BMC Clinical Pathology | |
Low Mmp 9 and VEGF levels predict good oncologic outcome in mid and low rectal cancer patients with neoadjuvant chemoradiation | |
Dursun Bugra1  Gulcin Yegen4  Evin Ademoglu6  Sevda Tanrikulu Kucuk6  Hasan Karanlik3  Vakur Olgac4  Emre Balik2  Oktar Asoglu2  Fatih Yanar2  Atilla Kurt5  | |
[1] Amerikan Hospital, General Surgery, Istanbul, Turkey;Istanbul Faculty of Medicine, General Surgery, Istanbul University, Millet Caddesi, Sehremini, Capa, 34093, , Fatih, Istanbul, Turkey;Istanbul Oncology Institute, General Surgery, Istanbul University, Istanbul, Turkey;Istanbul Oncology Institute, Pathology, Istanbul University, Istanbul, Turkey;General Surgery, Sivas Cumhuriyet University, Sivas, Turkey;Faculty of Medicine, Biochemistry, Istanbul Bilim University, Istanbul, Turkey | |
关键词: Rectal cancer; Prognosis; Apoptotic and angiogenic markers; | |
Others : 1085168 DOI : 10.1186/1472-6890-12-27 |
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received in 2012-06-02, accepted in 2012-12-19, 发布年份 2012 | |
【 摘 要 】
Background
The aim of this study was to evaluate apoptotic (Bcl-2, Bax expression, caspase-3 activity, and cytochrome-c) and angiogenic (MMP-9 levels and VEGF expression) markers in operable rectal cancer patients who were treated with preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Understanding these factors will facilitate the identification of potential pathological responders before treatment, leading to better local control and survival rates.
Methods
Between March 2006 and March 2008, 29 patients withTNM Stage III (cT3 N+) mid or low rectal cancer were included in this study. Our sample consisted of 17 males (58.6%) and 12 females (41.4%). The median age was 60 years (range 24-88 years). Biopsy samples were taken from different portions of the tumors using flexible endoscopy before neoadjuvant CRT. Preoperatively, all patients received radiation (45-50.4 gray (Gy) in 25 cycles with concurrent 5-florouracil (5-FU) chemotherapy.
Results
A complete response was observed in 7 of 29 patients (24%). Bax staining was negative in 1 of the 7 patients (14%) in the pathological complete response (PCR) group and in 18 of the 22 patients (82%) in the no pathological complete response (noPCR) group (p = 0.001). MMP-9 and VEGF levels were higher in the noPCR group than the PCR group (p = 0.04, p = 0.05 respectively). No statistically significant differences were found between VEGF and MMP-9 levels in nodal downstaging. No statistically significant relationships were found between the other apoptotic factors (Bcl 2, cytochrome-c, and caspase-3 activity) and pathological response rate (p > 0.05).
Conclusion
In neoadjuvant CRT patients, high levels of Bax expression and low levels of VEGF and MMP-9 expression on preoperative biopsies indicate that the patient will potentially be a good pathological responder.
【 授权许可】
2012 Kurt et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
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20150113171229390.pdf | 166KB | download |
【 参考文献 】
- [1]Hawk ET, Linburg PJ, Viner JL: Epidemiology and prevention of colorectal cancer. Surg Clin North Am 2002, 82:905-941.
- [2]Medich D, McGinty J, Parda D, et al.: Preoperative chemoradiotherapy and radical surgery for locally advanced distal rectal adenocarcinoma: pathologic findings and clinical implications. Dis Colon Rectum 2001, 44:1123-1128.
- [3]Ruo L, Tickoo S, Klimstra DS, et al.: Long-term prognostic significance of extent of rectal cancer response to preoperative radiation and chemotherapy. Ann Surg 2002, 236:75-81.
- [4]Valentini V, Coco C, Picciocchi A, et al.: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys 2002, 53:664-674.
- [5]Reerink O, Karrenbeld A, Plukker JT, et al.: Molecular prognostic factors in locally irresectable rectal cancer treated preoperatively by chemo-radiotherapy. Anticancer Res 2004, 24:1217-1221.
- [6]Theodoropoulos G, Wise WE, Padmanabhan A, et al.: T level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival. Dis Colon Rectum 2002, 45:895-903.
- [7]Bouzourene H, Bosman FT, Seelentag W, Matter M, Coucke P: Importance of tumor regression assessment in predicting the outcome in patients with locally advanced rectal carcinoma who are treated with preoperative radiotherapy. Cancer 2002, 94:1121-1130.
- [8]Wheeler JM, Dodds E, Warren BF, et al.: Preoperative chemoradiotherapy and total mesorectal excision surgery for locally advanced rectal cancer: correlation with rectal cancer regression grade. Dis Colon Rectum 2004, 47:2025-2031.
- [9]Ammann K, Kirchmayr W, Klaus A, et al.: Impact of neoadjuvant chemoradiation on anal sphincter function in patients with carcinoma of the midrectum and low rectum. Arch Surg 2003, 138:257-261.
- [10]Marijnen CA, Van de Velde CJ, Putter H, et al.: Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial. J Clin Oncol 2005, 23:1847-1858.
- [11]Peeters KC, van de Velde CJ, Leer JW, et al.: Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients. J Clin Oncol 2005, 23:6199-6206.
- [12]Birgisson H, Pahlman L, Gunnarsson U, Glimelius B: Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol 2005, 23:6126-6131.
- [13]Ward RL, Todd AV, Santiago F, O’Connor T, Hawkins NJ: Activation of the K-ras oncogene in colorectal neoplasms is associated with decreased apoptosis. Cancer 1997, 79:1106-1113.
- [14]Bedi A, Pasricha P, Akhtar AJ, et al.: Inhibition of apoptosis during development of colorectal cancer. Cancer Res 1995, 55:1811-1816.
- [15]Hashimoto S, Koji T, Kohara N, Kanematsu T, Nakane P: Frequency of apoptosis relates inversely to invasiveness and metastatic activity in human colorectal cancer. Virchow Arch 1997, 431:241-248.
- [16]Spilsbury K, Garret K, Shen WY, Costable IJ, Rakoczy PE: Overexpression of vascular endothelial growth factor (VEGF) in the retinal epithelium leads to the development of choroidal neovascularization. Am J Pathol 2000, 157:135-143.
- [17]Smith FM, Reynolds JV, Miller N, Stephens RB, Kennedy MJ: Pathological and molecular predictors of the response of rectal cancer to neoadjuvant radiochemotherapy. Eur J Surg Oncol 2006, 32:55-64.
- [18]Heald RJ: Total mesorectal excision (TME). Acta Chir Iugosl 2000, 47:17-18.
- [19]Quirke P, Durdey P, Dixon MF, Williams NS: Local recurrence of rectal adenocarcinoma due to inadequate surgical excision. Histopathological study of lateral tumor spread and surgical excision. Lancet 1986, 2:996-999.
- [20]Greene FL, Page DL, Fleming ID, et al.: AJCC Cancer Staging Manual. 6th edition. New York: Springer; 2002.
- [21]Dworak O, Keilholz L, Hoffmann A: Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997, 12:19-23.
- [22]Navarro M, Dotor E, Rivera F, et al.: A phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2006, 66:201-205.
- [23]Spitz FR, Giacco GG, Hess K, et al.: p53 immunohistochemical staining predicts residual disease after chemoradiation in patients with high-risk rectal cancer. Clin Cancer Res 1997, 3:1685-1690.
- [24]Fu CG, Tominaga O, Nagawa H, et al.: Role of p53 and p21/WAF1 detection in patient selection for preoperative radiotherapy in rectal cancer patients. Dis Colon Rectum 1998, 41:68-74.
- [25]Saw RP, Morgan M, Koorey D, et al.: p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy. Dis Colon Rectum 2003, 46:192-202.
- [26]Rau B, Sturm I, Lage H, et al.: Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol 2003, 21:3391-3401.
- [27]Sogawa N, Takiguchi N, Koda K, et al.: 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, 21:787-793.
- [28]Scopa CD, Vagianos C, Kardamakis D, Kalofonos HP, Batistatou A, Vagianos C: Bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with rectal cancer. Appl Immunohistochem Mol Morphol 2001, 9:329-334.
- [29]Diez M, Ramos P, Medrano MJ, et al.: Preoperatively irradiated rectal carcinoma: analysis of the histopathologic response and predictive value of proliferating cell nuclear antigen immunostaining. Oncology 2003, 64:213-219.
- [30]Aschele C, Lonardi S, Monfardini S: Thymidylate synthase expression as a predictor of clinical response to fluoropyrimidine-based chemotherapy in advanced colorectal cancer. Cancer Treat Rev 2002, 28:27-47.
- [31]Komuro Y, Watanabe T, Hosoi Y, et al.: The expression pattern of Ku correlates with tumor radiosensitivity and disease free survival in patients with rectal carcinoma. Cancer 2002, 95:1199-1205.
- [32]Garcia-Aguilar J, Chen Z, Smith DD, et al.: Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer. Ann Surg 2001, 254:486-493.
- [33]Scopa CD, Tsamandas AC, Zolo Kalofonos HP, Batistatou A, Vagianos C: The potential role of bcl-2 and Ki67 expression and apoptosis in colorectal carcinoma. A clinicopathologic study. Dig Dis Sci 2003, 48:1990-1997.
- [34]Chang HJ, Jung KH, Kim DY, et al.: Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma. Hum Pathol 2005, 36:364-371.
- [35]Tsamandas AC, Kardamakis D, Petsas T, et al.: Bcl-2, bax and p53 expression in rectal adenocarcinoma. Correlation with classic pathologic prognostic factors and patients’ outcome. In Vivo 2007, 21:113-118.
- [36]Nehls O, Okech T, Hsieh CJ, et al.: Low Bax protein expression corralates with disease recurrence in preoperatively irradiated rectal carcinoma. Int J Radiat Oncol Biol Phys 2005, 61:85-91.
- [37]Brown JM, Attardi LD: The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 2005, 5:231-237.
- [38]De Heer P, De Bruin EC, Klein-Kranenbarg E, et al.: Caspase-3 activity predicts local recurrence in rectal cancer. Clin Cancer Res 2007, 13:5810-5815.
- [39]Contu PC, Contu SS, Moreira LF: BCl-2 expression in rectal cancer. Arq Gastroenterol 2006, 43:284-287.
- [40]Liotta LA, Stetler-Stevenson WG: Metalloproteinases and cancer invasion. Semin Cancer Biol 1990, 1:99-106.
- [41]De Clerk YA, Shimada H, Taylor SM, Langley KE: Matrix metalloproteinases and their inhibitors in tumor progression. Ann N Y Acad Sci 1994, 732:222-232.
- [42]Unsal Kilic D, Uner A, Akyürek N, Erpolat P, Dursun A, Pak Y: Matrix metalloprotinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotheraphy. Int J Radiat Oncol 2003, 33:186-191.
- [43]Zhang C, Sheng ZY, Hu S, Gao JC, Yu S, Liu Y: The influence of apoptosis of mucosal epithelial cells on intestinal barrier integrity after scald in rats. Burns 2002, 28:731-737.
- [44]Wong MP, Cheung N, Yuen ST, et al.: Vascular endothelial GF is up-regulated in the early premalignant stage of colorectal tumor progression. Int J Cancer 1999, 81:845-850.
- [45]Nozue M, Isaka N, Fukao K: Over-expression of vascular endothelial growth factors after preoperative radiation therapy for rectal cancer. Oncol Rep 2001, 8:1247-1249.
- [46]Zlobec I, Steele R, Compton CC: VEGF as a predictive marker of rectal tumor response to preoperative radiotheraphy. Cancer 2005, 1104:2517-2521.