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Immunohistochemical Expression of Fatty Acid Synthase and Vascular Endothelial Growth Factor in Primary Colorectal Cancer: a Clinicopathological Study

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Abstract

Background

Fatty acid synthase (FAS) is a valuable lipid enzyme involved in lipid biosynthesis and suggested to contribute in tumor carcinogenesis. Vascular endothelial growth factor (VEGF) is considered a serious angiogenic growth factor in the angiogenic pathway which is a very important in tumor growth and metastasis. Thus, inhibition of lipid biosynthesis and tumor angiogenesis can be new goals for colorectal cancer (CRC) treatment.

Aim of the Work

The assessment of the expression of FAS and VEGF protein and the relationship between them in CRC with the clinicopathological parameters.

Methods

The present retrospective study included 63 paraffin blocks previously diagnosed as primary cases of CRC. The slides were subjected to FAS and VEGF immunohistochemical staining using a streptavidin-biotin-peroxidase. The relationships among FAS and VEGF expression and clinicopathological parameters were statistically analyzed.

Results

The expression rate of FAS was 81% and VEGF was 84.1% in the studied cases. FAS expression was significantly associated with histopathological type (p = 0.02) and grade (p = 0.04), and highly associated with lymph node metastasis and stage (p < 0.001).VEGF was significantly associated with histopathological type (p = 0.01) and tumor depth (p = 0.02); highly associated with grade, lymph node metastasis, and stage (p < 0.001). There was a positive association between FAS and VEGF expression in CRC (p < 0.001).

Conclusion

FAS and VEGF showed a highly significant expression in the studied primary CRC cases. A significant association was observed between their expressions, suggesting the involvement of FAS in tumor angiogenesis. So they constitute potential targets in cancer prevention and treatment and make FAS an attractive antiangiogenic target.

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References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. https://doi.org/10.3322/caac.21262.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi.org/10.3322/caac.21387.

    Article  PubMed  Google Scholar 

  3. Mokhtar N, Salama A, Badawy O, Khorshed E, Mohamed G, Ibrahim M, Abdelazim H. Gastrointestinal tract tumors. In: Cancer Pathology Registry. A 12-year Registry (2000–2001). 2016a. pp, 32–58.

  4. Mokhtar N, Salama A, Badawy O, Khorshed E, Mohamed G, Ibrahim M, Abdelazim H. General features of total series. In: Cancer Pathology Registry. A 12-year Registry (2000–2001) 2016b. pp, 1–6.

  5. Kuhajda FP. Fatty acid synthase and cancer : new application of an old pathway. Cancer Res. 2006;66(12):5977–81. https://doi.org/10.1158/0008-5472.CAN-05-4673.

    Article  CAS  PubMed  Google Scholar 

  6. Kusakabe T, Nashimoto A, Honma K, Suzuki T. Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach. Histopathol. 2002;40(1):71–9. https://doi.org/10.1046/j.1365-2559.2002.01289.x.

    Article  CAS  Google Scholar 

  7. Piyathilake C, Frost A, Manne U, Bell W, Weiss H, Heimburger D, et al. The expression of fatty acid synthase (FASE) is an early event in the development and progression of squamous cell carcinoma of the lung. Hum Pathol. 2000;31(9):1068–73. https://doi.org/10.1053/hupa.2000.9842.

    Article  CAS  PubMed  Google Scholar 

  8. Alò PL, Visca P, Marci A, Mangoni A, Botti C, Di Tondo U. Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer. 1996;77(3):474–82. https://doi.org/10.1002/(SICI)1097-0142(19960201)77:3<474::AID-CNCR8>3.0.CO;2-K.

    Article  PubMed  Google Scholar 

  9. Epstein JI, Carmichael M, Partin AW. OA-519 (fatty acid synthase) as an independent predictor of pathological stage in adenocarcinoma of the prostate. Urology. 1995;45(1):81–6. https://doi.org/10.1016/S0090-4295(95)96904-7.

    Article  CAS  PubMed  Google Scholar 

  10. Dvorak HF, Weaver VM, Tlsty TD, Bergers G. Tumor microenvironment and progression. J Surg Oncol. 2011;103(6):468–74. https://doi.org/10.1002/jso.21709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239–52. https://doi.org/10.1038/nrc2618.

    Article  CAS  PubMed  Google Scholar 

  12. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011;146(6):873–87. https://doi.org/10.1016/j.cell.2011.08.039.

    Article  CAS  Google Scholar 

  13. Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, et al. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci. 2008;121(Pt 20):3487–95. https://doi.org/10.1242/jcs.016410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lau T, Roslani A, Lian L, Lee P, Hilmi I, Goh K, et al. Association between EGF and VEGF functional polymorphisms and sporadic colorectal cancer in the Malaysian population. Genet Mol Res. 2014;13(3):5555–61. https://doi.org/10.4238/2014.July.25.9.

    Article  CAS  PubMed  Google Scholar 

  15. Hansen TF, Jakobsen A. Clinical implications of genetic variations in the VEGF system in relation to colorectal cancer. Pharmacogenomics. 2011;12(12):1681–93. https://doi.org/10.2217/pgs.11.118.

    Article  CAS  PubMed  Google Scholar 

  16. Jannuzzi A, Özhan G, Yanar H, Alpertunga B. VEGF gene polymorphisms and susceptibility to colorectal cancer. Genet Test Mol Biomarkers. 2015;19(3):133–7. https://doi.org/10.1089/gtmb.2014.0259.

    Article  CAS  PubMed  Google Scholar 

  17. Hamilton SR, Rubio CA, Vogelstein B, Sobin LH, Kudo S, Fogt F. Carcinoma of the colon and rectum. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, editors. WHO classification of tumours of the digestive system. 4th ed. IARC: Lyon; 2010. p. 134–46.

    Google Scholar 

  18. Wang H, Xi Q, Wu G. Fatty acid synthase regulates invasion and metastasis of colorectal cancer via Wnt signaling pathway. Cancer Med. 2016;5(7):1599–606. https://doi.org/10.1002/cam4.711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hafez N, Tahoun N. Expression of cyclooxygenase 2 and vascular endothelial growth factor in gastric carcinoma: relationship with clinicopathological parameters. J Egypt Natl Canc Inst. 2016;28(3):149–56. https://doi.org/10.1016/j.jnci.2016.05.005.

    Article  PubMed  Google Scholar 

  20. Zaytseva YY, Elliott VA, Rychahou P, Mustain WC, Kim JT, Valentino J, et al. Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer. Carcinogenesis. 2014;35(6):1341–51. https://doi.org/10.1093/carcin/bgu042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zaytseva YY, Rychahou PG, Gulhati P, Elliott VA, Mustain WC, O’Connor K, et al. Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res. 2012;72(6):1504–17. https://doi.org/10.1158/0008-5472.CAN-11-4057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kearney KE, Pretlow TG, Pretlow TP. Increased expression of fatty acid synthase in human aberrant crypt foci: possible target for colorectal cancer prevention. Int J Cancer. 2009;125:249–52. https://doi.org/10.1002/ijc.24356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Visca P, Alo PL, Nonno FD, Botti C, Trombetta G, Marandino F, et al. Immunohistochemical expression of fatty acid synthase, apoptotic-regulating genes, proliferating factors, and ras protein product in colorectal adenomas, carcinomas, and adjacent nonneoplastic mucosa. Clin Cancer Res. 1999;5(12):4111–8.

    CAS  PubMed  Google Scholar 

  24. Ogino S, Nosho K, Meyerhardt JA, Kirkner GJ, Chan AT, Kawasaki T, et al. Cohort study of fatty acid synthase expression and patient survival in colon cancer. J Clin Oncol. 2008;26:5713–20. https://doi.org/10.1200/JCO.2008.18.2675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Visca P, Sebastiani V, Botti C, Diodoro MG, Lasagni RP, Romagnoli F, et al. Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma. Anticancer Res. 2004;24:4169–73.

    CAS  PubMed  Google Scholar 

  26. Uddin S, Hussain AR, Ahmed M, Abubaker J, Al-Sanea N, Abduljabbar A, et al. High prevalence of fatty acid synthase expression in colorectal cancers in Middle Eastern patients and its potential role as a therapeutic target. Am J Gastroenterol. 2009;104(7):1790–801. https://doi.org/10.1038/ajg.2009.230.

    Article  CAS  PubMed  Google Scholar 

  27. Rashid A, Pizer ES, Moga M, Milgraum LZ, Zahurak M, Pasternack GR, et al. Elevated expression of fatty acid synthase and fatty acid synthetic activity in colorectal neoplasia. Am J Pathol. 1997;150:201–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhan Y, Ginanni N, Tota MR, Wu M, Bays NW, Richon VM, et al. Control of cell growth and survival by enzymes of the fatty acid synthesis pathway in HCT-116 colon cancer cells. Clin Cancer Res. 2008;14(18):5735–42. https://doi.org/10.1158/1078-0432.CCR-07-5074.

    Article  CAS  PubMed  Google Scholar 

  29. Li JN, Gorospe M, Chrest FJ, Kumaravel TS, Evans MK, Han WF, et al. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Cancer Res. 2001;61(4):1493–9.

    CAS  PubMed  Google Scholar 

  30. Kridel SJ, Axelrod F, Rozenkrantz N, Smith JW. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 2004;64(6):2070–5.

    Article  CAS  PubMed  Google Scholar 

  31. Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene. 2005;24(1):39–46. https://doi.org/10.1038/sj.onc.1208174.

    Article  CAS  PubMed  Google Scholar 

  32. Little JL, Wheeler FB, Fels DR, Koumenis C, Kridel SJ. Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells. Cancer Res. 2007;67(3):1262–9. https://doi.org/10.1158/0008-5472.CAN-06-1794.

    Article  CAS  PubMed  Google Scholar 

  33. Graner E, Tang D, Rossi S, Baron A, Migita T, Weinstein LJ, et al. The isopeptidasUSP2a regulates the stability of fatty acid synthase in prostate cancer. Cancer Cell. 2004;5(3):253–61.

    Article  CAS  PubMed  Google Scholar 

  34. Menendez JA, Lupu R, Colomer R. Inhibition of tumor-associated fatty acid synthase hyperactivity induces synergistic chemosensitization of HER-2/neu-overexpressing human breast cancer cells to docetaxel (taxotere). Breast Cancer Res Treat. 2004;84:183–95. https://doi.org/10.1023/B:BREA.0000018409.59448.60.

    Article  CAS  PubMed  Google Scholar 

  35. Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, MoYY HS, et al. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 2008;68(4):1003–11. https://doi.org/10.1158/0008-5472.CAN-07-2489.

    Article  CAS  PubMed  Google Scholar 

  36. Zhao HC, Qin R, Chen XX, Sheng X, Wu JF, Wang DB, et al. Microvessel density is a prognostic marker of human gastric cancer. World J Gastroenterol. 2006;12(47):7598–603. https://doi.org/10.3748/wjg.v12.i47.7598.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zhao ZQ, Yang S, Lu HS. Expression of midkine and vascular endothelial growth factor in gastric cancer and the association of high levels with poor prognosis and survival. Mol Med Rep. 2012;5(2):415–9. https://doi.org/10.3892/mmr.2011.649.

    Article  CAS  PubMed  Google Scholar 

  38. Xu T, Chen D, Chen J. Expression of vascular endothelial growth factor C and its correlation with lymph node metastasis in colorectal carcinoma. J Huazhong Univ Sci Technolog Med Sci. 2004;24(6):596–8.

    Article  CAS  PubMed  Google Scholar 

  39. Vahedi L, Ghasemi M, Yazdani J, Mehrabian-Fard M, Sajadi N. Evaluation of VEGF immunohistochemical expression and correlation with clinicopathologic features in colorectal Cancer. Govaresh. 2015;20(3):199–204.

    Google Scholar 

  40. Soumaoro LT, Uetake H, Takagi Y, Iida S, Higuchi T, Yasuno M, et al. Coexpression of VEGF-C and Cox-2 in human colorectal cancer and its association with lymph node metastasis. Dis Colon Rectum. 2006;49(3):392–8. https://doi.org/10.1007/s10350-005-0247-x.

    Article  PubMed  Google Scholar 

  41. Xu Q, Chen RX, Wang ZW, Ni QC, Qian JJ, Sheng HX. Clinical research on angiogenesis in colorectal carcinoma and expression of CK20 mRNA in peripheral blood. Zhonghua Yi Xue Za Zhi. 2005;85(17):1205–8. https://doi.org/10.3760/j:issn:0376-2491.2005.17.015.

    Article  CAS  PubMed  Google Scholar 

  42. Mohamed HAD, Abd El All HS, Kamel AA, Yossef WT, Hammam MM. Correlation of vascular endothelial growth factor expression and neovascularization with colorectal carcinoma: a pilot study. J Adenocarcinoma. 2016;1:1–5. https://doi.org/10.21767/2572-309X.10005.

    Article  Google Scholar 

  43. Jia Y, Li Z, He Y, Liang W, Yang H, Ma H. Expression of vascular endothelial growth factor-C and the relationship between lymphangiogenesis and lymphatic metastasis in colorectal cancer. World J Gastroenterol. 2004;10(22):3261–3. https://doi.org/10.3748/wjg.v10.i22.3261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zheng S, Han MY, Xiao ZX, Peng JP, Dong Q. Clinical significance of vascular endothelial growth factor expression and neovascularization in colorectal carcinoma. World J Gastroenterol. 2003;9(6):1227–30. https://doi.org/10.3748/wjg.v9.i6.1227.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wen L, Wang R, Lu X, You C. Expression and clinical significance of vascular endothelial growth factor and fms-related tyrosine kinase 1 in colorectal cancer. Oncol Lett. 2015;9(5):2414–8. https://doi.org/10.3892/ol.2015.3013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hedaya M, Helmy A, H E, Hammam O. Cyclo-oxygenase-2 and vascular endothelial growth factor expression in colorectal cancer patients. The Egyptian Journal of Surgery. 2015;34(1):35–40. https://doi.org/10.4103/1110-1121.153369.

    Article  Google Scholar 

  47. van Triest B, Pinedo HM, Blaauwgeers JL, van Diest PJ, Schoenmakers PS, Voorn DA, et al. Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor and proliferation markers in colorectal cancer. Clin Cancer Res. 2000;6(3):1063–72.

    PubMed  Google Scholar 

  48. Hashim AF, Al-Janabi AA, Mahdi LH, Al-Toriahi KM, Yasseen AA. Vascular endothelial growth factor (VEGF) receptor expression correlates with histologic grade and stage of colorectal cancer. Libyan J Med. 2010;5(1):5059. https://doi.org/10.3402/ljm.v5i0.5059.

    Article  Google Scholar 

  49. Minagawa N, Nakayama Y, Hirata K, Onitsuka K, Inoue Y, Nagata N, et al. Correlation of plasma level and immunohistochemical expression of vascular endothelial growth factor in patients with advanced colorectal cancer. Anticancer Res. 2002;22(5):2957–63.

    CAS  PubMed  Google Scholar 

  50. White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 2002;62(6):1669–75.

    CAS  PubMed  Google Scholar 

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  1. Department of Pathology, Faculty of Medicine, Zagazig University, Ash Sharqia Governorate, Zagazig, 44519, Egypt

    Asmaa Hussein Mohamed & Nelly Mohamed Said

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Mohamed, A.H., Said, N.M. Immunohistochemical Expression of Fatty Acid Synthase and Vascular Endothelial Growth Factor in Primary Colorectal Cancer: a Clinicopathological Study. J Gastrointest Canc 50, 485–492 (2019). https://doi.org/10.1007/s12029-018-0104-5

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