Eurasian Journal of Biosciences

Early IL-5 transgenesis of colitis-associated colorectal cancer (CA-CRC) mouse model exacerbate the disease severity


Aims: To explore the role of IL-5 in eosinophils induction and cytokine modulation on the development of colitis-associated colorectal cancer mouse model (CA-CRC).
Methods and Material: A plasmid carrying the mouse IL-5 gene (IL-5 transgenesis) was injected to the mice with concurrently induction of CA-CRC mouse model, Then (CA-CRC) development, cytokine gene expression, cell dynamics in tumor vicinity and peritoneal cavity were analysed.
Results: A protumorigenic role of IL-5 was shown on early stages of CRC development as mice experienced severe physical symptoms including: rectal bleeding, diarrhea and significant reduction in body weight gain. Late findings of IL-5 transgenesis revealed higher tumor rates (89.0% vs 50%), significantly higher tumor count (15.1±7.2 vs 7.3±10.6 per colon), higher average tumor size (9.1±5.2 vs 4.4±6.5 mm), higher invasiveness index and shorter colon length. Microscopic examination of tumors revealed the presence of higher plasma cell count but lower eosinophils in AOM-DSS-pIL-5 treated group when compared to AOM-DSS group. Cytokine gene expression pointed out to the downregulation of IL-10 and TGF-β and the overexpression of IFN-γ in both tumor bearing groups compared to pIL-5 group. IL-5 treatment of AOM-DSS mice resulted in insignificant reduction in IL-5 gene expression in colon tissue that was associated with lower eosinophil count in the peritoneal cavity wash.
Conclusions: Immunomodulatory effect of early IL-5 expression in the CA-CRC and its role in the early migration of eosinophils to colon epithelia during colitis development raised the colitis severity and induced higher polyp rate formation and consequently higher tumor load.


  • Al-Omari, M., Razan B Al-Ghariebeh, Abed Alkarem Abu Alhaija, Heba Al-Zoubi, & Khaled M Al-Qaoud. (2019). Camel milk Whey Inhibits Inflammatory Colorectal Cancer Development Via Down regulation of Pro-inflammatory Cytokines in Induced AOM/DSS Mouse Model. Emirates Journal of Food and Agriculture., 256-262. DOI
  • Anagnostopoulos, G., Sakorafas, G., Kostopoulos, P., Margantinis, G., Tsiakos, S., Terpos, E.,. Arvanitidis, D. (2005). Disseminated colon cancer with severe peripheral blood eosinophilia and elevated serum levels of interleukine-2, interleukine-3, interleukine-5, and GM-CSF. The Journal of Surgical Oncology, 89, 273–275.
  • Asadullah, K., Sterry, W., & Volk, H. D. (2003). Interleukin-10 therapy—review of a new approach. Pharmacological Reviews, 55(2), 241–269. DOI:
  • Baier, P. K., Wolff-Vorbeck, G., Eggstein, S., Baumgartner, U., & Hopt, U. T. (2005). Cytokine expression in colon carcinoma. Anticancer research, 25(3B), 2135-2139.
  • Brynjolfsson, S. F., Persson Berg, L., Olsen Ekerhult, T., Rimkute, I., Wick, M. J., Mårtensson, I. L., & Grimsholm, O. (2018). Long-lived plasma cells in mice and men. Frontiers in Immunology, 9, 2673.
  • Čačev, T., Radošević, S., Križanac, Š., & Kapitanović, S. (2008). Influence of interleukin-8 and interleukin-10 on sporadic colon cancer development and progression. Carcinogenesis, 29(8), 1572–1580.
  • Castro-Giner, F., & Aceto, N. (2020). Tracking cancer progression: from circulating tumor cells to metastasis. Genome Medicine, 12(1), 1–12.
  • Cho, H., Lim, S. J., Won, K. Y., Bae, G. E., Kim, G. Y., Min, J. W., & Noh, B. J. (2016). Eosinophils in colorectal neoplasms associated with expression of CCL11 and CCL24. Journal of pathology and translational medicine, 50(1), 45. DOI:
  • Cohen, M. C., & Cohen, S. (1996). Cytokine function: a study in biologic diversity. American Journal of Clinical Pathology, 105(5), 589–598.
  • Di Caro, G., Bergomas, F., Grizzi, F., Doni, A., Bianchi, P., Malesci, A., & Marchesi, F. (2014). Occurrence of tertiary lymphoid tissue is associated with T-cell infiltration and predicts better prognosis in early-stage colorectal cancers. Clinical Cancer Research, 20(8), 2147–2158. DOI: 10.1158/1078-0432.CCR-13-2590
  • Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D. M., Piñeros, M.,... Bray, F. (2019). Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer, 144(8), 1941–1953.
  • Fridman WH, P. F., Sautès-Fridman C, Galon J. (2012). The immune contexture in human tumours: impact on clinical outcome. Nature Reviews Cancer, 12(4), 298.
  • Gotlib, J. (2015). World Health Organization‐defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management. American Journal of Hematology, 90(11), 1077–1089.
  • Greenfeder, Scott & Umland, Shelby & Cuss, Francis & Chapman, Richard & Egan, & Robert. (2001). Th2 cytokines and asthma — The role of interleukin-5 in allergic eosinophilic disease. Respiratory Research, 2, 71-79.
  • Ikutani, M., Yanagibashi, T., Ogasawara, M., Tsuneyama, K., Yamamoto, S., Hattori, Y., & Takatsu, K. (2012). Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity. Journal of Immunology, 188(2), 703–713.
  • Inoue, T., Murano, M., Kuramoto, T., Ishida, K., Kawakami, K., Abe, Y., & Maemura, K. (2007). Increased proliferation of middle to distal colonic cells during colorectal carcinogenesis in experimental murine ulcerative colitis. Oncology Reports, 18(6), 1457–1462.
  • Kanzaki, M., Shibagaki, N., Hatsushika, K., Mitsui, H., Inozume, T., Okamoto, A., & Nakao, A. (2007). Human eosinophils have an intact Smad signaling pathway leading to a major transforming growth factor-β target gene expression. International Archives of Allergy and Immunology, 142(4), 309–317.
  • Kato, H., Kohata, K., Yamamoto, J., Ichikawa, S., Watanabe, M., Ishizawa, K.,... Harigae, H. (2010). Extreme eosinophilia caused by interleukin-5-producing disseminated colon cancer. Int. J. Hematol, 91(2), 328–330.
  • Khaled AQ, Sana Y, Abdulrahman R, Raida K, & AH., S. (2015). Blocking of Histamine Release and IgE Binding to FcεRI on Human Basophils by Antibodies Produced in Camels. Allergy, Asthma & Immunology Research, 7(6), 583-589.
  • Kinashi, T., Harada, N., Severinson, E., Tanabe, T., Sideras, P., Konishi, M., & Matsuda, F. (1986). Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II. Nature, 324(6092), 70–73.
  • Lee, S. M., Kim, N., Son, H. J., Park, J. H., Nam, R. H., Ham, M. H., & Sung, J. (2016). The effect of sex on the azoxymethane/dextran sulfate sodium-treated mice model of colon cancer. Journal of cancer prevention, 21(4), 271.
  • Matsushita M, Matsuzaki K, Date M, & al., e. (1999). Down-regulation of TGF-beta receptors in human colorectal cancer: implications for cancer development. British Journal of Cancer, 80(1-2), 194-205.
  • Mumm, J. B., Emmerich, J., Zhang, X., Chan, I., Wu, L., Mauze, S., & Sheppard, C. (2011). IL-10 elicits IFNγ-dependent tumor immune surveillance. Cancer Cell, 20(6), 781–796.
  • Ni, C., Ma, P., Qu, L., Wu, F., Hao, J., Wang, R., & Qin, Z. (2017). Accelerated tumour metastasis due to interferon‐γ receptor‐mediated dissociation of perivascular cells from blood vessels. The Journal of pathology, 242(3), 334–346.
  • Ohnmacht, C., Pullner, A., Rooijen, N., & Voehringer, D. (2007). Analysis of eosinophil turnover in vivo reveals their active recruitment to and prolonged survival in the peritoneal cavity. The Journal of Immunology, 179(7), 4766–4774.
  • Parang, B., Barrett, C. W., & Williams, C. S. (2016). AOM/DSS Model of Colitis-Associated Cancer. Methods in molecular biology (Clifton, N.J.), 1422, 297-307.
  • Reichman, H., Itan, M., Rozenberg, P., Yarmolovski, T., Brazowski, E., Varol, C., & Karo-Atar, D. (2019). Activated eosinophils exert antitumorigenic activities in colorectal cancer. Cancer Immunol Res, 7(3), 388–400.
  • Sakkal, S., Miller, S., Apostolopoulos, V., & Nurgali, K. (2016). Eosinophils in cancer: favourable or unfavourable? Current Medicinal Chemistry, 23(7), 650–666.
  • Tanaka, T., Kohno, H., Suzuki, R., Yamada, Y., Sugie, S., & Mori, H. (2003). A novel inflammation‐related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate. Cancer Science, 94(11), 965–973.
  • Tartour, E., & Fridman, W. H. (1998). Cytokines and Cancer. International Reviews of Immunology, 16(5–6), 683–704.
  • Villalba, M., Evans, S. R., Vidal-Vanaclocha, F., & Calvo, A. (2017). Role of TGF-β in metastatic colon cancer: it is finally time for targeted therapy. Cell and Tissue Research, 370(1), 29–39.
  • Wang, J., Han, W., Zborowska, E., Liang, J., Wang, X., Willson, J. K., & Brattain, M. G. (1996). Reduced expression of transforming growth factor β type I receptor contributes to the malignancy of human colon carcinoma cells. Journal of Biological Chemistry, 271(29), 17366–17371.
  • Wen, T., & Rothenberg, M. E. (2016). The regulatory function of eosinophils. Microbiology spectrum, 4(5).
  • Xie, Q., Shen, Z. J., Oh, J., Chu, H., & Malter, J. S. (2011). Transforming growth factor-β1 antagonizes interleukin-5 pro-survival signaling by activating calpain-1 in primary human eosinophils. Journal of Clinical & Cellular Immunology. DOI: 10.4172/2155-9899.S1-003
  • Zaidi, M. R. (2019). The interferon-gamma paradox in cancer. Journal of Interferon & Cytokine Research, 39(1), 30–38.
  • Zhang, J. M., & An, J. (2007). Cytokines, inflammation and pain. International Anesthesiology Clinics, 45(2), 27.
  • Zhou et al. (2019). Risk of Colorectal Cancer in Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis. Gastroenterology Research and Practice, 2019, 5363261.


This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.