Angiogenic potential of circulating peripheral blood neutrophils in kidney cancer

The role of neutrophils in kidney cancer is currently being studied. Their role in carcinogenesis is ambiguous. As one of the most abundant blood leukocytes, neutrophils play an important role in cancer progression through multiple mechanisms, including promotion of angiogenesis, immunosuppression, and cancer metastasis. Neutrophils synthesize and release pro-angiogenic factors that are able to directly or indirectly stimulate the growth and migration of endothelial cells, which in turn causes the formation of new blood vessels from pre-existing ones. The production of various factors by neutrophils, including proangiogenic ones, is mediated by the expression of the genes of these molecules. Functional heterogeneity is characterized by differences in neutrophil gene expression patterns. The aim of this study was to evaluate the angiogenic potential of circulating neutrophils in kidney cancer. The object of the study were blood neutrophils of patients with verified clear cell kidney cancer at stage I (T1N0M0G1, n = 28, median age 60), stage II (T2N0M0G2, n = 15, median age 61) and stage III (T3N0M0G2, n = 15, median age 63) before surgery. The control group consisted of apparently healthy donors (n = 15, median age 54). Serum levels of IL-8 and VEGF-A were assessed by enzyme immunoassay. Expression of the CXCL8 and VEGF-A genes in circulating neutrophils was determined by reverse transcription quantitative PCR. As a result of our study, an increase in the level of IL-8 and VEGF-A in the blood serum of patients with kidney cancer in all studied groups compared with the control group was revealed. We observed a direct correlation between serum levels of IL-8 and VEGF-A in patients with kidney cancer (r = 0.429; p = 0.016), which confirms the relationship of these angiogenic factors. A significant increase in CXCL8 gene expression by circulating neutrophils was found in patients on II (2.91, Q_0.25-Q_0.75: (1.296-4.99), p = 0.02) and III (1.93, Q_0.25-Q_0.75: (0.755-11.36, p = 0.014) stages of kidney cancer compared with the control group (1.50, Q_0.25-Q_0.75: (0.80-4.05)). However, VEGF-A gene expression by circulating neutrophils did not differ from those in the control group. Blood neutrophils in kidney cancer exercise their angiogenic potential through the production of IL-8.

1. Bakouny Z., Choueiri T.K. IL-8 and cancer prognosis on immunotherapy. Nat. Med., 2020, Vol. 26, no. 5, pp. 650-651.

2. David J.M., Dominguez C., Hamilton D.H., Palena C. The IL-8/IL-8R axis: A double agent in tumor immune resistance. Vaccines, 2016, Vol. 4, no. 3, 22. doi: 10.3390/vaccines4030022.

3. de Palma M., Biziato D., Petrova T.V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer, 2017, Vol. 17, no. 8, pp. 457-474.

4. Díaz-Montero C.M., Rini B.I., Finke J.H. The immunology of renal cell carcinoma. Nat. Rev. Nephrol., 2020, Vol. 16, no. 12, pp. 721-735.

5. Guðbrandsdottir G., Hjelle K.M., Frugård J., Bostad L., Aarstad H.J., Beisland C. Preoperative high levels of serum vascular endothelial growth factor are a prognostic marker for poor outcome after surgical treatment of renal cell carcinoma. Scand. J. Urol., 2015, Vol. 49, no. 5, pp. 388-394.

6. Ha H., Debnath B., Neamati N. Role of the CXCL8-CXCR1/2 axis in cancer and inflammatory diseases. Theranostic, 2017, Vol. 7, no. 6, pp. 1543-1588. doi: 10.7150/thno.15625.

7. Jaillon S., Ponzetta A., di Mitri D., Santoni A., Bonecchi R., Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat. Rev. Cancer, 2020, Vol. 20, no. 9, pp. 485-503.

8. Kraus R.F., Gruber M.A. Neutrophils-from bone marrow to first-line defense of the innate immune system. Front. Immunol., 2021. Vol. 12, 767175. doi: 10.3389/fimmu.2021.767175.

9. Margaroli C., Cardenas M.A., Jansen C.S., Moon Reyes A., Hosseinzadeh F., Hong G., Zhang Y., Kissick H., Tirouvanziam R., Master V.A. The immunosuppressive phenotype of tumor-infiltrating neutrophils is associated with obesity in kidney cancer patients. Oncoimmunology, 2020, Vol. 9, no. 1, 1747731. doi: 10.1080/2162402X.2020.1747731.

10. Maskarinec S.A., McKelvy M., Boyle K., Hotchkiss H., Duarte M.E., Addison B., Amato N., Khandelwal S., Arepally G.M., Lee G.M. Neutrophil functional heterogeneity is a fixed phenotype and is associated with distinct gene expression profiles. J. Leukoc. Biol., 2022, Vol. 112, no. 6, pp. 1485-1495.

11. Rincón E., Rocha-Gregg B.L., Collins S.R. A map of gene expression in neutrophil-like cell lines. BMC Genomics, 2018, Vol. 19, no. 1, 573. doi: 10.1186/s12864-018-4957-6.

12. Sanmamed M.F., Carranza-Rua O., Alfaro C., Oñate C., Martín-Algarra S., Perez G., Landazuri S.F., Gonzalez A., Gross S., Rodriguez I., Muñoz-Calleja C., Rodríguez-Ruiz M., Sangro B., López-Picazo J.M., Rizzo M., Mazzolini G., Pascual J.I., Andueza M.P., Perez-Gracia J.L., Melero I. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin. Cancer Res., 2014, Vol. 20, no. 22, pp. 5697-5708.

13. Savchenko A.A., Borisov A.G., Kudryavtsev I.V., Gvozdev I.I., Moshev A.V. Immunophenotype and metabolism are linked in peripheral blood neutrophils from patients with kidney cancer. Medical Immunology (Russia), 2020, Vol. 22, no. 5, pp. 887-896.