p21 and CD166 as predictive markers of poor response and outcome after fluorouracil-based chemoradiotherapy for the patients with rectal cancer

BMC Cancer

Jee Hyun Kim⁵  Hye Seung Lee³  Jae-Sung Kim⁴  Keun-Yong Eom⁴  Sung-Bum Kang²  Duck-Woo Kim²  Keun-Wook Lee⁵  Yu Jung Kim⁵  Mi-Hyun Kang¹  Sung Hoon Sim⁵ 

[1]Medical Science Research Institute, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

[2]Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

[3]Department of Pathology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam 463-707, Korea

[4]Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

[5]Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-ro 173 beon-gil, Bundang-gu, Seongnam 463-707, Korea

关键词: CD166;    p21;    Cancer stem cell;    Chemoradiotherapy;    Rectal cancer;   

Others  :  858916
DOI  :  10.1186/1471-2407-14-241

 received in 2013-07-02, accepted in 2014-03-27,  发布年份 2014

【 摘 要 】

Background

Pre-operative chemoradiotherapy (CRT) is the standard treatment in clinical stage T3/4 or node positive rectal cancer. However, there are no established biomarkers that can predict the pathological response and clinical outcome to CRT.

Methods

Immunohistochemical staining was performed in tissue arrays constructed from core tissue specimens taken before treatment and from operative specimens from 112 patients who received 5-FU based pre-operative CRT and surgery. Expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1 were assessed and correlated with tumor regression grades and disease free survival.

Results

Of the 112 patients (M/F 74/38, median age: 62), 20 (17.9%) patients achieved pathologic complete remission (pCR). In analyzing the associations between marker expressions and tumor regression grades, high p21 expression at the pretreatment biopsy was significantly associated with non-pCR (p = 0.022) and poor disease free survival (median DFS - low vs high p21: 75.8 vs 58.1 months, p = 0.002). In the multivariate analysis, high p21 expression level at the pre-treatment biopsy was significantly associated with poor DFS (p = 0.001, HR 6.14; 95% CI 2.03, 18.55). High CD166 expression level at the pretreatment biopsy was also associated with poor DFS (p = 0.003; HR 5.61; 95% CI 1.81, 17.35).

Conclusion

These show high p21 and CD166 expression at the pretreatment biopsy were associated with tumor regression and poor prognosis in patients treated with 5-FU based CRT. Larger, prospective and functional studies are warranted to determine the role of p21 and CD166 as predictive biomarker of response to CRT.

【 授权许可】

   
2014 Sim et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004, 351(17):1731-1740.
• [2]Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind C: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005, 23(34):8688-8696.
• [3]Kim NK, Park JK, Lee KY, Yang WI, Yun SH, Sung J, Min JS: p53, BCL-2, and Ki-67 expression according to tumor response after concurrent chemoradiotherapy for advanced rectal cancer. Ann Surg Oncol 2001, 8(5):418-424.
• [4]Kikuchi M, Mikami T, Sato T, Tokuyama W, Araki K, Watanabe M, Saigenji K, Okayasu I: High Ki67, Bax, and thymidylate synthase expression well correlates with response to chemoradiation therapy in locally advanced rectal cancers: proposal of a logistic model for prediction. Br J Cancer 2009, 101(1):116-123.
• [5]Sogawa N, Takiguchi N, Koda K, Oda K, Satomi D, Kato K, Ishikura H, Miyazaki M: Value of expression of p21WAF1/CIP1 as a prognostic factor in advanced middle and lower rectal cancer patients treated with preoperative radio-chemotherapy. Int J Oncol 2002, 21(4):787-793.
• [6]Yoshikawa R, Yanagi H, Kusunoki M, Fujiwara Y, Noda M, Hashimoto-Tamaoki T, Yamamura T: Prognostic values of radiation-induced p53 in adjacent normal mucosa and p21WAF1/CIP1 expression in rectal cancer patients. Int J Oncol 2002, 21(6):1223-1228.
• [7]Kuremsky JG, Tepper JE, McLeod HL: Biomarkers for response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys 2009, 74(3):673-688.
• [8]Reya T, Morrison SJ, Clarke MF, Weissman IL: Stem cells, cancer, and cancer stem cells. Nature 2001, 414(6859):105-111.
• [9]Sagar J, Chaib B, Sales K, Winslet M, Seifalian A: Role of stem cells in cancer therapy and cancer stem cells: a review. Cancer Cell Int 2007, 7:9. BioMed Central Full Text
• [10]Ishii H, Iwatsuki M, Ieta K, Ohta D, Haraguchi N, Mimori K, Mori M: Cancer stem cells and chemoradiation resistance. Cancer Sci 2008, 99(10):1871-1877.
• [11]Lugli A, Iezzi G, Hostettler I, Muraro MG, Mele V, Tornillo L, Carafa V, Spagnoli G, Terracciano L, Zlobec I: Prognostic impact of the expression of putative cancer stem cell markers CD133, CD166, CD44s, EpCAM, and ALDH1 in colorectal cancer. Br J Cancer 2010, 103(3):382-390.
• [12]Schwandner O, Bruch HP, Broll R: p21, p27, cyclin D1, and p53 in rectal cancer: immunohistology with prognostic significance? Int J Colorectal Dis 2002, 17(1):11-19.
• [13]Rau B, Sturm I, Lage H, Berger S, Schneider U, Hauptmann S, Wust P, Riess H, Schlag PM, Dorken B, Daniel PT: Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol 2003, 21(18):3391-3401.
• [14]Horst D, Kriegl L, Engel J, Kirchner T, Jung A: Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. Cancer Invest 2009, 27(8):844-850.
• [15]Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M: Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 2009, 16(12):3488-3498.
• [16]Levin TG, Powell AE, Davies PS, Silk AD, Dismuke AD, Anderson EC, Swain JR, Wong MH: Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology 2010, 139(6):2072-2082. e2075
• [17]Andrade NR, Oshima CT, Gomes TS, Neto RA, Forones NM: Imunoexpression of Ki-67 and p53 in rectal cancer tissue after treatment with neoadjuvant chemoradiation. J Gastrointest Cancer 2011, 42(1):34-39.
• [18]Dworak O, Keilholz L, Hoffmann A: Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997, 12(1):19-23.
• [19]Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A: Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol 2007, 60(10):1112-1116.
• [20]Viale A, De Franco F, Orleth A, Cambiaghi V, Giuliani V, Bossi D, Ronchini C, Ronzoni S, Muradore I, Monestiroli S, Gobbi A, Alcalay M, Minucci S, Pelicci PG: Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 2009, 457(7225):51-56.
• [21]O'Brien CA, Kreso A, Ryan P, Hermans KG, Gibson L, Wang Y, Tsatsanis A, Gallinger S, Dick JE: ID1 and ID3 Regulate the Self-Renewal Capacity of Human Colon Cancer-Initiating Cells through p21. Cancer Cell 2012, 21(6):777-792.
• [22]Bertolini F, Bengala C, Losi L, Pagano M, Iachetta F, Dealis C, Jovic G, Depenni R, Zironi S, Falchi AM, Luppi G, Conte PF: Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007, 68(5):1455-1461.
• [23]Mezzanzanica D, Fabbi M, Bagnoli M, Staurengo S, Losa M, Balladore E, Alberti P, Lusa L, Ditto A, Ferrini S, Pierotti MA, Barbareschi M, Pilotti S, Canevari S: Subcellular localization of activated leukocyte cell adhesion molecule is a molecular predictor of survival in ovarian carcinoma patients. Clin Cancer Res 2008, 14(6):1726-1733.
• [24]Gastl G, Spizzo G, Obrist P, Dunser M, Mikuz G: Ep-CAM overexpression in breast cancer as a predictor of survival. Lancet 2000, 356(9246):1981-1982.
• [25]Gosens MJ, van Kempen LC, van de Velde CJ, van Krieken JH, Nagtegaal ID: Loss of membranous Ep-CAM in budding colorectal carcinoma cells. Mod Pathol 2007, 20(2):221-232.
• [26]O'Brien CA, Pollett A, Gallinger S, Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007, 445(7123):106-110.
• [27]Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF: Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 2007, 104(24):10158-10163.
• [28]Kijima N, Hosen N, Kagawa N, Hashimoto N, Nakano A, Fujimoto Y, Kinoshita M, Sugiyama H, Yoshimine T: CD166/activated leukocyte cell adhesion molecule is expressed on glioblastoma progenitor cells and involved in the regulation of tumor cell invasion. Neuro Oncol 2012, 14(10):1254-1264.
• [29]Lunter PC, van Kilsdonk JW, van Beek H, Cornelissen IM, Bergers M, Willems PH, van Muijen GN, Swart GW: Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a novel actor in invasive growth, controls matrix metalloproteinase activity. Cancer Res 2005, 65(19):8801-8808.
• [30]Verma A, Shukla NK, Deo SV, Gupta SD, Ralhan R: MEMD/ALCAM: a potential marker for tumor invasion and nodal metastasis in esophageal squamous cell carcinoma. Oncology 2005, 68(4–6):462-470.
• [31]Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Koike Y, Fujikawa H, Inoue Y, Miki C, Kusunoki M: Clinical significance of CD133 and hypoxia inducible factor-1alpha gene expression in rectal cancer after preoperative chemoradiotherapy. Clin Oncol (R Coll Radiol) 2011, 23(5):323-332.