The significance of combining VEGFA, FLT1, and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab

Zhang, Shudong; McCrudden, Cian M.; Meng, Chen; Lin, Yao; Kwok, Hang Fai

doi:10.2147/ott.s80518

Cited by 19 publications

(12 citation statements)

References 43 publications

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“…Similarly, mixed results have also been observed in phase III trials in lung 34 , 35 and colon cancers 36 , 37 . Together with our previous findings in lung and colon cancer patient cohorts 28 , 29 , our results suggest that this three-gene signature may have clinical application in terms of predicting response towards anti-angiogenic agents in various types of cancer, and that this warrants further clinical evaluation, especially in a prospective trial setting.…”

Section: Discussionsupporting

confidence: 82%

“…Interestingly, in the present study, we have shown that co-expression of these genes also confers prognostic significance in glioma, suggesting that VEGFA - FLT1 - KDR three-gene signature may be a potential prognostic indicator for glioma patients. We previously reported that expression profiling of this three-gene signature could also predict response to bevacizumab in colon cancer patients 29 . Bevacizumab is an anti-angiogenic agent that has also been shown to be effective in glioblastoma patients; as no dataset comprising glioblastoma patients who have received bevacizumab exist in the public domain, and as there is also a lack of success in identification of biomarker for anti-angiogenic agents 30 , the value of this three-gene signature for prediction of response to bevacizumab in glioblastoma patients warrants further investigation.…”

Section: Discussionmentioning

confidence: 98%

“…Anti-angiogenesis has been shown to be an effective strategy in treatment of patients with glioblastoma, the most aggressive type of glioma. Previously, we have shown that the co-overexpression of VEGFA and its receptors, FLT1 and KDR , is associated with poor prognosis in both lung and colon cancers 28 , 29 , malignancies that benefit from anti-angiogenesis therapy. Interestingly, in the present study, we have shown that co-expression of these genes also confers prognostic significance in glioma, suggesting that VEGFA - FLT1 - KDR three-gene signature may be a potential prognostic indicator for glioma patients.…”

Section: Discussionmentioning

confidence: 99%

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The Prognostic Significance of Combining VEGFA, FLT1 and KDR mRNA Expressions in Brain Tumors

Zhang¹,

Leung²,

McCrudden³

et al. 2015

J. Cancer

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Tumor cells require angiogenesis to deliver nutrients and oxygen to support their fast growth and metabolism. The vascular endothelial growth factor (VEGF) pathway plays an important role in promoting angiogenesis, including tumor-induced angiogenesis. Recent clinical trials have demonstrated the benefit of targeting VEGF in the treatment of glioblastoma. However, the prognostic significance of the expression of VEGFA and its receptors VEGFR1 (FLT1) and VEGFR2 (KDR) are still largely elusive. In the present study, we aimed to investigate the prognostic significance of these three factors, alone or in combination, in glioma patients. Gene mRNA expression was extracted from three independent brain tumor cohorts totaling 242 patients and the association between gene expression and survival was tested. We found that when VEGFA, FLT1 and KDR expressions were considered alone, only VEGFA demonstrated a significant association with patient survival. Patients with high expression of both VEGFA and either receptor had significantly worse survival than patients expressing both factors at a low level. Importantly, we found that those patients whose tumors overexpressed all three genes had a significantly shorter survival compared to those patients with a low level expression of these genes. Our results suggest that a high level expression of VEGFA and its receptors, both FLT1 and KDR, may be required for brain tumor progression, and that these three factors should be considered together as a prognostic indicator for brain tumor patients.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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The Prognostic Significance of Combining VEGFA, FLT1 and KDR mRNA Expressions in Brain Tumors

Zhang¹,

Leung²,

McCrudden³

et al. 2015

J. Cancer

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“…Sox10 is a member of the SOX transcription factor family, which regulates canonical Wnt/β-catenin signaling; therefore, elevated Sox10 expression has been suggested to promote tumor progression [34]. Kdr(Vegfr2) plays a crucial role in colon cancer progression; thus, heightened Kdr expression can predict a poor prognosis in colon cancer patients [35]. Mcm2 regulates DNA replication; therefore, an enhanced Mcm complex including Mcm2 has been suggested to regulate various types of tumor development [36].…”

Section: Resultsmentioning

confidence: 99%

Differential expression of tumor-associated genes and altered gut microbiome with decreased Akkermansia muciniphila confer a tumor-preventive microenvironment in intestinal epithelial Pten-deficient mice

Howe

Kim

Mitchell

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Phosphatase and tensin homolog (Pten) antagonizes PI3K-Akt signaling; therefore, Pten impairment causes tumorigenesis. However, the correlation between Pten deficiency and colon cancer has remained elusive due to numerous opposite observations. To study this correlation, we examined whether Pten deficiency in intestinal epithelial cells (IECs) induces tumorigenesis. With mucosal biopsies of human colon cancer and normal colon, Pten mRNA was evaluated by quantitative PCR. Using IEC-specific Pten knockout mice (PtenΔIEC/ΔIEC), we examined the mitotic activity of IECs; and PtenΔIEC/ΔIEC; Apcmin/+ mice were generated by combining PtenΔIEC/ΔIEC with Apcmin/+ mice. Tumor-associated gene was evaluated by micro-array analysis. Fecal microbiome was analyzed through 16S rRNA gene sequencing. We found that Pten mRNA level was reduced in human colon cancer relative to normal tissues. Augmented chromatids, increased Ki-67 and PCNA expression, and enhanced Akt activation were identified in IECs of PtenΔIEC/ΔIEC mice compared to Pten+/+ littermate. Combining PtenΔIEC/ΔIEC with Apcmin/+ condition caused rapid and aggressive intestinal tumorigenesis. However, PtenΔIEC/ΔIEC mice did not develop any tumors. While maintaining the tumor-driving potential, these data indicated that IEC-Pten deficiency alone did not induce tumorigenesis in mice. Furthermore, the expression of tumor-promoting and tumor-suppressing genes was decreased and increased, respectively, in the intestine of Pten ΔIEC/ΔIEC mice compared to controls. The abundance of Akkermansia muciniphila, capable of inducing chronic intestinal inflammation, was diminished in PtenΔIEC/ΔIEC mice compared to controls. These findings suggested that altered tumor-associated gene expression and changed gut microbiotashape a tumor-preventive microenvironment to counteract the tumor-driving potential, leading to the tumor prevention in PtenΔIEC/ΔIEC mice.

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“…Therefore, the expression of this three-gene signature ( VEGFA , VEGFR1 , and VEGFR2 ) was reported to represent robust prognostic indicator in this patient population. 40 …”

Section: Biomarkers Of Angiogenesismentioning

confidence: 99%

Biomarkers of Angiogenesis in Colorectal Cancer

2015

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Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 10% of all new cancer diagnoses. Angiogenesis is a tightly regulated process that is mediated by a group of angiogenic factors such as vascular endothelial growth factor and its receptors. Given the widespread use of antiangiogenic agents in CRC, there has been considerable interest in the development of methods to identify novel markers that can predict outcome in the treatment of this disease with angiogenesis inhibitors. Multiple biomarkers are in various phases of development and include tissue, serum, and imaging biomarkers. The complexity of the angiogenesis pathway and the overlap between the various angiogenic factors present a significant challenge to biomarker discovery. In our review, we discuss the angiogenesis pathway and the most promising evolving concepts in biomarker discovery, as well as highlight the landmark studies that identify subgroups of patients with CRC who may preferentially benefit from angiogenesis inhibitors.

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The significance of combining VEGFA, FLT1, and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab

Cited by 19 publications

References 43 publications

The Prognostic Significance of Combining VEGFA, FLT1 and KDR mRNA Expressions in Brain Tumors

The Prognostic Significance of Combining VEGFA, FLT1 and KDR mRNA Expressions in Brain Tumors

Differential expression of tumor-associated genes and altered gut microbiome with decreased Akkermansia muciniphila confer a tumor-preventive microenvironment in intestinal epithelial Pten-deficient mice

Biomarkers of Angiogenesis in Colorectal Cancer

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