Predictive value of Smac, VEGF and Ki-67 in rectal cancer treated with neoadjuvant therapy

Yan,Hongjiang; Wang,Renben; Yu,Jinming; Jiang,Shumei; Zhu,Kunli; Mu,Dianbin; Xu,Zhongfa

doi:10.3892/ol_00000113

Predictive value of Smac, VEGF and Ki-67 in rectal cancer treated with neoadjuvant therapy

Authors:
- Hongjiang Yan
- Renben Wang
- Jinming Yu
- Shumei Jiang
- Kunli Zhu
- Dianbin Mu
- Zhongfa Xu
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Affiliations: Department of Radiation Oncology, Shandong Tumor Hospital, Jinan 250117, P.R. China
Published online on: July 1, 2010 https://doi.org/10.3892/ol_00000113
Pages: 641-647

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Abstract

The present study aimed to identify whether second mitochondria-derived activator of caspase (Smac), vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (Ki-67) expression in pre-treatment tumor biopsies are useful predictive markers of tumor response in patients with rectal cancer undergoing pre-operative chemoradiotherapy (CRT). Paraffin-embedded tissues obtained before and after therapy were evaluated by immunohistochemical staining for Smac, VEGF and Ki-67. The study evaluated the correlation of Smac, VEGF and Ki-67 immunoreactivity in tumor biopsies before treatment of tumor response to pre-operative CRT. Regarding Smac, patients with a favorable response to neoadjuvant CRT had higher pre-therapy levels (p=0.011). The level of Smac expression decreased after neoadjuvant therapy (p=0.044). However, VEGF expression was found to be negatively and significantly correlated with a favorable tumor response to neoadjuvant CRT (p=0.010). A transient increase in VEGF expression was detected in the resected specimens following neoadjuvant therapy (p=0.030). In addition, tumors with a low Ki-67 labeling index (Ki-67-LI) expression were found to be more sensitive to neoadjuvant therapy than those with a high expression of Ki-67-LI (p=0.034). In contrast to VEGF, the Ki-67 expression level decreased after neoadjuvant therapy. Smac, VEGF and Ki-67 expression levels, assessed immunohistochemically from pre-treatment tumor biopsies, may be useful predictive markers of rectal tumor response to pre-operative CRT.

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1	Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 351:1731–1740. 2004. View Article : Google Scholar : PubMed/NCBI
2	Bosset JF, Calais G, Mineur L, et al: Enhanced tumoricidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results-EORTC 22921. J Clin Oncol. 23:5620–5627. 2005. View Article : Google Scholar : PubMed/NCBI
3	Bosset JF, Collette L, Calais G, et al: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 355:1114–1123. 2006. View Article : Google Scholar : PubMed/NCBI
4	Gerard J, Romestaing P, Bonnetain F, et al: Preoperative chemoradiotherapy (CT-RT) improves local control in T3-4 rectal cancers: results of the FFCD 9203 randomised trial. Int J Radiat Oncol Biol Phys. 63:2–3. 2005. View Article : Google Scholar
5	Das P and Crane CH: Preoperative and adjuvant treatment of localized rectal cancer. Curr Oncol Rep. 8:167–173. 2006. View Article : Google Scholar : PubMed/NCBI
6	McLean CM and Duncan W: Rectal cancer: a review of randomized trials of adjuvant radiotherapy. Clin Oncol. 7:349–358. 1995. View Article : Google Scholar : PubMed/NCBI
7	Friedmann P, Garb JL, Park WC, et al: Pace OT survival following moderate-dose preoperative radiation therapy for carcinoma of the rectum. Cancer. 55:967–973. 1985. View Article : Google Scholar : PubMed/NCBI
8	Kerman HD, Roberson SH, Bloom TS, et al: Rectal carcinoma. Long-term experience with moderately high-dose preoperative radiation and low anterior resection. Cancer. 69:2813–2819. 1992. View Article : Google Scholar : PubMed/NCBI
9	Kim DW, Lim SB, Kim DY, et al: Pre-operative chemo-radiotherapy improves the sphincter preservation rate in patients with rectal cancer located within 3 cm of the anal verge. Eur J Surg Oncol. 32:162–167. 2006. View Article : Google Scholar : PubMed/NCBI
10	Minsky BD: Oxaliplatin-based combined-modality therapy for rectal cancer. Semin Oncol. 30:26–33. 2003. View Article : Google Scholar : PubMed/NCBI
11	Du C, Fang M, Li Y, Li L and Wang X: Smac, a mitochondrial protein that promotes cytochrome c dependent caspase activation by elimination IAP inhibition. Cell. 102:33–42. 2000. View Article : Google Scholar : PubMed/NCBI
12	Kang S-M, Maeda K, Onoda N, et al: Combined analysis of p53 and vascular endothelial growth factor in CRC for determination of tumor vascularity and liver metastasis. Int J Cancer. 74:502–507. 1997. View Article : Google Scholar : PubMed/NCBI
13	Wong MP, Cheung N, Yuen ST, Leung SY and Chung LP: Vascular endothelial GF is up-regulated in the early pre-malignant stage of colorectal tumor progression. Int J Cancer. 81:845–850. 1999. View Article : Google Scholar : PubMed/NCBI
14	Tonini T, Rossi F and Claudio PP: Molecular basis of angiogenesis and cancer. Oncogene. 22:6549–6556. 2003. View Article : Google Scholar : PubMed/NCBI
15	Lutsenko SV, Kiselev SM and Severin SE: Molecular mechanisms of tumor angiogenesis. Biochem. 68:286–300. 2003.
16	Ferrara N, Gerber H-P and LeCouter J: The biology of VEGF and its receptors. Nat Med. 9:669–676. 2003. View Article : Google Scholar : PubMed/NCBI
17	Falm E: Angiogenesis inhibitors in clinical development; where are we now and where are we going? Br J Cancer. 90:1–7. 2004. View Article : Google Scholar : PubMed/NCBI
18	Ferrara N: Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 25:581–611. 2004. View Article : Google Scholar : PubMed/NCBI
19	Harmey JH and Bouchier-Hayes D: Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. Bioessays. 24:280–283. 2002. View Article : Google Scholar : PubMed/NCBI
20	Willett C, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has anti-vascular effects in human rectal cancer. Nat Med. 10:145–147. 2004. View Article : Google Scholar : PubMed/NCBI
21	Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U and Stein H: Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 133:1710–1715. 1984.PubMed/NCBI
22	Song Z, Yao X and Wu M: Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J Biol Chem. 278:23130–23140. 2003. View Article : Google Scholar : PubMed/NCBI
23	Roberts DL, Merrison W, MacFarlane M and Cohen GM: The inhibitor of apoptosis protein-binding domain of Smac is not essential for its proapoptotic activity. J Cell Biol. 153:221–228. 2001. View Article : Google Scholar : PubMed/NCBI
24	Sekimura A, Konishi A, Mizuno K, et al: Expression of Smac/DIABLO is a novel prognostic marker in lung cancer. Oncol Rep. 11:797–802. 2004.PubMed/NCBI
25	Zheng LD, Xiong ZF, Zhu JW and Wang ZH: Effects of Smac gene over-expression on the radiotherapeutic sensitivities of cervical cancer cell line HeLa [J]. Chin Med J. 118:226–230. 2005.PubMed/NCBI
26	Jia L, Patwari Y, Kelsey SM, et al: Role of Smac in human leukaemic cell apoptosis and proliferation. Oncogene. 22:1589. 2003. View Article : Google Scholar : PubMed/NCBI
27	Zlobec I, Steele R and Compton CC: VEGF as a predictive marker of rectal tumor response to preoperative radiotherapy. Cancer. 104:2517–2521. 2005. View Article : Google Scholar : PubMed/NCBI
28	Giralt J, Navalpotro B, Hermosilla E, et al: Prognostic significance of vascular endothelial growth factor and cyclooxygenase-2 in patients with rectal cancer treated with preoperative radiotherapy. Oncology. 71:312–319. 2006. View Article : Google Scholar
29	Kakeji Y, Koga T, Sumiyoshi Y, et al: Clinical significance of vascular endothelial growth factor expression in gastric cancer. J Exp Clin Cancer Res. 21:125–129. 2002.PubMed/NCBI
30	Inoue Y, Ojima E, Watanabe H, et al: Does preoperative chemo-radiotherapy enhance the expression of vascular endothelial growth factor in patients with rectal cancer? Oncol Rep. 18:369–375. 2007.PubMed/NCBI
31	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. 21:3391–3401. 2003. View Article : Google Scholar : PubMed/NCBI
32	Kim NK, Park JK, Lee KY, et al: p53, BCL-2 and Ki-67 expression according to tumor response after concurrent chemoradiotherapy for advanced rectal cancer. Ann Surg Oncol. 8:418–424. 2001. View Article : Google Scholar : PubMed/NCBI
33	Scholzen T and Gerdes J: The Ki-67 protein: from the known and the unknown. J Cell Physiol. 182:311–322. 2000. View Article : Google Scholar : PubMed/NCBI
34	Adell G, Zhang H, Jansson A, Sun XF, Stål O and Nordenskjöld B: Decreased tumor cell proliferation as an indicator of the effect of preoperative radiotherapy of rectal cancer. Int J Radiat Oncol Biol Phys. 50:659–663. 2001. View Article : Google Scholar : PubMed/NCBI
35	Debucquoy A, Goethals L, Geboes K, Roels S, Mc Bride WH and Haustermans K: Molecular responses of rectal cancer to preoperative chemoradiation. Radiother Oncol. 80:172–177. 2006. View Article : Google Scholar : PubMed/NCBI