• 華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬同濟(jì)醫(yī)院整形外科（武漢 430030）;

目的  探討在低血清胰島素樣生長(zhǎng)因子-1（IGF-1）水平與正常IGF-1水平的小鼠乳腺癌模型中應(yīng)用血管生長(zhǎng)抑制劑人參皂甙（GS）Rg3后，IGF-1對(duì)血管生成的影響。方法  應(yīng)用7，12-二甲基苯蒽（DMBA）誘導(dǎo)肝臟特異性IGF-1基因敲除鼠（LID鼠）及對(duì)照鼠建立原發(fā)乳腺癌模型，應(yīng)用GS Rg3進(jìn)行干預(yù)治療，利用免疫組化法檢測(cè)乳腺癌組織中血管內(nèi)皮生長(zhǎng)因子（VEGF）和Ⅷ因子相關(guān)抗原（F8-RAg）表達(dá)水平，同時(shí)利用基因芯片技術(shù)檢測(cè)小鼠乳腺癌及正常乳腺組織中相關(guān)基因的表達(dá)情況。結(jié)果  LID鼠乳腺癌的發(fā)生率低于對(duì)照鼠(P＜0.05)； LID鼠乳腺癌組織中VEGF表達(dá)水平與微血管密度均低于對(duì)照組(P＜0.05)。LID鼠乳腺癌組織中IGF-1、成纖維細(xì)胞生長(zhǎng)因子(FGF)-1、肝細(xì)胞生長(zhǎng)因子(HGF)和轉(zhuǎn)化生長(zhǎng)因子(TGF)-β1基因較對(duì)照組上調(diào)，成纖維細(xì)胞生長(zhǎng)因子受體(FGFR)-2、血小板源性生長(zhǎng)因子(PDGF)-A和PDGF-B基因較對(duì)照組下調(diào)； 應(yīng)用GS Rg3后，LID鼠乳腺癌組織中VEGFa、表皮生長(zhǎng)因子(EGF)、表皮生長(zhǎng)因子受體(EGFR)、PDGF-A和FGFR-2基因較對(duì)照組上調(diào)，而IGF-1和TGF-β1基因較對(duì)照組下調(diào)。結(jié)論  IGF-1促進(jìn)小鼠乳腺癌的發(fā)生、發(fā)展，且與血管生長(zhǎng)密切相關(guān)。血管生長(zhǎng)抑制劑可能通過(guò)IGF-1及TGF-β1發(fā)揮抗腫瘤作用。

引用本文： 任玉萍,葉子榮,唐泓波,張軍,張珊,陳國(guó)慶,吳毅平. 利用IGF-1基因敲除鼠乳腺癌模型研究IGF-1對(duì)血管生成的影響. 中國(guó)普外基礎(chǔ)與臨床雜志, 2008, 15(11): 820-824. doi: 復(fù)制

1. Yakar S, Liu JL, Stannard B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor Ⅰ [J]. Proc Natl Acad Sci USA, 1999; 96(13)∶ 7324.
2. Yakar S, Liu JL, Fernandez AM， et al. Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity [J]. Diabetes, 2001; 50(5)∶ 1110.
3. Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma [J]. J Natl Cancer Inst, 1992; 84(24)∶ 1875.
4. Affymetrix, Inc. GeneChip Expression Analysis Technical Manual. http://www.affymetrix.com/support/technical/manual/expression_manual. affx, 2002.
5. Ibrahim YH, Yee D. Insulin-like growth factor-Ⅰ and breast cancer therapy [J]. Clin Cancer Res, 2005; 11(2 Pt 2)∶ 944s.
6. Wu Y, Cui K, Miyoshi K, et al. Reduced circulating insulin-like growth factor Ⅰ levels delay the onset of chemically and genetically induced mammary tumors [J]. Cancer Res, 2003; 63(15)∶4384.
7. Yakar S, Pennisi P, Zhao H, et al. Circulating IGF-1 and its role in cancer: lessons from the IGF-1 gene deletion (LID) mouse [J]. Novartis Found Symp, 2004; 262∶ 3.
8. 王 喜， 凌昌全. 中藥有效成份抗腫瘤轉(zhuǎn)移的研究進(jìn)展 [J]. 中國(guó)中西醫(yī)結(jié)合雜志, 2004; 24(2)∶ 178.
9. van der Meer W, Mackenzie MA, Dinnissen JW, et al. Pseudoplatelets: a retrospective study of their incidence and interference with platelet counting [J]. J Clin Pathol, 2003; 56(10)∶772.
10. Grulich-Henn J, Ritter J, Mesewinkel S, et al. Transport of insulin-like growth factor-Ⅰ across endothelial cell monolayers and its binding to the subendothelial matrix [J]. Exp Clin Endocrinol Diabetes, 2002; 110(2)∶67.
11. Slomiany MG, Rosenzweig SA. Hypoxia-inducible factor-1-dependent and -independent regulation of insulin-like growth factor-1-stimulated vascular endothelial growth factor secretion [J]. J Pharmacol Exp Ther, 2006; 318(2)∶ 666.
12. Lee OH, Bae SK, Bae MH, et al. Identification of angiogenic properties of insulin-like growth factor Ⅱ in in vitro angiogenesis models [J]. Br J Cancer, 2000; 82(2)∶ 385.
13. Jain RK, Duda DG, Clark JW, et al. Lessons from phase Ⅲ clinical trials on anti-VEGF therapy for cancer [J]. Nat Clin Pract Oncol, 2006; 3(1)∶ 24.
14. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine [J]. Genes Dev, 2008; 22(10)∶ 1276.
15. Uutela M, Laurén J, Bergsten E, et al. Chromosomal location, exon structure, and vascular expression patterns of the human PDGFC and PDGFC genes [J]. Circulation, 2001; 103(18)∶2242.
16. Del Rizzo DF, Yurkova N, Moon MC, et al. Platelet-derived growth factor-induced expression of c-fos in human vascular smooth muscle cells: implications for long-term graft patency [J]. Ann Thorac Surg, 2002; 74(1)∶ 90.
17. van Adrichem LN, Hoogeboom AJ, Wolvius EB. Genetics of craniofacial development [J]. Ned Tijdschr Tandheelkd, 2008; 115(2)∶ 61.
18. Bommireddy R, Doetschman T. TGFbeta1 and Treg cells: alliance for tolerance [J]. Trends Mol Med, 2007; 13(11)∶ 492.
19. Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-beta [J]. Pharmacol Ther, 2003; 98(2)∶ 257.
  1. 1. Yakar S, Liu JL, Stannard B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor Ⅰ [J]. Proc Natl Acad Sci USA, 1999; 96(13)∶ 7324.
  2. 2. Yakar S, Liu JL, Fernandez AM， et al. Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity [J]. Diabetes, 2001; 50(5)∶ 1110.
  3. 3. Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma [J]. J Natl Cancer Inst, 1992; 84(24)∶ 1875.
  4. 4. Affymetrix, Inc. GeneChip Expression Analysis Technical Manual. http://www.affymetrix.com/support/technical/manual/expression_manual. affx, 2002.
  5. 5. Ibrahim YH, Yee D. Insulin-like growth factor-Ⅰ and breast cancer therapy [J]. Clin Cancer Res, 2005; 11(2 Pt 2)∶ 944s.
  6. 6. Wu Y, Cui K, Miyoshi K, et al. Reduced circulating insulin-like growth factor Ⅰ levels delay the onset of chemically and genetically induced mammary tumors [J]. Cancer Res, 2003; 63(15)∶4384.
  7. 7. Yakar S, Pennisi P, Zhao H, et al. Circulating IGF-1 and its role in cancer: lessons from the IGF-1 gene deletion (LID) mouse [J]. Novartis Found Symp, 2004; 262∶ 3.
  8. 8. 王 喜， 凌昌全. 中藥有效成份抗腫瘤轉(zhuǎn)移的研究進(jìn)展 [J]. 中國(guó)中西醫(yī)結(jié)合雜志, 2004; 24(2)∶ 178.
  9. 9. van der Meer W, Mackenzie MA, Dinnissen JW, et al. Pseudoplatelets: a retrospective study of their incidence and interference with platelet counting [J]. J Clin Pathol, 2003; 56(10)∶772.
  10. 10. Grulich-Henn J, Ritter J, Mesewinkel S, et al. Transport of insulin-like growth factor-Ⅰ across endothelial cell monolayers and its binding to the subendothelial matrix [J]. Exp Clin Endocrinol Diabetes, 2002; 110(2)∶67.
  11. 11. Slomiany MG, Rosenzweig SA. Hypoxia-inducible factor-1-dependent and -independent regulation of insulin-like growth factor-1-stimulated vascular endothelial growth factor secretion [J]. J Pharmacol Exp Ther, 2006; 318(2)∶ 666.
  12. 12. Lee OH, Bae SK, Bae MH, et al. Identification of angiogenic properties of insulin-like growth factor Ⅱ in in vitro angiogenesis models [J]. Br J Cancer, 2000; 82(2)∶ 385.
  13. 13. Jain RK, Duda DG, Clark JW, et al. Lessons from phase Ⅲ clinical trials on anti-VEGF therapy for cancer [J]. Nat Clin Pract Oncol, 2006; 3(1)∶ 24.
  14. 14. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine [J]. Genes Dev, 2008; 22(10)∶ 1276.
  15. 15. Uutela M, Laurén J, Bergsten E, et al. Chromosomal location, exon structure, and vascular expression patterns of the human PDGFC and PDGFC genes [J]. Circulation, 2001; 103(18)∶2242.
  16. 16. Del Rizzo DF, Yurkova N, Moon MC, et al. Platelet-derived growth factor-induced expression of c-fos in human vascular smooth muscle cells: implications for long-term graft patency [J]. Ann Thorac Surg, 2002; 74(1)∶ 90.
  17. 17. van Adrichem LN, Hoogeboom AJ, Wolvius EB. Genetics of craniofacial development [J]. Ned Tijdschr Tandheelkd, 2008; 115(2)∶ 61.
  18. 18. Bommireddy R, Doetschman T. TGFbeta1 and Treg cells: alliance for tolerance [J]. Trends Mol Med, 2007; 13(11)∶ 492.
  19. 19. Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-beta [J]. Pharmacol Ther, 2003; 98(2)∶ 257.