Pre-Therapeutic VEGF Level in Plasma Is a Prognostic Bio-Marker in Head and Neck Squamous Cell Carcinoma (HNSCC)

Abstract

Vascular endothelial growth factor (VEGF) is centrally involved in cancer angiogenesis. We hypothesized that pre-therapeutic VEGF levels in serum and plasma differ in their potential as biomarkers for outcomes in head and neck squamous cell carcinoma (HNSCC) patients. As prospectively defined in the study protocols of TRANSCAN-DietINT and NICEI-CIH, we measured VEGF in pretreatment serum and plasma of 75 HNSCC test cohort (TC) patients. We analyzed the prognostic value of VEGF concentrations in serum (VEGFSerum) and plasma (VEGFPlasma) for event-free survival (EFS) utilizing receiver-operating characteristics (ROC). Mean VEGF concentrations in plasma (34.6, 95% CI 26.0–43.3 ng/L) were significantly lower (p = 3.35 × 10−18) than in serum (214.8, 95% CI 179.6–250.0 ng/L) but, based on ROC (area under the curve, AUCPlasma = 0.707, 95% CI 0.573–0.840; p = 0.006 versus AUCSerum = 0.665, 95% CI 0.528–0.801; p = 0.030), superiorly correlated with event-free survival (EFS) of TC patients. Youden indices revealed optimum binary classification with VEGFPlasma 26 ng/L and VEGFSerum 264 ng/L. Kaplan–Meier plots demonstrated superiority of VEGFPlasma in discriminating patients regarding outcome. Patients with VEGFPlasma < 26 ng/L had superior nodal (NC), local (LC) and loco-regional control (LRC) leading to significant prolonged progression-free survival (PFS) and EFS. We successfully validated VEGFPlasma according the cut-off <26 ng/L as predictive for superior outcome in an independent validation cohort (iVC) of 104 HNSCC patients from the studies DeLOS-II and LIFE and found better outcomes including prolonged tumor-specific (TSS) and overall survival (OS). Outcomes in TC and iVC combined again was related to VEGFPlasma, and multivariate Cox regression revealed that VEGFPlasma was an independent outcome predictor. In HNSCC, pre-therapeutic VEGFPlasma is prognostic for outcomes.

MAPKAPK2-centric transcriptome profiling reveals its major role in governing molecular crosstalk of IGFBP2, MUC4, and PRKAR2B during HNSCC pathogenesis

“…4 b portrays the regulatory network that represents the MAPK signaling cluster of the selected MK2 pathway genes (AUF1, CEBPδ, CUGBP1, HuR, MK2, MKP-1, p27, p38, TNF-α, TTP, and VEGF) in the transcriptome profiling data of the in vitro HNSCC cell line dataset (B vs A, normoxic microenvironment) indicated TNF-α and VEGF downregulation. Interestingly, the transcriptomic profiling results are in complete consonance with our recently published findings and hence succeed in potentiating and validating the hypothesis that MK2-knockdown destabilized TNF-α and VEGF in normoxia via RBP-mediated interactions [5] , [66] , [67] , [68] , [69] , [70] , [71] , [72] .…”

RNA-sequencing manifests the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis

“…Similarly, Figure 4b portrays the regulatory network that represents the MAPK signaling cluster of the selected MK2 pathway genes (AUF1, CEBP, CUGBP1δ, HuR, MK2, MKP-1, p27, p38, TNF-α, TTP, and VEGF) in the transcriptome profiling data of the in vitro HNSCC cell line dataset (B vs A, normoxic microenvironment) indicated TNF-α and VEGF downregulation. Interestingly, the transcriptomic profiling results are in complete consonance with our recently published findings and hence succeed in potentiating and validating the hypothesis that MK2-knockdown destabilized TNF-α and VEGF in normoxia via RBP-mediated interactions [5, 65, 66, 67, 68, 69, 70, 71, 72].…”

Immunomodulatory Therapy in Head and Neck Squamous Cell Carcinoma: Recent Advances and Clinical Prospects

“…The overexpression of VEGF is also associated with COX-2 expression suggesting the possible role of COX inhibitors as an adjuvant in VEGF mutated HNSCC. 110 STAT family of proteins are majorly responsible for various host responses. The upregulation of STAT-3 is seen in all cases of drug resistant HNSCC.…”

“…The overexpression of VEGF is also associated with COX-2 expression suggesting the possible role of COX inhibitors as an adjuvant in VEGF mutated HNSCC. 110 …”