Skip to main content

Advertisement

SpringerLink
Log in

Secretory Phospholipase A2 IIa Mediates Expression of Growth Factor Receptors in Esophageal Adenocarcinoma

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Receptor tyrosine kinases of the epidermal growth factor receptor (EGFR) family such as human epidermal receptor-2 (HER2) are involved in the development and progression of esophageal adenocarcinoma (EAC). Prior studies have demonstrated that group IIa secretory phospholipase A2 (sPLA2 IIa) can function as a ligand for the EGFR family of receptors and lead to an increase in receptor signaling.

Aims

We hypothesized that sPLA2 IIa inhibition downregulates the expression of EGFR and HER-2 in EAC and through this mechanism decreases proliferation in EAC.

Methods

Normal human esophageal epithelium, Barrett’s esophagus (BE), and EAC tissue samples were assayed for baseline expression of EGFR, HER-2, and sPLA2 IIa. sPLA2 IIa was attenuated via inhibitor or lentiviral knockdown in esophageal cell lines, and cells were assayed for EGFR and HER2 expression as well as proliferation. FLO1 EAC cells were injected into the flank of nude mice. After randomization, mice received daily group IIA sPLA2 inhibitor or a control solution, and tumor volume was measured with calipers.

Results

sPLA2 IIa, EGFR, and HER2 expression increased across the spectrum of normal esophageal epithelium to EAC. sPLA2 IIa inhibition and knockdown decreased the expression of HER-2 and EGFR and proliferation. Mice treated with sPLA2 IIa inhibitor had smaller tumors than controls.

Conclusions

sPLA2 IIa inhibition decreases EGFR and HER2 expression and lowers proliferation of human EAC. The discovery of sPLA2 IIa inhibition’s ability to attenuate growth factor receptor signaling underscores the exciting potential of sPLA2 IIa inhibitors as therapeutics in the treatment of EAC.

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

Similar content being viewed by others

Abbreviations

BE:

Barrett’s esophagus

BSA:

Bovine serum albumin

DMEM:

Dulbecco’s modified eagle medium

DMSO:

Dimethyl sulfoxide

EAC:

Esophageal adenocarcinoma

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HER2:

Human epidermal receptor-2

IHC:

Immunohistochemistry]

IP:

Intraperitoneal

MTS:

(3-(4,5-dimethylithiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)

RPMI:

Roswell Park Memorial Institute Media

SCC:

Squamous cell carcinoma

shRNA:

Short hairpin ribonucleic acid

sPLA2 IIa:

Group IIa secretory phospholipase A2

References

  1. Noone A-M, Cronin KA, Altekruse SF, et al. Cancer incidence and survival trends by subtype using data from the surveillance epidemiology and end results program, 1992–2013. Cancer Epidemiol Biomark Prev. 2017;26:632.

    Article  Google Scholar 

  2. Dong Z, Meller J, Succop P, et al. Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells. Int J Oncol. 2014;45:978–984.

    Article  CAS  Google Scholar 

  3. Lu S, Dong Z. Overexpression of secretory phospholipase A2-IIa supports cancer stem cell phenotype via HER/ERBB-elicited signaling in lung and prostate cancer cells. Int J Oncol. 2017;50:2113–2122.

    Article  CAS  Google Scholar 

  4. Sadaria MR, Meng X, Fullerton DA, et al. Secretory phospholipase A2 inhibition attenuates intercellular adhesion molecule-1 expression in human esophageal adenocarcinoma cells. Ann Thorac Surg. 2011;91:1539–1545.

    Article  Google Scholar 

  5. Sadaria MR, Yu JA, Meng X, et al. Secretory phospholipase A2 mediates human esophageal adenocarcinoma cell growth and proliferation via ERK 1/2 pathway. Anticancer Res. 2013;33:1337–1342.

    PubMed  CAS  Google Scholar 

  6. Mauchley D, Meng X, Johnson T, et al. Modulation of growth in human esophageal adenocarcinoma cells by group IIa secretory phospholipase A(2). J Thorac Cardiovasc Surg. 2010;139:591–599. (discussion 599).

    Article  CAS  Google Scholar 

  7. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–137.

    Article  CAS  Google Scholar 

  8. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25:282–303.

    Article  CAS  Google Scholar 

  9. Cronin J, McAdam E, Danikas A, et al. Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett’s esophagus (BE). Am J Gastroenterol. 2011;106:46–56.

    Article  CAS  Google Scholar 

  10. Goltsov AA, Fang B, Pandita TK, et al. HER2 confers resistance to foretinib inhibition of MET-amplified esophageal adenocarcinoma cells. Ann Thorac Surg. 2018;105:363–370.

    Article  Google Scholar 

  11. Hanawa M, Suzuki S, Dobashi Y, et al. EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer. 2006;118:1173–1180.

    Article  CAS  Google Scholar 

  12. Reichelt U, Duesedau P, Tsourlakis M, et al. Frequent homogeneous HER-2 amplification in primary and metastatic adenocarcinoma of the esophagus. Mod Pathol. 2007;20:120–129.

    Article  CAS  Google Scholar 

  13. Yamamoto Y, Yamai H, Seike J, et al. Prognosis of esophageal squamous cell carcinoma in patients positive for human epidermal growth factor receptor family can be improved by initial chemotherapy with docetaxel, fluorouracil, and cisplatin. Ann Surg Oncol. 2012;19:757–765.

    Article  Google Scholar 

  14. Yoon HH, Shi Q, Sukov WR, et al. Association of HER2/ErbB2 expression and gene amplification with pathologic features and prognosis in esophageal adenocarcinomas. Clin Cancer Res. 2012;18:546–554.

    Article  CAS  Google Scholar 

  15. Fichter CD, Przypadlo CM, Buck A, et al. A new model system identifies epidermal growth factor receptor-human epidermal growth factor receptor 2 (HER2) and HER2-human epidermal growth factor receptor 3 heterodimers as potent inducers of oesophageal epithelial cell invasion. J Pathol. 2017;243:481–495.

    Article  CAS  Google Scholar 

  16. Walch A, Bink K, Hutzler P, et al. HER-2/neu gene amplification by FISH predicts poor survival in Barrett’s esophagus-associated adenocarcinoma. Hum Pathol. 2000;31:1332–1334.

    PubMed  CAS  Google Scholar 

  17. Oleksowicz L, Liu Y, Bracken RB, et al. Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer. Prostate. 2012;72:1140–1149.

    Article  CAS  Google Scholar 

  18. Bennett DT, Reece TB, Foley LS, et al. C-terminal tensin-like protein mediates invasion of human lung cancer cells and is regulated by signal transducer and activator of transcription 3. J Thorac Cardiovasc Surg. 2015;149:369–375.

    Article  CAS  Google Scholar 

  19. Yu JA, Li H, Meng X, et al. Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells. J Thorac Cardiovasc Surg. 2012;144:1479–1485.

    Article  CAS  Google Scholar 

  20. Fichter CD, Timme S, Braun JA, et al. EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer. Int J Cancer. 2014;135:1517–1530.

    Article  CAS  Google Scholar 

  21. Guo K, Wang WP, Jiang T, et al. Assessment of epidermal growth factor receptor mutation/copy number and K-ras mutation in esophageal cancer. J Thorac Dis. 2016;8:1753–1763.

    Article  Google Scholar 

  22. Fassan M, Mastracci L, Grillo F, et al. Early HER2 dysregulation in gastric and oesophageal carcinogenesis. Histopathology. 2012;61:769–776.

    Article  Google Scholar 

  23. Bradley JD, Dmitrienko AA, Kivitz AJ, et al. A randomized, double-blinded, placebo-controlled clinical trial of LY333013, a selective inhibitor of group II secretory phospholipase A2, in the treatment of rheumatoid arthritis. J Rheumatol. 2005;32:417–423.

    PubMed  CAS  Google Scholar 

  24. Rosenson RS, Hislop C, Elliott M, et al. Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients. J Am Coll Cardiol. 2010;56:1079–1088.

    Article  CAS  Google Scholar 

  25. Rosenson RS, Hislop C, McConnell D, et al. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial. Lancet. 2009;373:649–658.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge the University of Colorado Research Histology Core Laboratory for assistance with immunohistochemistry and Dr. Jeffrey Kaplan, MD, for the pathologic interpretation of the immunohistochemistry.

Funding

This work was funded by the Department of Surgery, Division of Cardiothoracic Surgery, and American Cancer Society Institutional Research Grant #16-184-56.

Author information

Authors and Affiliations

  1. Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado School of Medicine, 1665 Aurora Court, Aurora, CO, 80045, USA

    Alison L. Halpern, Patrick D. Kohtz, Allana M. White, Anna K. Houk, Jacob F. Rehring, Levent Hanson, Xianzhong Meng, David A. Fullerton & Michael J. Weyant

  2. Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, 1665 Aurora Court, Aurora, CO, 80045, USA

    Martin. D. McCarter

  3. University of Colorado Anschutz Medical Campus Functional Genomics Core Facility, 12800 E 19th Street, RC1 North, P18-6222/6223, Aurora, CO, 80045, USA

    Molishree Joshi

  4. University of Colorado, 12631 E. 17th Ave., C302, Aurora, CO, 80045, USA

    Alison L. Halpern

Authors
  1. Alison L. Halpern
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick D. Kohtz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Allana M. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna K. Houk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jacob F. Rehring
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Levent Hanson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin. D. McCarter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Molishree Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xianzhong Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David A. Fullerton
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael J. Weyant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alison L. Halpern.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 12 kb)

Supplementary material 2 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Halpern, A.L., Kohtz, P.D., White, A.M. et al. Secretory Phospholipase A2 IIa Mediates Expression of Growth Factor Receptors in Esophageal Adenocarcinoma. Dig Dis Sci 66, 784–795 (2021). https://doi.org/10.1007/s10620-020-06241-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-020-06241-2

Keywords

Search

Navigation