Ekspresija hemokinske osovine CXCL12/CXCR4/CXCR7, markera hipoksije i angiogeneze u karcinomima bubrežnog parenhima

Abstract

Renal cell carcinoma (RCC) is the most common kidney cancer. Even though it represents 5% of all cancer diagnosis, it is considered one of the most lethal urologic malignancies. The most common subtype is clear cell RCC and the second in frequency is papillary RCC. At diagnosis 23% of patients already have metastatic disease and 25% will develop metastases within five years from nephrectomy. Up to date, all the factors that affect the development and prognosis of these tumors are still not fully clarified. Over the last decade, various biomarkers have been studied in order to elucidate the behavior of RCC but no consensus has been achieved. In this study we immunohistochemically examined the expression of chemokine CXCL12 and its receptors CXCR4 and CXCR7 on 98 paraffin embedded RCC samples obtained after radical nephrectomy. We have also studied the expression of Hypoxia inducible factor 1α, which regulates cell survival in hypoxic conditions, and Notch1 receptor, which is the component of the conservative Notch signaling pathway. The localization, percentage and the intensity of the expression of these biomarkers were studied with the application of histoscore. We analyzed their co-expression and their association with clinical and pathological parameters and survival of the patients. Positive membranous and cytoplasmatic CXCL12 and CXCR7 expression was present in over 90% of the samples, while about 60% expressed positive CXCR4 staining.We found association between tumor size and higher cytoplasmatic CXCL12 and CXCR7 expression. Over 70% of the samples were HIF1α positive, and higher values of cytoplasmatic HIF1α histoscore were associated with higher tumor grade. We also found the association between necrosis and cytoplasmatic CXCR7, HIF1α and Notch1 histoscore. Compared to ccRCC in pRCC significantly higher values of membranous CXCL12 as well as cytoplasmatic CXCL12, CXCR4, CXCR7 and HIF1α histoscore can be expected. CCRCC has 4 times higher probability of positive membranous CXCR4 expression and 20 times higher probability of positive membranous Notch1 eexpression. H higher membranous Notch1 histoscore is expected in cccRCC as well. Strong positive correlation was found between cyoplasmatic HIF1α histoscore and cytoplasmatic CXCL12 and CXCR7 histoscores, suggesting their co expression and potential interaction. Shorter survival can be predicted by higher clinical stage, the value of CXCL12 cytoplasmatic histoscore above 73 and by higher values of membranous CXCR7 histoscore. Examining the roles of these biomarkers in RCC could in the future bring useful implications in diagnosis, prognosis, prevention of the recidives and the development of target therapy in the most lethal urologic malignancy.