The Co-expression of HER Family Members and CD109 is common in Pancreatic Cancer.
Main Article Content
Abstract
In the absence of biomarkers for the early detection of pancreatic cancer and the development of more effective therapeutic interventions, pancreatic cancer is projected to become the second leading cause of death from cancer in the Western world. In the past four decades, aberrant expression and activation of human epidermal growth factor receptor (EGFR, also called HER) family members have been reported in a wide range of human cancers. Currently, of the various types of drugs targeting one or more members of the HER family, only the EGFR-specific tyrosine kinase inhibitor erlotinib and more recently Zenocutuzumab, a HER-2/HER3 bispecific antibody, were granted breakthrough therapy designation by the FDA for the treatment of patients with pancreatic cancer. However, the therapeutic benefit may be modest in some patients. Hence there is an urgent need for the identification of biomarkers as prognostic indicators, therapeutic targets, and for the response to therapy and the development of more effective therapeutic agents for this highly heterogeneous cancer. In this study, for the first time, we investigated the relative expression and prognostic significance of all members of the HER family, the type-III EGFR mutant (EGFRvIII), and CD109 in tissue microarrays (TMAs) and whole tumour specimens (WTS) from pancreatic cancer patients by immunohistochemistry. We found the positive expression of wild-type EGFR (wt-EGFR) (63%, 4.7%), HER2 (75%, 14%), HER3 (none, 14%), HER4 (45%, 21%), EGFRvIII (5%, 3%), and CD109 (67%, 55%) in TMAs (USA) and WTS (UK) from pancreatic cancer patients respectively. Our results also show that the co-expression of HER family members with CD109 occurs frequently in patients with pancreatic cancer. In addition, the co-expression of HER4/CD109 may also be associated with poorer overall survival in such patients. In this article, we shall discuss these findings and their implications and future opportunities for more effective targeting of HER positive pancreatic cancer using the HER inhibitors in combination with other drugs and therapeutic interventions.
Keywords:
Pancreatic Cancer
Article Details
How to Cite
KHAN, Tanzeel et al.
The Co-expression of HER Family Members and CD109 is common in Pancreatic Cancer..
Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4689>. Date accessed: 16 may 2024.
doi: https://doi.org/10.18103/mra.v11i11.4689.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
3. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4(6):567-579.
4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.
5. Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol. 2019;10(1):10-27.
6. Arias-Pinilla GA, Modjtahedi H. Therapeutic Application of Monoclonal Antibodies in Pancreatic Cancer: Advances, Challenges and Future Opportunities. Cancers (Basel). 2021;13(8).
7. Li Q, Zhang L, Li X, et al. The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer : HER1-4 protein expression and prognosis in pancreatic cancer. BMC Cancer. 2016;16(1):910.
8. Perini MV, Montagnini AL, Coudry R, et al. Prognostic significance of epidermal growth factor receptor overexpression in pancreas cancer and nodal metastasis. ANZ J Surg. 2015;85(3):174-178.
9. Mahipal A, McDonald MJ, Witkiewicz A, Carr BI. Cell membrane and cytoplasmic epidermal growth factor receptor expression in pancreatic ductal adenocarcinoma. Med Oncol. 2012;29(1):134-139.
10. Einama T, Ueda S, Tsuda H, et al. Membranous and cytoplasmic expression of epidermal growth factor receptor in metastatic pancreatic ductal adenocarcinoma. Exp Ther Med. 2012;3(6):931-936.
11. Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Modjtahedi H. Expression pattern and targeting of HER family members and IGF-IR in pancreatic cancer. Front Biosci (Landmark Ed). 2012;17:2698-2724.
12. Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK. Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(1):15-31.
13. Tebbutt N, Pedersen MW, Johns TG. Targeting the ERBB family in cancer: couples therapy. Nat Rev Cancer. 2013;13(9):663-673.
14. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966.
15. Schram AM, Goto K, Kim D-W, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. Journal of Clinical Oncology. 2022;40(16_suppl):105-105.
16. Lin M, Sutherland DR, Horsfall W, et al. Cell surface antigen CD109 is a novel member of the alpha(2) macroglobulin/C3, C4, C5 family of thioester-containing proteins. Blood. 2002;99(5):1683-1691.
17. Solomon KR, Sharma P, Chan M, Morrison PT, Finberg RW. CD109 represents a novel branch of the alpha2-macroglobulin/ complement gene family. Gene. 2004;327 (2): 171-183.
18. Arias-Pinilla GA, Dalgleish AG, Mudan S, Bagwan I, Walker AJ, Modjtahedi H. Development of novel monoclonal antibodies against CD109 overexpressed in human pancreatic cancer. Oncotarget. 2018;9(28): 19994-20007.
19. Zhang JM, Hashimoto M, Kawai K, et al. CD109 expression in squamous cell carcinoma of the uterine cervix. Pathol Int. 2005;55(4):165-169.
20. Sato T, Murakumo Y, Hagiwara S, et al. High-level expression of CD109 is frequently detected in lung squamous cell carcinomas. Pathol Int. 2007;57(11):719-724.
21. Hagiwara S, Murakumo Y, Sato T, et al. Up-regulation of CD109 expression is associated with carcinogenesis of the squamous epithelium of the oral cavity. Cancer Science. 2008;99(10):1916-1923.
22. Hagikura M, Murakumo Y, Hasegawa M, et al. Correlation of pathological grade and tumor stage of urothelial carcinomas with CD109 expression. Pathol Int. 2010;60(11): 735-743.
23. Ohshima Y, Yajima I, Kumasaka MY, et al. CD109 expression levels in malignant melanoma. J Dermatol Sci. 2010;57(2):140-142.
24. Tao J, Li H, Li Q, Yang Y. CD109 is a potential target for triple-negative breast cancer. Tumour Biol. 2014;35(12):12083-12090.
25. Emori M, Tsukahara T, Murata K, et al. Prognostic impact of CD109 expression in myxofibrosarcoma. J Surg Oncol. 2015;111 (8):975-979.
26. Hatsuzawa Y, Yamaguchi K, Takanashi T, et al. CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells. Pancreatology. 2020; 20(3):493-500.
27. Dong F, Lu C, Chen X, Guo Y, Liu J. CD109 is a novel marker for squamous cell/adenosquamous carcinomas of the gallbladder. Diagn Pathol. 2015;10:137.
28. Ozbay P, Ekinci T, Yiǧit S, et al. Investigation of prognostic significance of CD109 expression in women with vulvar squamous cell carcinoma. Onco Targets Ther. 2013;6:621-627.
29. Kim SY, Choi KU, Hwang C, et al. Prognostic Significance of CD109 Expression in Patients with Ovarian Epithelial Cancer. J Pathol Transl Med. 2019;53(4):244-252.
30. Yokoyama M, Ichinoe M, Okina S, et al. CD109, a negative regulator of TGF-β signaling, is a putative risk marker in diffuse large B-cell lymphoma. Int J Hematol. 2017; 105(5):614-622.
31. Taki T, Shiraki Y, Enomoto A, et al. CD109 regulates in vivo tumor invasion in lung adenocarcinoma through TGF-β signaling. Cancer Sci. 2020;111(12):4616-4628.
32. Hagiwara S, Murakumo Y, Mii S, et al. Processing of CD109 by furin and its role in the regulation of TGF-beta signaling. Oncogene. 2010;29(15):2181-2191.
33. Li C, Hancock MA, Sehgal P, Zhou S, Reinhardt DP, Philip A. Soluble CD109 binds TGF-β and antagonizes TGF-β signalling and responses. Biochem J. 2016;473(5):537-547.
34. Zhang JM, Murakumo Y, Hagiwara S, et al. CD109 attenuates TGF-β1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells. Biochem Biophys Res Commun. 2015;459(2):252-258.
35. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280(21):5350-5370.
36. Arias-Pinilla GA, Dalgleish AG, Mudan S, Bagwan I, Walker AJ, Modjtahedi H. Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer. Scientific Reports. 2020;10(1):537.
37. Khelwatty SA, Puvanenthiran S, Essapen S, Bagwan I, Seddon AM, Modjtahedi H. HER2 Expression Is Predictive of Survival in Cetuximab Treated Patients with RAS Wild Type Metastatic Colorectal Cancer. Cancers (Basel). 2021;13(4).
38. Puvanenthiran S, Essapen S, Haagsma B, et al. Co-expression and prognostic significance of the HER family members, EGFRvIII, c-MET, CD44 in patients with ovarian cancer. Oncotarget. 2018;9(28):19662 -19674.
39. Saxby AJ, Nielsen A, Scarlett CJ, et al. Assessment of HER-2 status in pancreatic adenocarcinoma: correlation of immunohistochemistry, quantitative real-time RT-PCR, and FISH with aneuploidy and survival. Am J Surg Pathol. 2005;29(9):1125-1134.
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