Abstract
Tumor microenvironment including endothelial and immune cells plays a crucial role in tumor progression and has been shown to dramatically influence cancer survival. In this study, we investigated the clinical relevance of the gene expression of key mediators of angiogenesis, VEGF isoforms 121, 165, and 189, and their receptors (VEGFR-1 and R-2) in a cohort of patients (n = 37) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL). In patients with ABC-like DLBCL, but not in patients with GCB-like DLBCL, low VEGF121 expression was associated with a significantly better survival than in those with high VEGF121 level: 4-year overall survival at 100% vs 36% (p = .011), respectively. A specific gene signature including 57 genes was correlated to VEGF121 expression level and was analyzed using a discovery process in 1,842 GSE datasets of public microarray studies. This gene signature was significantly expressed in other cancer datasets and was associated with immune response. In conclusion, low VEGF121 expression level was significantly associated with a good prognosis in relapsed/refractory ABC-like DLBCL, and with a well-conserved gene-expression profiling signature related to immune response. These findings pave the way for rationalization of drugs targeting immune response in refractory/relapsed ABC-like DLBCL.
Highlights
Tumor microenvironment plays a major role in tumor growth, with key players including immune cells, stromal cells, extracellular matrix and angiogenesis [1]
Low level of soluble VEGF121 mRNA is significantly associated with a better prognosis in Activated B-Cell like (ABC)-like diffuse large B-cell lymphoma (DLBCL)
In patients with ABC-like DLBCL, low VEGF121 level was associated with a significantly better survival than in those with high VEGF121 level: 4 year-progression-free survival (PFS) at 57% vs 27%, p = .0533 and 4-year overall survival (OS) at 100% vs 36% (p = .0111)
Summary
Tumor microenvironment plays a major role in tumor growth, with key players including immune cells, stromal cells, extracellular matrix and angiogenesis [1]. Angiogenesis is precisely regulated by genes encoding for the vascular endothelial growth factor (VEGF) and its receptors (VEGFR). VEGF (referred to as VEGF-A) belongs to a gene family that includes placenta growth factor (PlGF), VEGF-B, VEGF-C, and VEGF-D [2]. VEGF mRNA is expressed in the vast majority of human tumors, including lung, breast, gastrointestinal tract, kidney, bladder, ovary, and endometrium carcinoma and several intracranial tumors including glioblastoma (see [3] for review). In the last 10 years, the clinical impact of VEGF expression has been a breakthrough, with an important link between tumor angiogenesis and survival, and the demonstration of a clinical benefit in inhibiting VEGF, increasing survival in patients with advanced malignancies
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