, et al. A novel anti-apoptosis gene: re-expression of survivin messenger RNA as a prognosis marker in non–small-cell lung cancers. J Clin Oncol. 1999;17(7):2100.

  26. 26.

    Hassan MH, Khatoon N, Curiel DT, Hamada FM, Arafa HM, al-Hendy A. Toward gene therapy of uterine fibroids: targeting modified adenovirus to human leiomyoma cells. Hum Reprod. 2008;23(3):514–24.

  27. 27.

    Al-Hendy, Ayman, et al. "Ovarian cancer gene therapy: repeated treatment with thymidine kinase in an adenovirus vector and ganciclovir improves survival in a novel immunocompetent murine model." American journal of obstetrics and gynecology 182.3 (2000);553-559.

  28. 28.

    Al-Hendy, A., Lee, E. J., Wang, H. Q., & Copland, J. A. Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice. American journal of obstetrics and gynecology, (2004);191(5):1621-1631.

  29. 29.

    Salama, S. A., Kamel, M., Christman, G., Wang, H. Q., Fouad, H. M., & Al-Hendy, A. Gene therapy of uterine leiomyoma: adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir treatment inhibits growth of human and rat leiomyoma cells in vitro and in a nude mouse model. Gynecologic and obstetric investigation, (2007);63(2):61-70.

  30. 30.

    Henriques C, et al. In vivo imaging of mice infected with bioluminescent Trypanosoma cruzi unveils novel sites of infection. Parasit Vectors. 2014;7:89.

  31. 31.

    Kotz S, Balakrishnan N, Read CB, Vidakovic B. Encyclopedia of statistical sciences. 2nd ed. Hoboken: Wiley-Interscience; 2006.

  32. 32.

    Nair, S., Curiel, D. T., Rajaratnam, V., Thota, C., & Al-Hendy, A. Targeting adenoviral vectors for enhanced gene therapy of uterine leiomyomas. Human Reproduction, (2013);28(9):2398-2406.

  33. 33.

    Fogh J, Fogh JM, Orfeo T. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. 1977;59(1):221–6.

  34. 34.

    Kishimoto H, Kojima T, Watanabe Y, Kagawa S, Fujiwara T, Uno F, et al. In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus. Nat Med. 2006;12(10):1213–9.

  35. 35.

    Ray S, Paulmurugan R, Patel MR, Ahn BC, Wu L, Carey M, et al. Noninvasive imaging of therapeutic gene expression using a bidirectional transcriptional amplification strategy. Mol Ther. 2008;16(11):1848–56.

  36. 36.

    Qiao J, Doubrovin M, Sauter BV, Huang Y, Guo ZS, Balatoni J, et al. Tumor-specific transcriptional targeting of suicide gene therapy. Gene Ther. 2002;9(3):168–75.

  37. 37.

    Iyer M, et al. Two-step transcriptional amplification as a method for imaging reporter gene expression using weak promoters. Proc Natl Acad Sci. 2001;98(25):14595–600.

  38. 38.

    Iyer M, Salazar FB, Lewis X, Zhang L, Carey M, Wu L, et al. Noninvasive imaging of enhanced prostate-specific gene expression using a two-step transcriptional amplification-based lentivirus vector. Mol Ther. 2004;10(3):545–52.

  39. 39.

    Huyn ST, et al. A potent, imaging adenoviral vector driven by the cancer-selective mucin-1 promoter that targets breast cancer metastasis. Clin Cancer Res. 2009;15(9):3126–34.

  40. 40.

    Kim JW, et al. A comparative study of replication-incompetent and-competent adenoviral therapy-mediated immune response in a murine glioma model. Mol Ther Oncol. 2017;5:97–104.

  41. 41.

    Jönsson F, Kreppel F. Barriers to systemic application of virus-based vectors in gene therapy: lessons from adenovirus type 5. Virus Genes. 2017;53(5):692–9.

  42. 42.

    Park JY, Kricka LJ. Prospects for the commercialization of chemiluminescence-based point-of-care and on-site testing devices. Anal Bioanal Chem. 2014;406(23):5631–7.

Download references

Author information

Dr. Al-Hendy conceived the idea, developed the theory, designed the study, edited and revised the manuscript; Dr. Shahinaz Shalaby and Dr. Mostafa Khater collected, analyzed the data, wrote the manuscript. Ms. Archana Laknaur prepared for the experiments. Dr. Arbab facilitated the spectral imaging studies, revised the protocols, and edited the manuscript. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Correspondence to Ayman Al-Hendy.

Ethics declarations

Conflict of Interest

Dr. Ayman Al-Hendy is consulting Abbvie, Bayer, Allergan, MD Stem Cells for research support. Dr. Ali Arbab declares that he has no conflict of interest. Ms. Archana Laknaur declares that she has no conflict of interest. Dr.Mostafa Khater declares that he has no conflict of interest. Dr. Shahinaz Shalaby declares that she has no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, and IACUC approval of Augusta University was taken. This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shalaby, S., Khater, M., Laknaur, A. et al. Molecular Bio-Imaging Probe for Non-Invasive Differentiation Between Human Leiomyoma Versus Leiomyosarcoma. Reprod. Sci. (2020) doi:10.1007/s43032-019-00067-8

Download citation


  • Molecular imaging probe
  • Leiomyosarcoma
  • Sarcoma-specific promoter