J Pathol Transl Med.  2019 Jul;53(4):244-252. 10.4132/jptm.2019.04.16.

Prognostic Significance of CD109 Expression in Patients with Ovarian Epithelial Cancer

• Kim SY
• Choi KU
• Hwang C
• Lee HJ
• Lee JH
• Shin DH
• Kim JY
• Sol MY
• Kim JH
• Kim KH
• Suh DS
• Kwon BS

• KMID: 2454604
• DOI: http://doi.org/10.4132/jptm.2019.04.16

Abstract

BACKGROUND
Ovarian epithelial cancer (OEC) is the second-most common gynecologic malignancy. CD109 expression is elevated in human tumor cell lines and carcinomas. A previous study showed that CD109 expression is elevated in human tumor cell lines and CD109 plays a role in cancer progression. Therefore, this study aimed to determine whether CD109 is expressed in OEC and can be useful in predicting the prognosis.
METHODS
Immunohistochemical staining for CD109 and reverse transcription-quantitative polymerase chain reaction was performed. Then we compared CD109 expression and chemoresistance, overall survival, and recurrence-free survival of OEC patients. Chemoresistance was evaluated by dividing into good-response group and poor-response group by the time to recurrence after chemotherapy.
RESULTS
CD109 expression was associated with overall survival (p = .020), but not recurrence-free survival (p = .290). CD109 expression was not an independent risk factor for overall survival due to its reliability (hazard ratio, 1.58; p = .160; 95% confidence interval, 0.82 to 3.05), although we found that CD109 positivity was related to chemoresistance. The poor-response group showed higher rates of CD109 expression than the good-response group (93.8% vs 66.7%, p = .047). Also, the CD109 mRNA expression level was 2.88 times higher in the poor-response group as compared to the good-response group (p = .001).
CONCLUSIONS
Examining the CD109 expression in patients with OEC may be helpful in predicting survival and chemotherapeutic effect.

Keyword

Ovarian epithelial carcinoma; CD109; Prognosis

MeSH Terms

Cell Line, Tumor
Drug Therapy
Humans
Polymerase Chain Reaction
Prognosis
Recurrence
Risk Factors
RNA, Messenger
RNA, Messenger

Figure

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  Fig. 1. Immunohistochemical staining of CD109 in ovarian epithelial carcinoma. (A) Positive in serous carcinoma. (B) Positive in mucinous carcinoma. (C) Positive in endometrioid carcinoma. (D) Positive in clear cell carcinoma. (E) Positive in undifferentiated carcinoma. (F) Negative in serous carcinoma.

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  Fig. 2. Expression of CD109 protein is associated with overall survival. Prognosis is estimated by Kaplan-Meier plots (p=.020).

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  Fig. 3. Expression of CD109 protein is not significantly associated with recurrence. Prognosis is estimated by Kaplan-Meier plots (p=.290).

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  Fig. 4. Relationship between chemoresistance and CD109 mRNA expression (n=12).

Reference

1. Montes AF, Gomez JG, Viejo MN, Bermejo MA, Urrutia SA, Mata JG. Epidemiology and etiology of ovarian cancer. In : Farghaly S, editor. Ovarian cancer: basic science perspective. Vancouver: InTech;2012. p. 1–16.

2. Flam F, Einhorn N, Sjövall K. Symptomatology of ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 1988; 27:53–7.

3. Goff BA, Mandel L, Muntz HG, Melancon CH. Ovarian carcinoma diagnosis. Cancer. 2000; 89:2068–75.

4. Liu J, Matulonis UA. New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances. Clin Cancer Res. 2014; 20:5150–6.

5. Hartmann LC, Podratz KC, Keeney GL, et al. Prognostic significance of p53 immunostaining in epithelial ovarian cancer. J Clin Oncol. 1994; 12:64–9.

6. Luo H, Xu X, Ye M, Sheng B, Zhu X. The prognostic value of HER2 in ovarian cancer: a meta-analysis of observational studies. PLoS One. 2018; 13:e0191972.

7. 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; 99:1683–91.

8. Hasegawa M, Hagiwara S, Sato T, et al. CD109, a new marker for myoepithelial cells of mammary, salivary, and lacrimal glands and prostate basal cells. Pathol Int. 2007; 57:245–50.

9. Leivonen SK, Kähäri VM. Transforming growth factor-beta signaling in cancer invasion and metastasis. Int J Cancer. 2007; 121:2119–24.

10. Zhang JM, Hashimoto M, Kawai K, et al. CD109 expression in squamous cell carcinoma of the uterine cervix. Pathol Int. 2005; 55:165–9.

11. Sato T, Murakumo Y, Hagiwara S, et al. High-level expression of CD109 is frequently detected in lung squamous cell carcinomas. Pathol Int. 2007; 57:719–24.

12. 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.

13. Ozbay PÖ, Ekinci T, Yigˇit S, et al. Investigation of prognostic significance of CD109 expression in women with vulvar squamous cell carcinoma. Onco Targets Ther. 2013; 6:621–7.

14. Emori M, Tsukahara T, Murase M, et al. High expression of CD109 antigen regulates the phenotype of cancer stem-like cells/cancerinitiating cells in the novel epithelioid sarcoma cell line ESX and is related to poor prognosis of soft tissue sarcoma. PLoS One. 2013; 8:e84187.

15. Emori M, Tsukahara T, Murata K, et al. Prognostic impact of CD109 expression in myxofibrosarcoma. J Surg Oncol. 2015; 111:975–9.

16. Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumours of female reproductive organs. 4th ed. Lyon: International Agency for Research on Cancer;2014. p. 11–40.

17. Shimizu Y, Kamoi S, Amada S, Akiyama F, Silverberg SG. Toward the development of a universal grading system for ovarian epithelial carcinoma: testing of a proposed system in a series of 461 patients with uniform treatment and follow-up. Cancer. 1998; 82:893–901.

18. Pecorelli S, Benedet JL, Creasman WT, Shepherd JH. FIGO staging of gynecologic cancer. 1994-1997 FIGO Committee on Gynecologic Oncology. International Federation of Gynecology and Obstetrics. Int J Gynaecol Obstet. 1999; 65:243–9.

19. Yuan JS, Reed A, Chen F, Stewart CN Jr. Statistical analysis of realtime PCR data. BMC Bioinformatics. 2006; 7:85.

20. Hashimoto M, Ichihara M, Watanabe T, et al. Expression of CD109 in human cancer. Oncogene. 2004; 23:3716–20.

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 Sci. 2008; 99:1916–23.

22. 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; 29:2181–91.

23. Cuppini L, Calleri A, Bruzzone MG, et al. Prognostic value of CD109+ circulating endothelial cells in recurrent glioblastomas treated with bevacizumab and irinotecan. PLoS One. 2013; 8:e74345.

24. Hasegawa M, Moritani S, Murakumo Y, et al. CD109 expression in basal-like breast carcinoma. Pathol Int. 2008; 58:288–94.

25. Tao J, Li H, Li Q, Yang Y. CD109 is a potential target for triple-negative breast cancer. Tumour Biol. 2014; 35:12083–90.

26. Mancuso P, Calleri A, Gregato G, et al. A subpopulation of circulating endothelial cells express CD109 and is enriched in the blood of cancer patients. PLoS One. 2014; 9:e114713.

27. Tsai YL, Ha DP, Zhao H, et al. Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-beta signaling. Proc Natl Acad Sci U S A. 2018; 115:E4245–54.

28. Sunagawa M, Mii S, Enomoto A, et al. Suppression of skin tumorigenesis in CD109-deficient mice. Oncotarget. 2016; 7:82836–50.

29. Bhola NE, Balko JM, Dugger TC, et al. TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013; 123:1348–58.

30. Oshimori N, Oristian D, Fuchs E. TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015; 160:963–76.

31. De Vita A, Recine F, Mercatali L, et al. Myxofibrosarcoma primary cultures: molecular and pharmacological profile. Ther Adv Med Oncol. 2017; 9:755–67.