Expression of growth factors and tyrosine kinase receptors in the primary tumor and tumor thrombus cells in patients with renal cell carcinoma

Abstract

Objective: to assess the expression and prognostic value of vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and their receptors VEGFR-1, -2; FGFR-1, -2, as well as platelet-derived growth factor receptors (PDGFR-α, PDGFR-β) in paired samples of primary tumors and tumor thrombi in renal cell carcinoma (RCC).Materials and methods. Expression of VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β was studied in paired surgical samples of primary tumors and tumor thrombi in 25 patients with clear cell RCC pT3a–T4N0–1M0–1 and tumor venous thrombosis by immunohistochemical assay using the appropriate Abcam/Santa Cruz Biotech antibodies from the immunohistochemical staining kit Invitrogen. Expression levels were evaluated by a semi-quantitative method (H-score). The analysis of the correlation between expression levels of VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β and RCC characteristics, as well as evaluation of their influence on the outcome of RCC were performed.Results. VEGF-A, FGF-2, as well as VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β were expressed in the cytoplasm and on the membrane of the primary tumor and tumor thrombus cells in RCC patients. Tumor thrombus cells were characterized by lower expression of VEGFR-1, VEGFR-2, PDGFR-α (p <0.05 for all) and tendency to lower expression of VEGF-A (p = 0.060), FGF-2 (p = 0.046), FGFR-1 (p = 0.077) and FGFR-2 (p = 0.090) compared with primary tumor cells. RCC Furman grade correlated with the expression levels of VEGFR-1 (p = 0.035) and FGFR-1 (p = 0.022) in the primary tumor cells, tumor invasion into venous wall correlated with the expression levels of VEGFR-1 (p = 0.023) and FGFR-2 (p = 0.005) on the thrombus cells. VEGFR-2 overexpression in the primary tumor cells was associated with significant decrease of overall survival (OS) rate (p = 0.011). There was a tendency to OS deterioration in cases with overexpression of VEGFR-2 (p = 0.093) and VEGF-A (p = 0.095) in the tumor thrombus cells. One-year OS in patients with ³2 identified risk factors was 27.3 %, <2 risk factors – 87.5 % (p = 0.004).Conclusion. Tumor thrombus cells in RCC patients expressed VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β less active than the cells of the primary tumor. Overexpression of growth factors and tyrosine kinases correlated with RCC Furman grade and tumor venous wall invasion. Overexpression of VEGFR-2 in both primary tumor and thrombus cells in combination with hypoexpression of VEGF-A in the thrombus negatively influenced on OS.

Fibrinogen Levels in Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab: Results of a Multicenter Prospective Trial

“…More importantly, fibrinogen, which is synthesized by cancer cells, promotes the proliferation of fibroblast growth factor-2 (FGF2) [25]. In turn, activation of the FGF-FGFR pathway stimulates the pathogenesis of RCC and is a possible mechanism of resistance to immunotherapy [26][27][28][29]. The studies of fibrinogendeficient mice suggest that fibrinogen plays an important role in spontaneous metastasis, facilitating the stable adhesion and/or survival of metastatic emboli after tumor cell intravasation [30].…”

Molecular mechanisms of resistance to tyrosine kinase inhibitor in clear cell renal cell carcinoma

“… 67 A recent study analyzed the expression of FGF2 and FGFR2 by immunohistochemical analysis in RCC. 68 FGF2 and FGFR2 expression were observed in about 60% and 66% of RCC patients, respectively. Another study anayzed the expression of FGF2 by immunohistchemical analysis.…”