Date Published: July 9, 2017
Author(s): Nadine Gelbrich, Hannes Ahrend, Anne Kaul, Lars-Ove Brandenburg, Uwe Zimmermann, Alexander Mustea, Martin Burchardt, Denis Gümbel, Matthias B. Stope.
Cytokines and chemokines are widely involved in cancer cell progression and thus represent promising candidate factors for new biomarkers.
Four renal cell cancer (RCC) cell lines (Caki-1, 786-O, RCC4, and A498) and a nonmalignant renal cell line (RC-124) were examined with respect to their proliferation. The cytokine and chemokine expression pattern was examined by a DNA array (Human Cytokines & Chemokines RT2 Profiler PCR Array; Qiagen, Hilden, Germany), and expression profiles were compared.
Caki-1 and 786-O cells exhibited significantly increased proliferation rates, whereas RCC4 and A498 cells demonstrated attenuated proliferation, compared to nonmalignant RC-124 cells. Expression analysis revealed 52 cytokines and chemokines primarily involved in proliferation and inflammation and differentially expressed not only in malignant and nonmalignant renal cells but also in the four RCC cell lines.
This is the first study examining the expression of 84 cytokines and chemokines in four RCC cell lines compared to that in a nonmalignant renal cell line. VEGFA, NODAL, and BMP6 correlated with RCC cell line proliferation and, thus, may represent putative clinical biomarkers for RCC progression as well as for RCC diagnosis and prognosis.
Renal cell cancer (RCC) represents the deadliest neoplasm of the urinary tract, due to the fact that a majority of patients are diagnosed at a very advanced stage [1, 2]. Tumor progression is based on various molecular mechanisms, and thus, further examinations of RCC tumor biology are necessary in order to understand the progression and, furthermore, to identify novel biomarkers for diagnosis and prognosis of RCC [1, 3–5].
In contrast to the elevated proliferation rates of Caki-1 and 786-O cells compared to those of nonmalignant RC-124 cells, both, RCC4 and A498 cells, showed a markedly reduced cell growth (Figure 1). These differences in proliferation prompted us to investigate whether cytokines and chemokines may control the individual growth properties of the RCC cell lines.
The process of tumorigenesis is driven by several mechanisms including an increased proliferation, angiogenesis, and immunomodulation . Cytokines and chemokines, in general, are primarily regulators of immune defense. CCL5, in particular, supports leukocyte diapedesis by integrin induction [14, 15]. Interestingly, CCL5 expression in all four RCC cell lines was highly upregulated. Since tumorigenesis is associated with inflammatory response, elevated CCL5 secretion by RCC cells may be part of cancer-related inflammation. Corresponding to this observation is the finding that the expression levels of proinflammatory interleukins IL1A and IL1B are increased in all of the four RCC cell lines. Interestingly, overexpression of the anti-inflammatory IL1RN  could only be observed in the lowly proliferative RCC4 and A498 cells. This could mean that IL1RN may interfere with antiproliferative pathways or that anti-inflammatory processes generally attenuate cell growth.