• 1.湖北醫(yī)藥學院附屬太和醫(yī)院內(nèi)分泌血管外科(湖北十堰 442000);;
  • 2. 湖北醫(yī)藥學院基礎醫(yī)學研究所(湖北十堰 442000);

目的  分析Delta樣配體4(Delta-like ligand 4,DLL4)及S100鈣結(jié)合蛋白A4(S100 calcium binding protein A4,S100A4)在不同乳腺癌分子亞型組織中的表達并討論其臨床意義。
方法  采用免疫組織化學SP法檢測十堰市太和醫(yī)院 Luminal A型乳腺癌組織51例、Luminal B型乳腺癌組織26例、HER-2過表達型乳腺癌組織17例、基底細胞樣型乳腺癌組織14例和乳腺癌癌旁組織40例中DLL4和S100A4的表達情況,并分析其與乳腺癌臨床病理特征之間的關系。
結(jié)果  在乳腺癌組織中,DLL4和S100A4的表達陽性率分別為67.6%(73/108)和62.0%(67/108),均高于其在癌旁組織中的表達陽性率〔22.5%(9/40),45.0%(18/40)〕,P<0.05。在不同乳腺癌分子亞型組織中,HER-2過表達型和基底細胞樣型乳腺癌組織中DLL4和S100A4的表達陽性率均高于Luminal A型和Luminal B型(P<0.05)。有淋巴結(jié)轉(zhuǎn)移的乳腺癌患者,DLL4和S100A4呈高表達 (P<0.05)。乳腺癌組織中DLL4表達與S100A4表達呈正相關關系(rs=0.217,P<0.01)。
結(jié)論  DLL4和S100A4在基底細胞樣型和HER-2過表達型乳腺癌組織中呈高表達,與預后相關。DLL4和S100A4共同參與乳腺癌的發(fā)生、發(fā)展以及浸潤轉(zhuǎn)移過程。臨床聯(lián)合檢測兩種蛋白表達可評估乳腺癌的潛在轉(zhuǎn)移和預后。

引用本文: 王群,余明華,王耕,王明華. DLL4和S100A4在不同分子亞型乳腺癌組織中的表達及意義. 中國普外基礎與臨床雜志, 2012, 19(9): 957-961. doi: 復制

1. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study[J]. JAMA, 2006, 295(21):2492-2502.
2. Patel NS, Li JL, Generali D. et al. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function[J]. Caner Res, 2005, 65(19):8690-8697.
3. Wang YY, Ye ZY, Zhao ZS, et al. High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer[J]. Ann Surg Oncol, 2010, 17(1): 89-97.
4. Boye K, Maelandsmo GM. S100A4 and metastasis: a small actor playing many roles[J]. Am J pathol, 2010, 176(2):528-535.
5. Singletary SE, Allred C, Ashley P, et al. Staging system for breast cancer:revisions for the 6th edition of the AJCC Cancer Staging Manual[J]. Surg Clin North Am, 2003, 83(4):803-819.
6. Kopfstein L, Christofori G. Metastasis:cell-autonomous mechanisms versus contributions by the tumor microenviroment[J]. Cell Mol Life Sci, 2006,63(4): 449-468.
7. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003, 3(6):401-410.
8. Joyce JA. Therapeutic targeting of the tumor microenvironment[J]. Cancer Cell, 2005, 7(6):513-520.
9. Kerbel RS. Tumor angiogenesis[J]. N Engl J Med, 2008, 358(19):2039-2049.
10. Thurston G, Noguera-Troise I, Yancopoulos GD. The delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth[J]. Nat Rev Cancer, 2007, 7(5):327-331.
11. Bray SJ. Notch signaling:a simple pathway becomes complex[J]. Nat Rev Mol Cell Biol, 2006, 7(9):678-689.
12. Benedito R, Trindade A, Hirashima M, et al. Loss of Notch signalling induced by DLL4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli[J]. BMC Dev Biol, 2008, 8:117.
13. Li JL, Sainson RC, Shi W, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo[J]. Cancer Res, 2007, 67 (23): 11244-11253.
14. Buchler P, Gazdhar A,Schubert M, et al. The Notch signaling pathway is related to neurovaseular progression of pancreaticcancer[J]. Ann Surg, 2005, 242(6):791-801.
15. Mullendore ME, Koorstra JB, Li YM, et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer[J]. Clin Cancer Res, 2009, 15(7):2291-2301.
16. Martinez JC, Muller MM,Turley H, et al. Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissues[J]. Histopathology, 2009, 54(5):598-606.
17. Grigorian M, Lukanidin E. Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53[J]. Genetika, 2003, 39(7): 900-908.
18. Fernandez-Fernandez MR, Veprintsev DB, Fersht AR. Proteins of the s100 family regulate the oligomerization of p53 tumorsuppressor[J]. Proc Natl Acad Sci USA, 2005, 102(13):4735-4740.
19. Lee WY, Su WC, Lin PW, et al. Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer[J]. Oncology, 2004, 66(6):429-438.
20. 李欣, 張麗杰, 宋英. S100A4蛋白在乳腺癌組織的表達及臨床意義[J]. 現(xiàn)代腫瘤醫(yī)學, 2008,16(3):359-361.
21. Rudland PS, Platt Higgins A, Renshaw C, et al. Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer[J]. Cancer Res, 2000, 60(6): 1595-1603.
22. Ambartsumian N, Grigorian M, Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4 (mts1) protein in metastatic mammary cancer[J].J Dairy Res, 2005, 72 (S1): 27-33.
23. Schmidt-Hansen B, Ornas D, Grigorian M, et al. Extracellular S100A4 (mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity[J]. Oncogene, 2004, 23(32): 5487-5495.
24. 魯林源, 艾開興, 黃新余, 等. S100A4、VEGF的表達與胰腺癌預后的關系[J]. 腫瘤, 2008, 28(4): 326-329.
25. Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with AnnexinⅡand accelerated plasmin formation[J]. J Biol Chem, 2005, 280(21): 20833-20841.
  1. 1. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study[J]. JAMA, 2006, 295(21):2492-2502.
  2. 2. Patel NS, Li JL, Generali D. et al. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function[J]. Caner Res, 2005, 65(19):8690-8697.
  3. 3. Wang YY, Ye ZY, Zhao ZS, et al. High-level expression of S100A4 correlates with lymph node metastasis and poor prognosis in patients with gastric cancer[J]. Ann Surg Oncol, 2010, 17(1): 89-97.
  4. 4. Boye K, Maelandsmo GM. S100A4 and metastasis: a small actor playing many roles[J]. Am J pathol, 2010, 176(2):528-535.
  5. 5. Singletary SE, Allred C, Ashley P, et al. Staging system for breast cancer:revisions for the 6th edition of the AJCC Cancer Staging Manual[J]. Surg Clin North Am, 2003, 83(4):803-819.
  6. 6. Kopfstein L, Christofori G. Metastasis:cell-autonomous mechanisms versus contributions by the tumor microenviroment[J]. Cell Mol Life Sci, 2006,63(4): 449-468.
  7. 7. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch[J]. Nat Rev Cancer, 2003, 3(6):401-410.
  8. 8. Joyce JA. Therapeutic targeting of the tumor microenvironment[J]. Cancer Cell, 2005, 7(6):513-520.
  9. 9. Kerbel RS. Tumor angiogenesis[J]. N Engl J Med, 2008, 358(19):2039-2049.
  10. 10. Thurston G, Noguera-Troise I, Yancopoulos GD. The delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth[J]. Nat Rev Cancer, 2007, 7(5):327-331.
  11. 11. Bray SJ. Notch signaling:a simple pathway becomes complex[J]. Nat Rev Mol Cell Biol, 2006, 7(9):678-689.
  12. 12. Benedito R, Trindade A, Hirashima M, et al. Loss of Notch signalling induced by DLL4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli[J]. BMC Dev Biol, 2008, 8:117.
  13. 13. Li JL, Sainson RC, Shi W, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo[J]. Cancer Res, 2007, 67 (23): 11244-11253.
  14. 14. Buchler P, Gazdhar A,Schubert M, et al. The Notch signaling pathway is related to neurovaseular progression of pancreaticcancer[J]. Ann Surg, 2005, 242(6):791-801.
  15. 15. Mullendore ME, Koorstra JB, Li YM, et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer[J]. Clin Cancer Res, 2009, 15(7):2291-2301.
  16. 16. Martinez JC, Muller MM,Turley H, et al. Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissues[J]. Histopathology, 2009, 54(5):598-606.
  17. 17. Grigorian M, Lukanidin E. Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53[J]. Genetika, 2003, 39(7): 900-908.
  18. 18. Fernandez-Fernandez MR, Veprintsev DB, Fersht AR. Proteins of the s100 family regulate the oligomerization of p53 tumorsuppressor[J]. Proc Natl Acad Sci USA, 2005, 102(13):4735-4740.
  19. 19. Lee WY, Su WC, Lin PW, et al. Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer[J]. Oncology, 2004, 66(6):429-438.
  20. 20. 李欣, 張麗杰, 宋英. S100A4蛋白在乳腺癌組織的表達及臨床意義[J]. 現(xiàn)代腫瘤醫(yī)學, 2008,16(3):359-361.
  21. 21. Rudland PS, Platt Higgins A, Renshaw C, et al. Prognostic significance of the metastasis-inducing protein S100A4 (p9Ka) in human breast cancer[J]. Cancer Res, 2000, 60(6): 1595-1603.
  22. 22. Ambartsumian N, Grigorian M, Lukanidin E. Genetically modified mouse models to study the role of metastasis-promoting S100A4 (mts1) protein in metastatic mammary cancer[J].J Dairy Res, 2005, 72 (S1): 27-33.
  23. 23. Schmidt-Hansen B, Ornas D, Grigorian M, et al. Extracellular S100A4 (mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity[J]. Oncogene, 2004, 23(32): 5487-5495.
  24. 24. 魯林源, 艾開興, 黃新余, 等. S100A4、VEGF的表達與胰腺癌預后的關系[J]. 腫瘤, 2008, 28(4): 326-329.
  25. 25. Semov A, Moreno MJ, Onichtchenko A, et al. Metastasis-associated protein S100A4 induces angiogenesis through interaction with AnnexinⅡand accelerated plasmin formation[J]. J Biol Chem, 2005, 280(21): 20833-20841.