OVER SERÖZ KARSİNOMUNDA VE BORDERLİNE SERÖZ TÜMÖRDE İMMÜNHİSTOKİMYASAL PINCH/LIMS-1 ANTİKOR EKSPRESYONUNUN KLİNİKOPATOLOJİK DEĞERİ

Öz

Amaç Özellikle ilginç cys-his zengin proteinin (PINCH/LIMS- 1), tümörlerdeki ve tümörle ilişkili stromadaki kanser hücrelerinin gelişimini ve yayılımını denetlediği varsayılmaktadır. Bu çalışmanın amacı, seröz borderline tümör (SBT) ve seröz karsinomda (SC) tümör ve peritümöral stromadaki PINCH-1 ekspresyonunu değerlendirmek ve ekspresyonu ile çeşitli klinik ve patolojik parametreler arasındaki ilişkileri incelemektir. Gereç ve Yöntem Yirmi bir SBT ve 89 SK vakasında PINCH-1 antikorunun ekspresyonu streptavidin/HRP-biotin ile indirekt immünoperoksidaz tekniği kullanılarak analiz edilmiştir. PINCH-1'in tümör ve peritümöral stromadaki boyanma paterni semikantitatif skorlama yöntemi kullanılarak değerlendirilmiştir. Çalışmada kullanılan boyama yöntemi PINCH-1 ekspresyonunun tanımlanmasına olanak sağlamış ve semikantitatif skorlama yöntemiyle PINCH-1 boyanmasının yaygınlığı ve yoğunluğu değerlendirilmiştir. Böylece, PINCH-1 ekspresyonu ile hasta yaşı, tümör boyutu, FIGO evresi, intraabdominal yıkama sitolojisi, kapsül invazyonu, tümör yerleşimi, tümör derecesi ve tanı anındaki kanser antijen 125 (CA125) seviyeleri gibi çeşitli klinik ve patolojik faktörler arasındaki korelasyon incelenmiştir. Bulgular Çalışmada PINCH-1'in SK vakalarında SBT vakalarına göre daha yaygın olduğu bulunmuştur. SK’ler SBT vakalarındakilere göre daha güçlü boyanma göstermiştir (p<0,001). Çalışmada ayrıca, tümörü çevreleyen dokudaki PINCH-1 boyanmasının yaygınlığı ve yoğunluğu ile tümörün tek ya da bilateral overde yer alması arasında pozitif bir korelasyon bulunmuştur (dağılım için p = 0,038, yoğunluk için p = 0,024). Bununla birlikte, PINCH-1 boyanması ile tümör boyutu arasında negatif bir korelasyon vardı (yaygınlık için p=0.019, yoğunluk için p=0.007). Ayrıca, PINCH-1 tümör boyanmasının yoğunluğu, FIGO evresi ve tümör dereceleri arttıkça istatistiksel anlamlılık sergilemiştir (sırasıyla p = 0,032 ve p = 0,001). Sonuç Bu çalışmanın sonuçları, SK'lerin SBT'lere göre daha yüksek düzeyde PINCH-1 boyanma yoğunluğu sergilediğini göstermektedir. Ayrıca, FIGO evresindeki ve tümör derecesindeki artış, tümör dokusunda artan PINCH-1 boyanma yoğunluğu ile ilişkilidir. Peritümöral stromadaki PINCH-1 boyanmasının yayılımı ve yoğunluğu bilateral tümör vakalarında daha dikkat çekicidir, ancak tümör boyutuyla ters orantılıdır. PINCH-1 ekspresyonu ile önemli klinikopatolojik faktörler arasında gözlenen ilişki, bu molekülün seröz over kanseri gelişiminde rol oynayabileceğini düşündürmektedir. Çalışmamız PINCH-1'in tümörogenezdeki rolünün daha iyi anlaşılmasına katkıda bulunabilir ve bu yolağı hedefleyen yeni terapötik stratejilerin geliştirilmesi için yol gösterici olabilir.

Anahtar Kelimeler

• FIGO evresi
• PINCH/LIMS-1
• Seröz borderline tümör
• Seröz karsinom
• Seröz over karsinomunda PINCH ekspresyonu

CLINICOPATHOLOGIC VALUE OF IMMUNOHISTOCHEMICAL PINCH/LIMS-1 ANTIBODY EXPRESSION IN OVARIAN SEROUS CARCINOMA AND BORDERLINE SEROUS TUMOR

Öz

Objective Particularly interesting cys-his rich protein (PINCH/ LIMS-1), a protein implicated in cell adhesion, is assumed to oversee the development and invasion of cancer cells in tumors and tumor-associated stroma. This study aimed to assess PINCH-1 expression in serous borderline tumor (SBT) and serous carcinoma (SC) in the tumor and peritumoral stroma and scrutinize any associations between its expression and various clinical and pathological parameters. Material and Method In this study, the expression of the PINCH-1 antibody was analyzed in 21 cases of SBT and 89 cases of SC using the indirect immunoperoxidase technique with streptavidin/HRP-biotin. The staining pattern of PINCH-1 in the tumor and peritumoral stroma was evaluated using a semiquantitative scoring method. The staining procedure used in the study allowed for the accurate identification of PINCH-1 expression, and the data obtained through the semiquantitative scoring method provided a reliable of assessing the degree and intensity of PINCH-1 staining. Thus, the correlation between PINCH-1 expression and various pathologic factors such as patient age, tumor size, FIGO stage, intra-abdominal washing cytology, capsule invasion, tumor location in the ovary, tumor grade, and cancer antigen 125 (CA125) levels at the time of diagnosis was examined. Results The study found that PINCH-1 was more prevalent in cases of SC than in SBT cases. The tumors in SC cases had stronger staining than those in SBT cases (p<0.001). The study also found a positive correlation between the diffusiveness and intensity of PINCH-1 staining in the tissue surrounding the tumor and whether the tumor was located on one or both sides of the ovaries (p = 0.038 for diffusiveness, p = 0.024 for intensity). However, there was a negative correlation between PINCH-1 staining and tumor size (p=0.019 for diffusiveness, p=0.007 for intensity). Furthermore, the intensity of PINCH-1 tumor staining exhibited statistical significance in Figo stage and tumor grades as these increased (p = 0.032 and p = 0.001, respectively). Conclusion The results of this study indicate that SCs exhibit a higher level of PINCH-1 staining intensity than SBTs. Furthermore, an increase in the FIGO stage and tumor grade is associated with increased intensity of PINCH-1 staining in the tumor tissue. Additionally, the diffusiveness and intensity of PINCH-1 staining in the peritumoral stroma is more remarkable in cases of bilateral tumors but is inversely correlated with tumor size. The observed association between PINCH-1 expression and important clinicopathologic factors suggests that this molecule may be involved in developing serous ovarian cancer. Overall, these findings may contribute to a better understanding of the role of PINCH-1 in ovarian tumorigenesis and may have implications for developing novel therapeutic strategies targeting this pathway.

Anahtar Kelimeler

• FIGO stage
• PINCH/LIMS-1
• PINCH expression in serous ovarian carcinoma
• Serous borderline tumor
• Serous carcinoma

Kaynakça

1. 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan;64(1):9–29
2. 2. Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch. 2012 Mar;460(3):237–49.
3. 3. Desai A, Xu J, Aysola K, Qin Y, Okoli C, Hariprasad R, et al. Epithelial ovarian cancer: An overview. World J Transl Med. 2014 Apr 12;3(1):1–8.
4. 4. Prat J. Pathology of cancers of the female genital tract. In: Denny L, editor. International Journal of Gynecology & Obstetrics. 2012. p. S137-50.
5. 5. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019 Mar 23;393(10177):1240–53.
6. 6. Arora T, Mullangi S, Lekkala MR. Ovarian Cancer [Internet]. StatPearls Publishing; 2023 [cited 2023 Aug 23]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK567760/
7. 7. McCluggage WG, Singh N, Gilks CB. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology. 2022 Apr;80(5):762–78.
8. 8. Fukuda T, Chen K, Shi X, Wu C. PINCH-1 is an obligate partner of integrin-linked kinase (ILK) functioning in cell shape modulation, motility, and survival. J Biol Chem. 2003 Dec 19;278(51):51324–33.

9. 9. Lööf J, Rosell J, Bratthäll C, Doré S, Starkhammar H, Zhang H, et al. Impact of PINCH expression on survival in colorectal cancer patients. BMC Cancer. 2011 Mar 22;11:103.
10. 10. Yang Y, Wang X, Hawkins CA, Chen K, Vaynberg J, Mao X, et al. Structural basis of focal adhesion localization of LIM-only adaptor PINCH by integrin-linked kinase. J Biol Chem. 2009 Feb 27;284(9):5836–44.
11. 11. Wu C. PINCH, N(i)ck and the ILK: network wiring at cell-matrix adhesions. Trends Cell Biol. 2005 Sep;15(9):460–6.
12. 12. Wu C. Integrin-linked kinase and PINCH: partners in regulation of cell-extracellular matrix interaction and signal transduction. J Cell Sci. 1999 Dec;112 ( Pt 24):4485–9.
13. 13. 1Dougherty GW, Jose C, Gimona M, Cutler ML. The Rsu-1- PINCH1-ILK complex is regulated by Ras activation in tumor cells. Eur J Cell Biol. 2008 Sep;87(8–9):721–34.
14. 14. Eke I, Koch U, Hehlgans S, Sandfort V, Stanchi F, Zips D, et al. PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1alpha. J Clin Invest. 2010 Jul;120(7):2516–27.
15. 15. Montanez E, Karaköse E, Tischner D, Villunger A, Fässler R. PINCH-1 promotes Bcl-2-dependent survival signalling and inhibits JNK-mediated apoptosis in the primitive endoderm. J Cell Sci. 2012 Nov 1;125(Pt 21):5233–40.
16. 16. Sun X-F, Zhang H. Clinicopathological significance of stromal variables: angiogenesis, lymphangiogenesis, inflammatory infiltration, MMP and PINCH in colorectal carcinomas. Mol Cancer. 2006 Oct 6;5:43.
17. 17. Scaife CL, Shea J, Emerson L, Boucher K, Firpo MA, Beckerle MC, et al. Prognostic significance of PINCH signalling in human pancreatic ductal adenocarcinoma. HPB. 2010 Jun;12(5):352–8.
18. 18. Davidson B. The diagnostic and molecular characteristics of malignant mesothelioma and ovarian/peritoneal serous carcinoma. Cytopathology. 2011 Feb;22(1):5–21.
19. 19. Wang M-W, Gu P, Zhang Z-Y, Zhu Z-L, Li Y-M, Zhao H-X, et al. Expression of PINCH protein in gliomas and its clinicopathological significance. Oncology. 2007;72(5–6):343–6.
20. 20. Zhang H-Z, Li X-H, Zhang X, Zhang Z-Y, Meng Y-L, Xu S-W, et al. PINCH protein expression in normal endometrium, atypical endometrial hyperplasia and endometrioid endometrial carcinoma. Chemotherapy. 2010 Aug 11;56(4):291–7.
21. 21. Zhu Z-L, Yan B-Y, Zhang Y, Yang Y-H, Wang Z-M, Zhang H-Z, et al. PINCH expression and its clinicopathological significance in gastric adenocarcinoma. Dis Markers. 2012;33(4):171–8.
22. 22. Foulkes WD, Ragoussis J, Stamp GW, Allan GJ, Trowsdale J. Frequent loss of heterozygosity on chromosome 6 in human ovarian carcinoma. Br J Cancer. 1993 Mar;67(3):551–9.
23. 23. Jacobs IJ, Smith SA, Wiseman RW, Futreal PA, Harrington T, Osborne RJ, et al. A deletion unit on chromosome 17q in epithelial ovarian tumors distal to the familial breast/ovarian cancer locus. Cancer Res. 1993 Mar 15;53(6):1218–21.
24. 24. Bandera CA, Takahashi H, Behbakht K, Liu PC, LiVolsi VA, Benjamin I, et al. Deletion mapping of two potential chromosome 14 tumor suppressor gene loci in ovarian carcinoma. Cancer Res. 1997 Feb 1;57(3):513–5.
25. 25. Brown MR, Chuaqui R, Vocke CD, Berchuck A, Middleton LP, Emmert-Buck MR, et al. Allelic loss on chromosome arm 8p: analysis of sporadic epithelial ovarian tumors. Gynecol Oncol. 1999 Jul;74(1):98–102.
26. 26. Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, et al. Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management. Mol Oncol. 2009 Apr;3(2):97–137.
27. 27. Tingulstad S, Skjeldestad FE, Halvorsen TB, Hagen B. Survival and prognostic factors in patients with ovarian cancer. Obstet Gynecol. 2003 May;101(5 Pt 1):885–91.
28. 28. Gilks CB, Ionescu DN, Kalloger SE, Köbel M, Irving J, Clarke B, et al. Tumor cell type can be reproducibly diagnosed and is of independent prognostic significance in patients with maximally debulked ovarian carcinoma. Hum Pathol. 2008 Aug;39(8):1239–51.
29. 29. Kurman RJ, Ellenson LH, Ronnett BM. Blaustein’s pathology of the female genital tract. 7th ed. Cham, Switzerland: Springer International Publishing; 2019. 1508 p.
30. 30. Gao J, Arbman G, Rearden A, Sun X-F. Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer. Neoplasia. 2004 Nov;6(6):796–801.
31. 31. Wang-Rodriguez J, Dreilinger AD, Alsharabi GM, Rearden A. The signaling adapter protein PINCH is up-regulated in the stroma of common cancers, notably at invasive edges. Cancer. 2002 Sep 15;95(6):1387–95.
32. 32. Scaife CL, Shea JE, Dai Q, Firpo MA, Prestwich GD, Mulvihill SJ. Synthetic extracellular matrix enhances tumor growth and metastasis in an orthotopic mouse model of pancreatic adenocarcinoma. J Gastrointest Surg. 2008 Jun;12(6):1074–80.
33. 33. Kholodenko BN, Hoek JB, Westerhoff HV. Why cytoplasmic signalling proteins should be recruited to cell membranes. Trends Cell Biol. 2000 May;10(5):173–8.