Detecting the Role of CCR7-CCL21/CCL19 Axis in Breast Cancer Progression and Lymph Node Metastasis Incidence
Background: Metastasis is the main cause of death in breast cancer patients. Lymph node metastasis is associated with poor overall survival and is often associated with recurrences. The molecular mechanisms controlling tumor metastasis are complex and there is an emerging evidence supporting the direct involvement of the chemokines and their receptors in this process. To the interest of this study, previous data from the literature show that the CCL21 and CCL19 and their receptor CCR7 are expressed in breast cancer and may be associated with lymph node metastasis. The aim of this study is to assess the expression of CCL19/CCL21 and their receptor CCR7 in breast cancer tissues and both negative and positive regional lymph nodes using RT-PCR technology .
Material and Methods: Formalin fixed paraffin embedded breast cancer specimens obtained from mastectomy were included in the study. RNA isolation using Acidic Phenol method was performed, and then RT-PCR was conducted on both primary tumor and corresponding lymph nodes using specific primers for the studied CCL21/CCL19 chemokines, CCR7 receptor and the positive control GAPDH.
Results: The results of this study have revealed a significant positive correlation in mRNA expression in the tumor samples between CCL21 vs.CCL19 (R2=0.9,P-value= 0.02), as well as between CCR7 vs CCL21, and CCR7vs.CCL19 (R2=0.87, P value= 0.04) (R2=0.98,P value= 0.002) respectively. Moreover, there was a significant positive correlation (R2=0.9 , P value= 0.02) in CCL19 expression in primary and secondary tumor. Furthermore, the expression of CCL21 chemokine in negative lymph nodes was more than the expression of it in positive lymph nodes with significant importance (P value = 0.01). The Study of the correlation between CCL21/CCL19 expression in breast tumors and the clinical and pathological parameters, has illustrated a significant correlation between CCL21 vs. CCL19 mRNA expression in breast tumors and triple negative of PR, ER, Her-2 receptors.
Conclusion: The results of the study have revealed a potential role of CCR7-CCL21/CCL19 axis in breast cancer. Moreover the results suggest an important role of CCL19 in Lymph nodes metastasis compared to CCL21. Furthermore, the study has showed that CCL21/CCL19 chemokines are expressed in breast tumors with poor prognosis.
- National Cancer Institute, S. Epidemiology and End results program database.
- Patnaik JL, B. et al. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer. Breast Cancer Res, 13(3), (2011), 64.
- Hart, I.R.F., I. J. Cancer invasion and metastasis. Q Rev Biol, 55 (2), (2011), 121-42.
- Achen, M.G.S.S.A. Molecular Control of Lymphatic Metastasis. Annals of the New York Academy of Sciences, 1131 (01), (2008), (1980), 225-234.
- Wang, J.M.D. et al. Chemokines and their role in tumor growth and metastasis. J Immunol Methods, 220 (1-2), (1998), 1-17.
- Ben-Baruch, A. Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumor–microenvironment interactions. Breast Cancer Research, 5 (1), (2003), 31-36.
- Luboshits, G.S. et al. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res, 59 (18), (1999).
- Cabioglu, N. et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clinical cancer research: an official journal of the American Association for Cancer Research, 11 (16), (2005), 5686-93.
- Mashino K, et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma.Cancer research, 62 (10), (2002), 2937-41.
- Takanami, I. Over expression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. International journal of cancer. Journal international du cancer, 105 (2), (2003), 186-9.
- Till, K.J. et al. The chemokine receptor CCR7 and alpha4 integrin are important for migration of chronic lymphocytic leukemia cells into lymph nodes. Blood, 99 (8), (2002), 2977-84.
- O'Hayre, M. et al. Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem J, 409 (3), (2008), 635-49.
- Murakami, T. et al. Chemokine receptors and melanoma metastasis. J Dermatol Sci, 36 (2), (2004), 71-8.
- Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature, 410 (6824), (2001), 50-6.
- Müller A, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature, 410 (6824), (2001), 50-6.
- Wang, J. et al. Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy. J Natl Cancer Inst, 100 (7), (2008), 502-12.
- Raju, R. et al. Differential ligand-signaling network of CCL19/CCL21-CCR7 system. Database: The Journal of Biological Databases and Curation, (2015), 106.
- Zhang, Q. et al. CCL19/CCR7 upregulates heparanase via specificity protein-1 (Sp1) to promote invasion of cell in lung cancer. Tumour Biol, 34 (5), (2013), 2703-8.
- Treilleux, I., et al. Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res, 10 (22), (2004), 7466-74.
- Shields, J. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell, 11 (6), (2007), 526-38.
- Shields, J. et al. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21.Science, 328 (5979), (2010), 749-52.
- Prendergast, G.C. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene, 27 (28), (2008), 3889-900.
- Stranford, S. et al. Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organs: Parallels with lymph node stroma. Frontiers in Immunology, (2012). 3 350.
- Hwang, T. et al. CCL7 and CCL21 over expression in gastric cancer is associated with lymph node metastasis and poor prognosis. World J Gastroenterol, 18 (11), (2012), 1249-56.
- Liu, Y. et al. Correlation effect of EGFR and CXCR4 and CCR7 chemokine receptors in predicting breast cancer metastasis and prognosis. Journal of Experimental and Clinical Cancer Research, 29 (1), (2010), 16.
- Takeuchi, H. et al. CCL21 Chemokine Regulates Chemokine Receptor CCR7 Bearing Malignant Melanoma Cells. Clinical Cancer Research, 10 (7), (2004), 2351-2358.
- Ehinger, A. et al. Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 2013.Acta Oncol, 56 (1), (2017), 68-74.
- Roberti, M et al. Protein expression changes during human triple negative breast cancer cell line progression to lymph node metastasis in a xenografted model in nude mice. Cancer Biol Ther, 13 (11), (2012), 1123-40.
Abstract Views: 15
PDF Views: 0