Correlation of CD44v6 expression with ovarian cancer progression and recurrence

BMC Cancer

Jun Shi¹  Zhou Zhou²  Wen Di¹  Ningli Li² 

[1] Department of Obstetrics and Gynecology, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China

[2] Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China

关键词: Recurrence;    Abdominal cavity metastasis;    Tumor progression;    CD44v6;    Ovarian cancer;   

Others  :  1079808
DOI  :  10.1186/1471-2407-13-182

 received in 2012-10-27, accepted in 2013-04-03,  发布年份 2013

【 摘 要 】

Background

Previously some groups demonstrated that CD44 variant 6 (CD44v6) is correlated with progression and metastasis of ovarian cancer. However, a number of other groups failed to find such an association. Moreover, epithelial ovarian cancer is known to easily metastasize to distinct sites such as the pelvic and abdominal cavities, but the potential association of CD44v6 expression with site-specific metastasis of ovarian cancer has not been explored. This study sought to evaluate the expression of CD44 standard (CD44s) and CD44v6 in primary, metastatic and recurrent epithelial ovarian cancer to explore the potential association of CD44s and CD44v6 with tumor progression and recurrence.

Methods

Tumor specimens were procured from patients with advanced (FIGO III, G3) and recurrent ovarian serous adenocarcinoma. CD44s and CD44v6 expression in the tumor tissues was evaluated by real-time RT-PCR and Western blot. Moreover, serum soluble CD44s or CD44v6 concentrations of early stage (FIGO I, G1), advanced (FIGO III, G3) and recurrent ovarian serous adenocarcinoma patients were determined by enzyme-linked immunosorbent assays (ELISA). CD44v6 expression in a different set of tumor samples on an ovarian cancer tissue chip was evaluated by immunohistochemistry (IHC) and the correlation of CD44v6 expression with clinicopathologic features was analyzed. Finally, the effects of knockdown of CD44v6 in SKOV3 cells on cell adhesion, invasion and migration were assessed.

Results

The expression of CD44v6, but not CD44s, is up-regulated in recurrent ovarian serous cancer compared to advanced primary tumor. CD44v6 expression is also preferentially increased in the tumor at the abdominal cavity metastasis site of advanced diseases. Consistently, serum soluble CD44v6 levels of recurrent ovarian cancer were higher than those of early stage and advanced primary diseases. The IHC data demonstrate that CD44v6 expression is correlated with clinicopathologic features and tumor progression. Lastly, knockdown of CD44v6 decreases the adhesion and migration but not invasion capacities of SKOV3 cells.

Conclusions

CD44v6 expression levels are associated with epithelial ovarian cancer progression, metastasis and relapse. Moreover, serum soluble CD44v6 may be used as a potential marker for identifying tumor relapse. Finally, CD44v6 may play a role in ovarian cancer metastasis by mediating tumor cell adhesion and migration.

【 授权许可】

   
2013 Shi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61(2):69-90.
• [2]Bast RC Jr, Hennessy B, Mills GB: The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer 2009, 9(6):415-428.
• [3]Bowtell DD: The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer 2010, 10(11):803-808.
• [4]Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D: Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer 2011, 11(10):719-725.
• [5]Goodison S, Urquidi V, Tarin D: CD44 cell adhesion molecules. Molecular pathology: MP 1999, 52(4):189-196.
• [6]Goodfellow PN, Banting G, Wiles MV, Tunnacliffe A, Parkar M, Solomon E, Dalchau R, Fabre JW: The gene, MIC4, which controls expression of the antigen defined by monoclonal antibody F10.44.2, is on human chromosome 11. Eur J Immunol 1982, 12(8):659-663.
• [7]Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U, Bell JI: Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA 1992, 89(24):12160-12164.
• [8]Stamenkovic I, Aruffo A, Amiot M, Seed B: The hematopoietic and epithelial forms of CD44 are distinct polypeptides with different adhesion potentials for hyaluronate-bearing cells. EMBO J 1991, 10(2):343-348.
• [9]Terpe HJ, Stark H, Prehm P, Gunthert U: CD44 variant isoforms are preferentially expressed in basal epithelial of non-malignant human fetal and adult tissues. Histochemistry 1994, 101(2):79-89.
• [10]Yang H, Binns RM: Isolation and characterization of the soluble and membrane-bound porcine CD44 molecules. Immunology 1993, 78(4):547-554.
• [11]Stamenkovic I, Yu Q: Shedding light on proteolytic cleavage of CD44: the responsible sheddase and functional significance of shedding. J Invest Dermatol 2009, 129(6):1321-1324.
• [12]Jalkanen ST, Bargatze RF, Herron LR, Butcher EC: A lymphoid cell surface glycoprotein involved in endothelial cell recognition and lymphocyte homing in man. Eur J Immunol 1986, 16(10):1195-1202.
• [13]Miyake K, Medina KL, Hayashi S, Ono S, Hamaoka T, Kincade PW: Monoclonal antibodies to Pgp-1/CD44 block lympho-hemopoiesis in long-term bone marrow cultures. J Exp Med 1990, 171(2):477-488.
• [14]Fenderson BA, Stamenkovic I, Aruffo A: Localization of hyaluronan in mouse embryos during implantation, gastrulation and organogenesis. Differentiation; research in biological diversity 1993, 54(2):85-98.
• [15]Alaish SM, Yager D, Diegelmann RF, Cohen IK: Biology of fetal wound healing: hyaluronate receptor expression in fetal fibroblasts. J Pediatr Surg 1994, 29(8):1040-1043.
• [16]Zoller M: CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 2011, 11(4):254-267.
• [17]Louderbough JM, Schroeder JA: Understanding the dual nature of CD44 in breast cancer progression. Molecular cancer research: MCR 2011, 9(12):1573-1586.
• [18]Hertweck MK, Erdfelder F, Kreuzer KA: CD44 in hematological neoplasias. Ann Hematol 2011, 90(5):493-508.
• [19]Omran OM, Ata HS: CD44s and CD44v6 in diagnosis and prognosis of human bladder cancer. Ultrastruct Pathol 2012, 36(3):145-152.
• [20]Galizia G, Gemei M, Del Vecchio L, Zamboli A, Di Noto R, Mirabelli P, Salvatore F, Castellano P, Orditura M, De Vita F: Combined CD133/CD44 expression as a prognostic indicator of disease-free survival in patients with colorectal cancer. Arch Surg 2012, 147(1):18-24.
• [21]Baek JM, Jin Q, Ensor J, Boulbes DR, Esteva FJ: Serum CD44 levels and overall survival in patients with HER2-positive breast cancer. Breast Cancer Res Treat 2011, 130(3):1029-1036.
• [22]Afify AM, Tate S, Durbin-Johnson B, Rocke DM, Konia T: Expression of CD44s and CD44v6 in lung cancer and their correlation with prognostic factors. Int J Biol Markers 2011, 26(1):50-57.
• [23]Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P: A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 1991, 65(1):13-24.
• [24]Seiter S, Arch R, Reber S, Komitowski D, Hofmann M, Ponta H, Herrlich P, Matzku S, Zoller M: Prevention of tumor metastasis formation by anti-variant CD44. J Exp Med 1993, 177(2):443-455.
• [25]Charpin C, Secq V, Giusiano S, Carpentier S, Andrac L, Lavaut MN, Allasia C, Bonnier P, Garcia S: A signature predictive of disease outcome in breast carcinomas, identified by quantitative immunocytochemical assays. International journal of cancer Journal international du cancer 2009, 124(9):2124-2134.
• [26]Ween MP, Oehler MK, Ricciardelli C: Role of Versican, Hyaluronan and CD44 in Ovarian Cancer Metastasis. Int J Mol Sci 2011, 12(2):1009-1029.
• [27]Gardner MJ, Catterall JB, Jones LM, Turner GA: Human ovarian tumour cells can bind hyaluronic acid via membrane CD44: a possible step in peritoneal metastasis. Clin Exp Metastasis 1996, 14(4):325-334.
• [28]Sliutz G, Tempfer C, Winkler S, Kohlberger P, Reinthaller A, Kainz C: Immunohistochemical and serological evaluation of CD44 splice variants in human ovarian cancer. Br J Cancer 1995, 72(6):1494-1497.
• [29]Kamura T, Sakai K, Kaku T, Kobayashi H, Mitsumoto M, Tsuneyoshi M, Nakano H: Comparison of p53 and CD44 variant 6 expression between paired primary and recurrent ovarian cancer: an immunohistochemical analysis. Oncol Rep 1999, 6(1):97-101.
• [30]Sakai K, Kaku T, Kamura T, Kinukawa N, Amada S, Shigematsu T, Hirakawa T, Kobayashi H, Ariyoshi K, Nakano H: Comparison of p53, Ki-67, and CD44v6 expression between primary and matched metastatic lesions in ovarian cancer. Gynecol Oncol 1999, 72(3):360-366.
• [31]Saegusa M, Machida D, Hashimura M, Okayasu I: CD44 expression in benign, premalignant, and malignant ovarian neoplasms: relation to tumour development and progression. J Pathol 1999, 189(3):326-337.
• [32]Stickeler E, Vogl FD, Denkinger T, Mobus VJ, Kreienberg R, Runnebaum IB: Soluble CD44 splice variants and pelvic lymph node metastasis in ovarian cancer patients. Int J Mol Med 2000, 6(5):595-601.
• [33]Afify AM, Ferguson AW, Davila RM, Werness BA: Expression of CD44S and CD44v5 is more common in stage III than in stage I serous ovarian carcinomas. Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 2001, 9(4):309-314.
• [34]Qu P, Jiao S, Gao Q: [Clinical significance of CD44 expression in ovarian epithelial tumors]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 2001, 23(1):46-49.
• [35]Sun Y, Shen Z, Ji X: [Study on the relationship between CD44v6, p53 gene mutation and ovarian carcinoma metastasis]. Zhonghua fu chan ke za zhi 2000, 35(4):225-228.
• [36]Bar JK, Grelewski P, Popiela A, Noga L, Rabczynski J: Type IV collagen and CD44v6 expression in benign, malignant primary and metastatic ovarian tumors: correlation with Ki-67 and p53 immunoreactivity. Gynecol Oncol 2004, 95(1):23-31.
• [37]Hong SC, Song JY, Lee JK, Lee NW, Kim SH, Yeom BW, Lee KW: Significance of CD44v6 expression in gynecologic malignancies. J Obstet Gynaecol Res 2006, 32(4):379-386.
• [38]Okayama H, Kumamoto K, Saitou K, Hayase S, Kofunato Y, Sato Y, Miyamoto K, Nakamura I, Ohki S, Sekikawa K: CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer. Oncol Rep 2009, 22(4):745-755.
• [39]Kawano T, Nakamura Y, Yanoma S, Kubota A, Furukawa M, Miyagi Y, Tsukuda M: Expression of E-cadherin, and CD44s and CD44v6 and its association with prognosis in head and neck cancer. Auris Nasus Larynx 2004, 31(1):35-41.
• [40]Gu H, Shang P, Zhou C: [Expression of CD44v6 and E-cadherin in prostate carcinoma and metastasis of prostate carcinoma]. Zhonghua nan ke xue = National journal of andrology 2004, 10(1):32-34. 38
• [41]Guo YJ, Liu G, Wang X, Jin D, Wu M, Ma J, Sy MS: Potential use of soluble CD44 in serum as indicator of tumor burden and metastasis in patients with gastric or colon cancer. Cancer Res 1994, 54(2):422-426.
• [42]Harn HJ, Ho LI, Shyu RY, Yuan JS, Lin FG, Young TH, Liu CA, Tang HS, Lee WH: Soluble CD44 isoforms in serum as potential markers of metastatic gastric carcinoma. J Clin Gastroenterol 1996, 22(2):107-110.
• [43]Fichtner I, Dehmel A, Naundorf H, Finke LH: Expression of CD44 standard and isoforms in human breast cancer xenografts and shedding of soluble forms into serum of nude mice. Anticancer Res 1997, 17(5A):3633-3645.
• [44]Liotta LA, Delisi C, Saidel G, Kleinerman J: Micrometastases formation: a probabilistic model. Cancer Lett 1977, 3(3–4):203-208.