• 上海交通大學(xué)醫(yī)學(xué)院附屬第三人民醫(yī)院普通外科（上海 201900）;

目的  介紹趨化因子及其受體，尤其是CCL19/CCL21-CCR7及CXCL12-CXCR4軸在胃癌發(fā)生、發(fā)展中的作用。方法  查閱國內(nèi)、外近年來有關(guān)趨化因子及其受體與胃癌關(guān)系的文獻(xiàn)并作綜述。結(jié)果  趨化因子及其受體通過對胃癌生長微環(huán)境的調(diào)控，CCL19/CCL21-CCR7在胃癌淋巴結(jié)轉(zhuǎn)移過程中起著突出作用，CXCL12-CXCR4軸在胃癌腹膜轉(zhuǎn)移過程中起著關(guān)鍵作用。CCR7可能成為特異性評價(jià)胃癌淋巴結(jié)轉(zhuǎn)移潛能的分子標(biāo)志物。阻斷CXCL12-CXCR4軸有助于推動(dòng)進(jìn)展期胃癌腹膜轉(zhuǎn)移治療策略的進(jìn)一步發(fā)展。結(jié)論  趨化因子及其受體從不同的方面促進(jìn)胃癌的演進(jìn)，了解這些方面的機(jī)理可以為未來的治療提供理論依據(jù)。以趨化因子及其受體作為一種胃癌標(biāo)志物和腫瘤治療的新靶點(diǎn)，在胃癌侵襲轉(zhuǎn)移的評估、預(yù)后判斷和治療方面將有著廣闊的臨床應(yīng)用前景。

引用本文： 陸瑞祺,俞繼衛(wèi),姜波健. 趨化因子及其受體與胃癌的關(guān)系. 中國普外基礎(chǔ)與臨床雜志, 2010, 17(6): 627-632. doi: 復(fù)制

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2. Zlotnik A, Yoshie O, Nomiyama H. The chemokine and chemokine receptor superfamilies and their molecular evolution [J]. Genome Biol, 2006; 7(12): 243.
3. Kehrl JH, Hwang IY, Park C. Chemoattract receptor signaling and its role in lymphocyte motility and trafficking [J]. Curr Top Microbiol Immunol, 2009; 334: 107-127.
4. Mashino K, Sadanaga N, Yamaguchi H, et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma [J]. Cancer Res, 2002; 62(10): 2937-2941.
5. Yan C, Zhu ZG, Yu YY, et al. Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis [J]. World J Gastroenterol, 2004; 10(6): 783-790.
6. Arigami T, Natsugoe S, Uenosono Y, et al. CCR7 and CXCR4 expression predicts lymph node status including micrometastasis in gastric cancer [J]. Int J Oncol, 2009; 35(1): 19-24.
7. Kruizinga RC, Bestebroer J, Berghuis P, et al. Role of chemokines and their receptors in cancer [J]. Curr Pharm Des, 2009; 15(29): 3396-3416.
8. Schmausser B, Endrich S, Brndlein S, et al. The chemokine receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, Helicobacter pylori gastritis, gastric carcinoma and its precursor lesions and up-regulated by H. pylori [J]. Clin Exp Immunol, 2005; 139(2): 323-327.
9. Müller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature, 2001; 410(6824): 50-56.
10. Pituch-Noworolska A, Drabik G, Szatanek R, et al. Immunophenotype of isolated tumour cells in the blood, bone marrow and lymph nodes of patients with gastric cancer [J]. Pol J Pathol, 2007; 58(2): 93-97.
11. Baek SK, Jung KY, Lee SH, et al. Prognostic significance of vascular endothelial growth factor-C expression and lymphatic vessel density in supraglottic squamous cell carcinoma [J]. Laryngoscope, 2009; 119(7): 1325-1330.
12. Ko YH, Jung CK, Lee MA, et al. Clinical significance of vascular endothelial growth factors (VEGF)-C and -D in resected non-small cell lung cancer [J]. Cancer Res Treat, 2008; 40(3): 133-140.
13. 吳立剛, 劉奇?zhèn)? 胡志強(qiáng). MMP-2和VEGF-C在甲狀腺乳頭狀癌中的表達(dá)及臨床意義 [J]. 中國普外基礎(chǔ)與臨床雜志, 2009; 16(11): 906-910.
14. Di JM, Zhou J, Zhou XL, et al. Cyclooxygenase-2 expression is associated with vascular endothelial growth factor-C and lymph node metastases in human prostate cancer [J]. Arch Med Res, 2009; 40(4): 268-275.
15. Zhong D, Li Y, Peng Q, et al. Expression of Tiam1 and VEGF-C correlates with lymphangiogenesis in human colorectal carcinoma [J]. Cancer Biol Ther, 2009; 8(8): 689-695.
16. Okazawa T, Yoshida T, Shirai Y, et al. Expression of vascular endothelial growth factor C is a prognostic indicator in esophageal cancer [J]. Hepatogastroenterology, 2008; 55(86-87): 1503-1508.
17. Wu S, Xing W, Peng J, et al. Tumor transfected with CCL21 enhanced reactivity and apoptosis resistance of human monocyte-derived dendritic cells[J]. Immunobiology, 2008; 213(5): 417-426.
18. 劉君, 胡三元, 楊美香， 等. 趨化因子受體CCR7在胃癌患者外周血淋巴細(xì)胞中的表達(dá)及其意義[J]. 山東大學(xué)學(xué)報(bào)(醫(yī)學(xué)版), 2008; 46(4): 391-393.
19. Ishigami S, Natsugoe S, Nakajo A, et al. Prognostic value of CCR7 expression in gastric cancer [J]. Hepatogastroenterology, 2007; 54(76): 1025-1028.
20. Kryczek I, Wei S, Keller E, et al. Stroma-derived factor(SDF-1/CXCL12) and human tumor pathogenesis [J]. Am J Physiol Cell Physiol, 2007; 292(3): C987-C995.
21. Ishigami S, Natsugoe S, Okumura H, et al. Clinical implication of CXCL12 expression in gastric cancer [J]. Ann Surg Oncol, 2007; 14(11): 3154-3158.
22. Kwak MK, Hur K, Park DJ, et al. Expression of chemokine receptors in human gastric cancer [J]. Tumor Biol, 2005; 26(2): 65-70.
23. Yasumoto K, Koizumi K, Kawashima A, et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer [J]. Cancer Res, 2006; 66(4): 2181-2187.
24. Roukos DH. Current status and future perspectives in gastric cancer management [J]. Cancer Treat Rev, 2000; 26(4): 243-255.
25. Iwanaga T, Iwasaki Y, Ohashi M, et al. Establishment of a CXCR4-expressing gastric cancer cell line in nude mice and the effect of AMD 3100 on tumor regression [J]. Gan To Kagaku Ryoho, 2007; 34(12): 1917-1919.
26. 丁印魯， 張建良， 唐思鋒， 等. 趨化因子基質(zhì)細(xì)胞衍生因子-1及其受體對胃癌腹膜轉(zhuǎn)移潛能的影響 [J]. 中華醫(yī)學(xué)雜志， 2008; 88（3）: 202-205.
27. 安麗文, 劉永軍, 趙丹懿， 等. 胃癌組織VEGF-C和CXCR4的表達(dá)與淋巴結(jié)轉(zhuǎn)移的關(guān)系 [J]. 世界華人消化雜志, 2007; 15(18): 2026-2030.
28. Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4 [J]. Cancer Res, 2002; 62(24): 7203-7206.
29. 孫梯業(yè), 趙永亮, 顏偉， 等. CXCR4在VEGF-C介導(dǎo)的胃癌淋巴道轉(zhuǎn)移中的作用 [J]. 第三軍醫(yī)大學(xué)學(xué)報(bào), 2008; 30(2): 161-165.
30. Zieker D, Knigsrainer I, Tritschler I, et al. Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer [J]. Int J Cancer, 2010; 126(6): 1513-1520.
31. Hashimoto I, Koizumi K, Tatematsu M, et al. Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells [J]. Eur J Cancer, 2008; 44(7): 1022-1029.
32. 江州華, 俞繼衛(wèi), 姜波健. 基質(zhì)金屬蛋白酶對胃癌微環(huán)境調(diào)控作用的研究進(jìn)展 [J]. 中國普外基礎(chǔ)與臨床雜志, 2009; 16(9): 768-772.
33. Sugasawa H, Ichikura T, Kinoshita M, et al. Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination [J]. Int J Cancer, 2008; 122(11): 2535-2541.
34. Sugasawa H, Ichikura T, Tsujimoto H, et al. Prognostic significance of expression of CCL5/RANTES receptors in patients with gastric cancer [J]. J Surg Oncol, 2008; 97(5): 445-450.
35. Lee JH, Cho YS, Lee JY, et al. The chemokine receptor CCR4 is expressed and associated with a poor prognosis in patients with gastric cancer [J]. Ann Surg, 2009; 249(6): 933-941.
36. Futagami S, Tatsuguchi A, Hiratsuka T, et al. Monocyte chemoattractant protein 1 and CD40 ligation have a synergistic effect on vascular endothelial growth factor production through cyclooxygenase 2 upregulation in gastric cancer [J]. J Gastroenterol, 2008; 43(3): 216-224.
37. Eck M, Schmausser B, Scheller K, et al. Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma [J]. Clin Exp Immunol, 2003; 134(3): 508-515.
  1. 1. Wu X, Lee VC, Chevalier E. Chemokine receptors as targets for cancer therapy [J]. Curr Pharm Des， 2009； 15(7): 742-757.
  2. 2. Zlotnik A, Yoshie O, Nomiyama H. The chemokine and chemokine receptor superfamilies and their molecular evolution [J]. Genome Biol, 2006; 7(12): 243.
  3. 3. Kehrl JH, Hwang IY, Park C. Chemoattract receptor signaling and its role in lymphocyte motility and trafficking [J]. Curr Top Microbiol Immunol, 2009; 334: 107-127.
  4. 4. Mashino K, Sadanaga N, Yamaguchi H, et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma [J]. Cancer Res, 2002; 62(10): 2937-2941.
  5. 5. Yan C, Zhu ZG, Yu YY, et al. Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis [J]. World J Gastroenterol, 2004; 10(6): 783-790.
  6. 6. Arigami T, Natsugoe S, Uenosono Y, et al. CCR7 and CXCR4 expression predicts lymph node status including micrometastasis in gastric cancer [J]. Int J Oncol, 2009; 35(1): 19-24.
  7. 7. Kruizinga RC, Bestebroer J, Berghuis P, et al. Role of chemokines and their receptors in cancer [J]. Curr Pharm Des, 2009; 15(29): 3396-3416.
  8. 8. Schmausser B, Endrich S, Brndlein S, et al. The chemokine receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, Helicobacter pylori gastritis, gastric carcinoma and its precursor lesions and up-regulated by H. pylori [J]. Clin Exp Immunol, 2005; 139(2): 323-327.
  9. 9. Müller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature, 2001; 410(6824): 50-56.
  10. 10. Pituch-Noworolska A, Drabik G, Szatanek R, et al. Immunophenotype of isolated tumour cells in the blood, bone marrow and lymph nodes of patients with gastric cancer [J]. Pol J Pathol, 2007; 58(2): 93-97.
  11. 11. Baek SK, Jung KY, Lee SH, et al. Prognostic significance of vascular endothelial growth factor-C expression and lymphatic vessel density in supraglottic squamous cell carcinoma [J]. Laryngoscope, 2009; 119(7): 1325-1330.
  12. 12. Ko YH, Jung CK, Lee MA, et al. Clinical significance of vascular endothelial growth factors (VEGF)-C and -D in resected non-small cell lung cancer [J]. Cancer Res Treat, 2008; 40(3): 133-140.
  13. 13. 吳立剛, 劉奇?zhèn)? 胡志強(qiáng). MMP-2和VEGF-C在甲狀腺乳頭狀癌中的表達(dá)及臨床意義 [J]. 中國普外基礎(chǔ)與臨床雜志, 2009; 16(11): 906-910.
  14. 14. Di JM, Zhou J, Zhou XL, et al. Cyclooxygenase-2 expression is associated with vascular endothelial growth factor-C and lymph node metastases in human prostate cancer [J]. Arch Med Res, 2009; 40(4): 268-275.
  15. 15. Zhong D, Li Y, Peng Q, et al. Expression of Tiam1 and VEGF-C correlates with lymphangiogenesis in human colorectal carcinoma [J]. Cancer Biol Ther, 2009; 8(8): 689-695.
  16. 16. Okazawa T, Yoshida T, Shirai Y, et al. Expression of vascular endothelial growth factor C is a prognostic indicator in esophageal cancer [J]. Hepatogastroenterology, 2008; 55(86-87): 1503-1508.
  17. 17. Wu S, Xing W, Peng J, et al. Tumor transfected with CCL21 enhanced reactivity and apoptosis resistance of human monocyte-derived dendritic cells[J]. Immunobiology, 2008; 213(5): 417-426.
  18. 18. 劉君, 胡三元, 楊美香， 等. 趨化因子受體CCR7在胃癌患者外周血淋巴細(xì)胞中的表達(dá)及其意義[J]. 山東大學(xué)學(xué)報(bào)(醫(yī)學(xué)版), 2008; 46(4): 391-393.
  19. 19. Ishigami S, Natsugoe S, Nakajo A, et al. Prognostic value of CCR7 expression in gastric cancer [J]. Hepatogastroenterology, 2007; 54(76): 1025-1028.
  20. 20. Kryczek I, Wei S, Keller E, et al. Stroma-derived factor(SDF-1/CXCL12) and human tumor pathogenesis [J]. Am J Physiol Cell Physiol, 2007; 292(3): C987-C995.
  21. 21. Ishigami S, Natsugoe S, Okumura H, et al. Clinical implication of CXCL12 expression in gastric cancer [J]. Ann Surg Oncol, 2007; 14(11): 3154-3158.
  22. 22. Kwak MK, Hur K, Park DJ, et al. Expression of chemokine receptors in human gastric cancer [J]. Tumor Biol, 2005; 26(2): 65-70.
  23. 23. Yasumoto K, Koizumi K, Kawashima A, et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer [J]. Cancer Res, 2006; 66(4): 2181-2187.
  24. 24. Roukos DH. Current status and future perspectives in gastric cancer management [J]. Cancer Treat Rev, 2000; 26(4): 243-255.
  25. 25. Iwanaga T, Iwasaki Y, Ohashi M, et al. Establishment of a CXCR4-expressing gastric cancer cell line in nude mice and the effect of AMD 3100 on tumor regression [J]. Gan To Kagaku Ryoho, 2007; 34(12): 1917-1919.
  26. 26. 丁印魯， 張建良， 唐思鋒， 等. 趨化因子基質(zhì)細(xì)胞衍生因子-1及其受體對胃癌腹膜轉(zhuǎn)移潛能的影響 [J]. 中華醫(yī)學(xué)雜志， 2008; 88（3）: 202-205.
  27. 27. 安麗文, 劉永軍, 趙丹懿， 等. 胃癌組織VEGF-C和CXCR4的表達(dá)與淋巴結(jié)轉(zhuǎn)移的關(guān)系 [J]. 世界華人消化雜志, 2007; 15(18): 2026-2030.
  28. 28. Bachelder RE, Wendt MA, Mercurio AM. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4 [J]. Cancer Res, 2002; 62(24): 7203-7206.
  29. 29. 孫梯業(yè), 趙永亮, 顏偉， 等. CXCR4在VEGF-C介導(dǎo)的胃癌淋巴道轉(zhuǎn)移中的作用 [J]. 第三軍醫(yī)大學(xué)學(xué)報(bào), 2008; 30(2): 161-165.
  30. 30. Zieker D, Knigsrainer I, Tritschler I, et al. Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer [J]. Int J Cancer, 2010; 126(6): 1513-1520.
  31. 31. Hashimoto I, Koizumi K, Tatematsu M, et al. Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells [J]. Eur J Cancer, 2008; 44(7): 1022-1029.
  32. 32. 江州華, 俞繼衛(wèi), 姜波健. 基質(zhì)金屬蛋白酶對胃癌微環(huán)境調(diào)控作用的研究進(jìn)展 [J]. 中國普外基礎(chǔ)與臨床雜志, 2009; 16(9): 768-772.
  33. 33. Sugasawa H, Ichikura T, Kinoshita M, et al. Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination [J]. Int J Cancer, 2008; 122(11): 2535-2541.
  34. 34. Sugasawa H, Ichikura T, Tsujimoto H, et al. Prognostic significance of expression of CCL5/RANTES receptors in patients with gastric cancer [J]. J Surg Oncol, 2008; 97(5): 445-450.
  35. 35. Lee JH, Cho YS, Lee JY, et al. The chemokine receptor CCR4 is expressed and associated with a poor prognosis in patients with gastric cancer [J]. Ann Surg, 2009; 249(6): 933-941.
  36. 36. Futagami S, Tatsuguchi A, Hiratsuka T, et al. Monocyte chemoattractant protein 1 and CD40 ligation have a synergistic effect on vascular endothelial growth factor production through cyclooxygenase 2 upregulation in gastric cancer [J]. J Gastroenterol, 2008; 43(3): 216-224.
  37. 37. Eck M, Schmausser B, Scheller K, et al. Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma [J]. Clin Exp Immunol, 2003; 134(3): 508-515.