Expression of HGF and c-met Detected by Tissue Microarray and Relationship with Tumor Angiogenesis in Human Colorectal Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIANG Yibo ¹ , CUI Lin ² , YU Jianxian ² , JI Ping ²

1.Department of General Surgery, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China;;
2.Department of Pathology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China;

Corresponding?author：

Keywords：

Hepatocyte growth factor; c-met; Colorectal cancer; Angiogenesis; Tissue microarray

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Objective To study hepatocyte growth factor (HGF) and its receptor (c-met) expressions in human colorectal cancer and non-neoplasm colorectal mucosa, and the relationship with tumor angiogenesis.
Methods Tissue microarrays (TMAs) were made up of 80 cases of colorectal cancer and 80 cases of nonneoplasm colorectal mucosa. The expressions of HGF and c-met were detected by immunohistochemistry (SP). CD105 was used as a marker to account microvessel density (MVD) in tumor tissue.
Results HGF was over expressed in 48 cases and c-met was over expressed in 63 cases of colorectal cancer tissue, and the correlation between HGF and c-met positive expression was significant (r=0.231, P lt;0.05). The high expression rate of HGF and cmet in colorectal cancer were significantly higher than that in non-neoplasm colorectal mucosa (χ2=35.387, P lt;0.05; χ2=59.854, P lt;0.05) of colorectal cancer. The overexpression of HGF was correlated with lymph node metastasis (χ2=4.743, P lt;0.05) and TNM staging (χ2=5.576, P lt;0.05). The overexpression of c-met was correlated with differentiation (χ2=15.767, P lt;0.05) and lymph node metastasis (χ2=5.765, P lt;0.05) of colorectal cancer. MVD was different between overexpression and lowexpression colorectal cancer tissues of HGF and cmet (t=2.150, P lt;0.05; t=2.052, P lt;0.05). There was statistical correlation between HGF and cmet overexpression (r=0.259, P lt;0.05). The overexpressions of HGF and cmet were correlated with lymph metastasis in moderate differentiation cancer (χ2=13.154, P lt;0.05; χ2=5.371, P lt;0.05). Conclusions The overexpressions of HGF and c-met in colorectal cancer may be related with tumor angiogenesis. Detecting the expressions of HGF and c-met is valuable to estimate the biological character of colorectal cancer.

Citation： LIANG Yibo ,CUI Lin,YU Jianxian,JI Ping. Expression of HGF and c-met Detected by Tissue Microarray and Relationship with Tumor Angiogenesis in Human Colorectal Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2010, 17(7): 713-718. doi: Copy

1.	Zeng Q, Chen S, You Z, et al. Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFκB [J]. J Biol Chem, 2002; 277(28): 2520325208.
2.	Jass JR, Atkin WS, Cuzick J, et al. The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases [J]. Histopathology, 1986; 10(5): 437459.
3.	Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual [M]. 6th edition. New York: SpringerVerlag, 2002: 143164.
4.	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1887.
5.	Fromowitz FB, Voila MV, Chao S, et al. ras p21 expression in the progression of breast cancer [J]. Hum Pathol, 1987; 18(12): 12681275.
6.	涂小煌, 王為忠, 王烈, 等. 直腸癌及其遠端黏膜p53和CD34的表達及意義 [J]. 中國普外基礎與臨床雜志, 2008; 15(9): 641645.
7.	Yu JX, Cui L, Zhang QY, et al. Expression of NOS and HIF1α in human colorectal carcinoma and implication in tumor angiogenesis [J]. World J Gastroenterol, 2006; 12(29): 46604664.
8.	于建憲, 崔琳, 張七一, 等. 組織芯片檢測大腸癌中NOS、HIF1α表達及與血管生成的關系 [J]. 病理診斷學雜志, 2007; 14(1): 4447.
9.	Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor [J]. Nature, 1989; 342(6248): 440443.
10.	Stoker M, Gherardi E, Perryman M, et al. Scatter factor is a fibroblastderived modulator of epithelial cell mobility [J]. Nature, 1987; 327(6119): 239242.
11.	Gherardi E, Stoker M. Hepatocytes and scatter factor [J]. Nature, 1990; 346(6281): 228.
12.	Miyazawa K, Tsubouchi H, Naka D, et al. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor [J]. Biochem Biophys Res Commun, 1989; 163(2): 967973.
13.	Rosenthal EL, Johnson TM, Allen ED, et al. Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor and scatter factorstimulated invasion of carcinoma cells [J]. Cancer Res, 1998; 58(22): 52215230.
14.	魏松鋒, 高明, 于洋, 等. HGF、CXCR4、VEGFD表達與甲狀腺乳頭狀癌頸淋巴結轉移的關系 [J]. 現代腫瘤醫學, 2008; 16(8): 12951297.
15.	Horiguchi N, Takayama H, Toyoda M, et al. Hepatocyte growth factor promotes hepatocarcinogenesis through cMet autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine [J]. Oncogene, 2002; 21(12): 17911799.
16.	Cooper CS, Park M, Blair DG, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line [J]. Nature, 1984; 311(5981): 2933.
17.	Park M, Dean M, Cooper CS, et al. Mechanism of met oncogene activation [J]. Cell, 1986; 45(6): 895904.
18.	Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the cmet protooncogene product [J]. Science, 1991; 251(4995): 802804.
19.	Ma PC, Maulik G, Christensen J, et al. cMet: structure, functions and potential for therapeutic inhibition [J]. Cancer Metastasis Rev, 2003; 22(4): 309325.
20.	Liu C, Park M, Tsao MS. Overexpression of cmet protooncogene but not epidermal growth factor receptor or cerbB2 in primary human colorectal carcinomas [J]. Oncogene, 1992; 7(1): 181185.
21.	Takeuchi H, Bilchik A, Saha S, et al. cMET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases [J]. Clin Cancer Res, 2003; 9(4): 14801488.
22.	Kermorgant S, Aparicio T, Dessirier V, et al. Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease over production. Evidence for PI3 kinase and PKC involvement [J]. Carcinogenesis, 2001; 22(7): 10351042.
23.	Xie Q, Liu KD, Hu MY, et al. SF/HGFcMet autocrine and paracrine promote metastasis of hepatocellular carcinoma [J]. World J Gastroenterol, 2001; 7(6): 816820.
24.	李可洲, 伍曉汀, 李寧, 等. 肝細胞生長因子對大鼠移植小腸粘膜結構的保護作用 [J]. 中國普外基礎與臨床雜志, 2003; 10(3): 236239.
25.	Qian CN, Guo X, Cao B, et al. Met protein expression level correlates with survival in patients with latestage nasopharyngeal carcinoma [J]. Cancer Res, 2002; 62(2): 589596.
26.	Edakuni G, Sasatomi E, Satoh T, et al. Expression of the hepatocyte growth factor/cMet pathway is increased at the cancer front in breast carcinoma [J]. Pathol Int, 2001; 51(3): 172178.
27.	Maulik G, Shrikhande A, Kijima T, et al. Role of the hepatocyte growth factor receptor cMet, in oncogenesis and potential for therapeutic inhibition [J]. Cytokine Growth Factor Rev, 2002; 13(1): 4159.
28.	Royal I, LamarcheVane N, Lamorte L, et al. Activation of cdc42, rac, PAK, and rhokinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation [J]. Mol Biol Cell, 2000; 11(5): 17091725.
29.	張春旭, 王強, 李延甫, 等. cmet蛋白在高細胞變異型甲狀腺乳頭狀癌中的表達 [J]. 中國普外基礎與臨床雜志, 2008; 15(5): 318322.
30.	李宏武, 單吉賢. HGF/SF對姜黃素誘導大腸癌細胞凋亡的作用 [J]. 中國普外基礎與臨床雜志, 2006; 13(1): 7476.
31.	Maulik G, Kijima T, Ma PC, et al. Modulation of the cMet/hepatocyte growth factor pathway in small cell lung cancer [J]. Clin Cancer Res, 2002; 8(2): 620627.
32.	Dong G, Chen Z, Li ZY, et al. Hepatocyte growth factor/scatter factorinduced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin8 and vascular endothelial growth factor in head and neck squamous cell carcinoma [J]. Cancer Res, 2001; 61(15): 59115918.
33.	Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amplification and overexpression of cmet and cerbB2 in human gastric carcinomas [J]. Cancer, 1999; 85 (9): 18941902.
34.	Chen BK, Ohtsuki Y, Furihata M, et al. Overexpression of cMet protein in human thyroid tumors correlated with lymph node metastasis and clinicopathologic stage [J]. Pathol Res Pract, 1999; 195(6): 427433.
35.	Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more [J]. Nat Rev Mol Cell Biol, 2003; 4(12): 915925.
36.	陳碧華，謝倩，劉康達. CMet信號阻斷對肝癌細胞生長和運動能力的影響 [J]. 中華肝臟病雜志, 2003; 11(8): 487489.
37.	Herynk MH, Stoeltzing O, Reinmuth N, et al. Downregulation of cMet inhibits growth in the liver of human colorectal carcinoma cells [J]. Cancer Res, 2003; 63(11): 29902996.

1. Zeng Q, Chen S, You Z, et al. Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFκB [J]. J Biol Chem, 2002; 277(28): 2520325208.
2. Jass JR, Atkin WS, Cuzick J, et al. The grading of rectal cancer: historical perspectives and a multivariate analysis of 447 cases [J]. Histopathology, 1986; 10(5): 437459.
3. Greene FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual [M]. 6th edition. New York: SpringerVerlag, 2002: 143164.
4. 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1887.
5. Fromowitz FB, Voila MV, Chao S, et al. ras p21 expression in the progression of breast cancer [J]. Hum Pathol, 1987; 18(12): 12681275.
6. 涂小煌, 王為忠, 王烈, 等. 直腸癌及其遠端黏膜p53和CD34的表達及意義 [J]. 中國普外基礎與臨床雜志, 2008; 15(9): 641645.
7. Yu JX, Cui L, Zhang QY, et al. Expression of NOS and HIF1α in human colorectal carcinoma and implication in tumor angiogenesis [J]. World J Gastroenterol, 2006; 12(29): 46604664.
8. 于建憲, 崔琳, 張七一, 等. 組織芯片檢測大腸癌中NOS、HIF1α表達及與血管生成的關系 [J]. 病理診斷學雜志, 2007; 14(1): 4447.
9. Nakamura T, Nishizawa T, Hagiya M, et al. Molecular cloning and expression of human hepatocyte growth factor [J]. Nature, 1989; 342(6248): 440443.
10. Stoker M, Gherardi E, Perryman M, et al. Scatter factor is a fibroblastderived modulator of epithelial cell mobility [J]. Nature, 1987; 327(6119): 239242.
11. Gherardi E, Stoker M. Hepatocytes and scatter factor [J]. Nature, 1990; 346(6281): 228.
12. Miyazawa K, Tsubouchi H, Naka D, et al. Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor [J]. Biochem Biophys Res Commun, 1989; 163(2): 967973.
13. Rosenthal EL, Johnson TM, Allen ED, et al. Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor and scatter factorstimulated invasion of carcinoma cells [J]. Cancer Res, 1998; 58(22): 52215230.
14. 魏松鋒, 高明, 于洋, 等. HGF、CXCR4、VEGFD表達與甲狀腺乳頭狀癌頸淋巴結轉移的關系 [J]. 現代腫瘤醫學, 2008; 16(8): 12951297.
15. Horiguchi N, Takayama H, Toyoda M, et al. Hepatocyte growth factor promotes hepatocarcinogenesis through cMet autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine [J]. Oncogene, 2002; 21(12): 17911799.
16. Cooper CS, Park M, Blair DG, et al. Molecular cloning of a new transforming gene from a chemically transformed human cell line [J]. Nature, 1984; 311(5981): 2933.
17. Park M, Dean M, Cooper CS, et al. Mechanism of met oncogene activation [J]. Cell, 1986; 45(6): 895904.
18. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the cmet protooncogene product [J]. Science, 1991; 251(4995): 802804.
19. Ma PC, Maulik G, Christensen J, et al. cMet: structure, functions and potential for therapeutic inhibition [J]. Cancer Metastasis Rev, 2003; 22(4): 309325.
20. Liu C, Park M, Tsao MS. Overexpression of cmet protooncogene but not epidermal growth factor receptor or cerbB2 in primary human colorectal carcinomas [J]. Oncogene, 1992; 7(1): 181185.
21. Takeuchi H, Bilchik A, Saha S, et al. cMET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases [J]. Clin Cancer Res, 2003; 9(4): 14801488.
22. Kermorgant S, Aparicio T, Dessirier V, et al. Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease over production. Evidence for PI3 kinase and PKC involvement [J]. Carcinogenesis, 2001; 22(7): 10351042.
23. Xie Q, Liu KD, Hu MY, et al. SF/HGFcMet autocrine and paracrine promote metastasis of hepatocellular carcinoma [J]. World J Gastroenterol, 2001; 7(6): 816820.
24. 李可洲, 伍曉汀, 李寧, 等. 肝細胞生長因子對大鼠移植小腸粘膜結構的保護作用 [J]. 中國普外基礎與臨床雜志, 2003; 10(3): 236239.
25. Qian CN, Guo X, Cao B, et al. Met protein expression level correlates with survival in patients with latestage nasopharyngeal carcinoma [J]. Cancer Res, 2002; 62(2): 589596.
26. Edakuni G, Sasatomi E, Satoh T, et al. Expression of the hepatocyte growth factor/cMet pathway is increased at the cancer front in breast carcinoma [J]. Pathol Int, 2001; 51(3): 172178.
27. Maulik G, Shrikhande A, Kijima T, et al. Role of the hepatocyte growth factor receptor cMet, in oncogenesis and potential for therapeutic inhibition [J]. Cytokine Growth Factor Rev, 2002; 13(1): 4159.
28. Royal I, LamarcheVane N, Lamorte L, et al. Activation of cdc42, rac, PAK, and rhokinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation [J]. Mol Biol Cell, 2000; 11(5): 17091725.
29. 張春旭, 王強, 李延甫, 等. cmet蛋白在高細胞變異型甲狀腺乳頭狀癌中的表達 [J]. 中國普外基礎與臨床雜志, 2008; 15(5): 318322.
30. 李宏武, 單吉賢. HGF/SF對姜黃素誘導大腸癌細胞凋亡的作用 [J]. 中國普外基礎與臨床雜志, 2006; 13(1): 7476.
31. Maulik G, Kijima T, Ma PC, et al. Modulation of the cMet/hepatocyte growth factor pathway in small cell lung cancer [J]. Clin Cancer Res, 2002; 8(2): 620627.
32. Dong G, Chen Z, Li ZY, et al. Hepatocyte growth factor/scatter factorinduced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin8 and vascular endothelial growth factor in head and neck squamous cell carcinoma [J]. Cancer Res, 2001; 61(15): 59115918.
33. Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amplification and overexpression of cmet and cerbB2 in human gastric carcinomas [J]. Cancer, 1999; 85 (9): 18941902.
34. Chen BK, Ohtsuki Y, Furihata M, et al. Overexpression of cMet protein in human thyroid tumors correlated with lymph node metastasis and clinicopathologic stage [J]. Pathol Res Pract, 1999; 195(6): 427433.
35. Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more [J]. Nat Rev Mol Cell Biol, 2003; 4(12): 915925.
36. 陳碧華，謝倩，劉康達. CMet信號阻斷對肝癌細胞生長和運動能力的影響 [J]. 中華肝臟病雜志, 2003; 11(8): 487489.
37. Herynk MH, Stoeltzing O, Reinmuth N, et al. Downregulation of cMet inhibits growth in the liver of human colorectal carcinoma cells [J]. Cancer Res, 2003; 63(11): 29902996.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression of HGF and c-met Detected by Tissue Microarray and Relationship with Tumor Angiogenesis in Human Colorectal Cancer

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