Detection of neuroendocrine tumors using promoter-specific secreted Gaussia luciferase

Tseng,Alan  Wei-Shun; Akerstrom,Victoria; Chen,Chiachen; Breslin,Mary  B.; Lan,Michael  S.

doi:10.3892/ijo.2015.3223

Detection of neuroendocrine tumors using promoter-specific secreted Gaussia luciferase

Authors:
- Alan Wei-Shun Tseng
- Victoria Akerstrom
- Chiachen Chen
- Mary B. Breslin
- Michael S. Lan
View Affiliations

Affiliations: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA
Published online on: October 30, 2015 https://doi.org/10.3892/ijo.2015.3223
Pages: 173-180

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Accurate detection of neuroendocrine (NE) tumors is critically important for better prognosis and treatment outcomes in patients. To demonstrate the efficacy of using an adenoviral vector for the detection of NE tumors, we have constructed a pair of adenoviral vectors which, in combination, can conditionally replicate and release Gaussia luciferase into the circulation after infecting the NE tumors. The expression of these two vectors is regulated upstream by an INSM1-promoter (insulinoma-associated-1) that is specifically active in NE tumors and developing NE tissues, but silenced in normal adult tissues. In order to retain the tumor-specificity of the INSM1 promoter, we have modified the promoter using the core insulator sequence from the chicken β-globin HS4 insulator and the neuronal restrictive silencing element (NRSE). This modified INSM1-promoter can retain NE tumor specificity in an adenoviral construct while driving a mutated adenovirus E1A gene (∆24E1A), the Metridia, or Gaussia luciferase gene. The in vitro cell line and mouse xenograft human tumor studies revealed the NE specificity of the INSM1-promoter in NE lung cancer, neuroblastoma, medulloblastoma, retinoblastoma, and insulinoma. When we combined the INSM1-promoter driven Gaussia luciferase with ∆24E1A, the co-infected NE tumor secreted higher levels of Gaussia luciferase as compared to the INSM1p-Gaussia virus alone. In a mouse subcutaneous xenograft tumor model, the combination viruses secreted detectable level of Gaussia luciferase after infecting an INSM1-positive NE lung tumor for ≥12 days. Therefore, the INSM1-promoter specific conditional replicating adenovirus represents a sensitive diagnostic tool to aid clinicians in the detection of NE tumors.

View Figures

View References

1	Rindi G and Wiedenmann B: Neuroendocrine neoplasms of the gut and pancreas: New insights. Nat Rev Endocrinol. 8:54–64. 2012. View Article : Google Scholar
2	Jann H, Roll S, Couvelard A, Hentic O, Pavel M, Müller-Nordhorn J, Koch M, Röcken C, Rindi G, Ruszniewski P, et al: Neuroendocrine tumors of midgut and hindgut origin: Tumor-node-metastasis classification determines clinical outcome. Cancer. 117:3332–3341. 2011. View Article : Google Scholar : PubMed/NCBI
3	Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M, Hedborg F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 11:1466–1477. 1993.PubMed/NCBI
4	Hayes FA, Green A, Hustu HO and Kumar M: Surgicopathologic staging of neuroblastoma: Prognostic significance of regional lymph node metastases. J Pediatr. 102:59–62. 1983. View Article : Google Scholar : PubMed/NCBI
5	Oyharcabal-Bourden V, Kalifa C, Gentet JC, Frappaz D, Edan C, Chastagner P, Sariban E, Pagnier A, Babin A, Pichon F, et al: Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: A French Society of Pediatric Oncology Study. J Clin Oncol. 23:4726–4734. 2005. View Article : Google Scholar : PubMed/NCBI
6	Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH, et al: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol. 17:2127–2136. 1999.PubMed/NCBI
7	Richardson GE and Johnson BE: The biology of lung cancer. Semin Oncol. 20:105–127. 1993.PubMed/NCBI
8	Mountain CF: Clinical biology of small cell carcinoma: Relationship to surgical therapy. Semin Oncol. 5:272–279. 1978.PubMed/NCBI
9	Argiris A and Murren JR: Staging and clinical prognostic factors for small-cell lung cancer. Cancer J. 7:437–447. 2001.PubMed/NCBI
10	Goto Y, De Silva MG, Toscani A, Prabhakar BS, Notkins AL and Lan MS: A novel human insulinoma-associated cDNA, IA-1, encodes a protein with ‘zinc-finger’ DNA-binding motifs. J Biol Chem. 267:15252–15257. 1992.PubMed/NCBI
11	Lan MS, Russell EK, Lu J, Johnson BE and Notkins AL: IA-1, a new marker for neuroendocrine differentiation in human lung cancer cell lines. Cancer Res. 53:4169–4171. 1993.PubMed/NCBI
12	Breslin MB, Zhu M, Notkins AL and Lan MS: Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: Identification of consensus IA-1 binding sequence. Nucleic Acids Res. 30:1038–1045. 2002. View Article : Google Scholar : PubMed/NCBI
13	Gierl MS, Karoulias N, Wende H, Strehle M and Birchmeier C: The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. Genes Dev. 20:2465–2478. 2006. View Article : Google Scholar : PubMed/NCBI
14	Wildner H, Gierl MS, Strehle M, Pla P and Birchmeier C: Insm1 (IA-1) is a crucial component of the transcriptional network that controls differentiation of the sympatho-adrenal lineage. Development. 135:473–481. 2008. View Article : Google Scholar
15	Farkas LM, Haffner C, Giger T, Khaitovich P, Nowick K, Birchmeier C, Pääbo S and Huttner WB: Insulinoma-associated 1 has a panneurogenic role and promotes the generation and expansion of basal progenitors in the developing mouse neocortex. Neuron. 60:40–55. 2008. View Article : Google Scholar : PubMed/NCBI
16	Xie J, Cai T, Zhang H, Lan MS and Notkins AL: The zinc-finger transcription factor INSM1 is expressed during embryo development and interacts with the Cbl-associated protein. Genomics. 80:54–61. 2002. View Article : Google Scholar : PubMed/NCBI
17	Mellitzer G, Bonné S, Luco RF, Van De Casteele M, Lenne-Samuel N, Collombat P, Mansouri A, Lee J, Lan M, Pipeleers D, et al: IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas. EMBO J. 25:1344–1352. 2006. View Article : Google Scholar : PubMed/NCBI
18	Lan MS and Breslin MB: Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation. FASEB J. 23:2024–2033. 2009. View Article : Google Scholar : PubMed/NCBI
19	El-Amouri SS, Cao P, Miao C and Pan D: Secreted luciferase for in vivo evaluation of systemic protein delivery in mice. Mol Biotechnol. 53:63–73. 2013. View Article : Google Scholar
20	Koutsoudakis G, Pérez-del-Pulgar S, González P, Crespo G, Navasa M and Forns X: A Gaussia luciferase cell-based system to assess the infection of cell culture- and serum-derived hepatitis C virus. PLoS One. 7:e532542012. View Article : Google Scholar
21	Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA and Harlow E: Association between an oncogene and an anti-oncogene: The adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 334:124–129. 1988. View Article : Google Scholar : PubMed/NCBI
22	Akerstrom V, Chen C, Lan MS and Breslin MB: Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas. Cancer Gene Ther. 19:828–838. 2012. View Article : Google Scholar : PubMed/NCBI
23	Aker M, Tubb J, Groth AC, Bukovsky AA, Bell AC, Felsenfeld G, Kiem HP, Stamatoyannopoulos G and Emery DW: Extended core sequences from the cHS4 insulator are necessary for protecting retroviral vectors from silencing position effects. Hum Gene Ther. 18:333–343. 2007. View Article : Google Scholar : PubMed/NCBI