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Fulltext Circulating biomarkers associated with placental dysfunction and their utility for predicting fetal growth restriction

Hong J, Kumar S

Clin Sci (Lond), 2023 Apr 26;137(8):579-595.
PMID: 37075762 DOI: 10.1042/CS20220300

Fetal growth restriction (FGR) leading to low birth weight (LBW) is a major cause of neonatal morbidity and mortality worldwide. Normal placental development involves a series of highly regulated processes involving a multitude of hormones, transcription factors, and cell lineages. Failure to achieve this leads to placental dysfunction and related placental diseases such as pre-clampsia and FGR. Early recognition of at-risk pregnancies is important because careful maternal and fetal surveillance can potentially prevent adverse maternal and perinatal outcomes by judicious pregnancy surveillance and careful timing of birth. Given the association between a variety of circulating maternal biomarkers, adverse pregnancy, and perinatal outcomes, screening tests based on these biomarkers, incorporating maternal characteristics, fetal biophysical or circulatory variables have been developed. However, their clinical utility has yet to be proven. Of the current biomarkers, placental growth factor and soluble fms-like tyrosine kinase 1 appear to have the most promise for placental dysfunction and predictive utility for FGR.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1
Fulltext Serum soluble FMS-like tyrosine kinase 1 and placental growth factor concentration as predictors of preeclampsia in high risk pregnant women

Hanita O, Alia NN, Zaleha AM, Nor Azlin MI

Malays J Pathol, 2014 Apr;36(1):19-26.
PMID: 24763231 MyJurnal

Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) contribute in the development of preeclampsia and are suggested as prediction markers in healthy pregnant women but limited data is available in women with major preeclampsia risk factors. This study aimed to determine the role of sFlt-1 and PlGF in predicting preeclampsia among high risk pregnant women. This was a prospective study and samples were collected for a period of ten months. Blood samples were obtained from 84 pregnant women who had at least one risk factor for preeclampsia at 25 to 28 weeks and at 29 to 36 weeks of gestation. SFlt-1 and PlGF concentrations were determined by immunoassay method. There were significantly higher median sFlt-1 and sFlt-1:PlGF ratio at gestational interval 25 to 28 weeks and sFlt-1:PlGF ratio at 29 to 36 weeks in high risk women who developed preeclampsia. Significant lower median serum PlGF levels at 25 to 28 weeks and 29 to 36 weeks were observed in this group of women. In conclusion, the concentrations of these markers were altered in high risk preeclamptic women, a similar pattern seen in low risk preeclamptic women. However the predictive value of these markers could not be established clearly.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1/blood*
Maternal plasma soluble fms-like tyrosine kinase-1 and placental growth factor levels as biochemical markers of gestational hypertension for Malaysian mothers

Nadarajah VD, Min RG, Judson JP, Jegasothy R, Ling EH

J Obstet Gynaecol Res, 2009 Oct;35(5):855-63.
PMID: 20149032 DOI: 10.1111/j.1447-0756.2009.01037.x

To establish baseline levels of maternal plasma soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) among normotensive Malaysian mothers and to compare the marker levels between normotensives and mothers with gestational hypertension (GH).

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1/blood*
Expression of Vascular Endothelial Growth Factor and Its Receptors in Thyroid Nodular Hyperplasia and Papillary Thyroid Carcinoma: A Tertiary Health Care Centre Based Study

Mohamad Pakarul Razy NH, Wan Abdul Rahman WF, Win TT

Asian Pac J Cancer Prev, 2019 Jan 25;20(1):277-282.
PMID: 30678450

Introduction: Vascular endothelial growth factor (VEGF) is an angiogenic factor that plays an important role in
thyroid cancer. VEGF is known to have high affinity to VEGF receptors such as VEGFR-1 (Flt-1) and VEGFR-2 (KDR).
Papillary thyroid carcinoma (PTC) is the most common thyroid cancer and studies showed the increasing incidence of
PTC arising in nodular hyperplasia. Targeted therapy on these growth factors and receptors are used in management
of both differentiated and undifferentiated thyroid carcinoma. This study aims to determine the expression of VEGF
and VEGF receptors (VEGFR) in thyroid nodular hyperplasia and PTC. Methods: A cross-sectional study based on
paraffinized archival tissue blocks of 113 nodular hyperplasias and 67 PTC from the thyroidectomy specimens in
the year of 2003 to 2014. The tissue sections were then stained by immunohistochemistry for VEGF, VEGFR-1 and
VEGFR-2. The lymph node involvement and extrathyroid extension also were determined. Results: The mean age of
PTC patients was 44.7±15.8 years and nodular hyperplasia were 42.2±13.6 years. There was a statistical difference
of VEGFR-1 (p=0.028) and VEGFR-2 (p=0.003) expression between nodular hyperplasia and PTC. However, no
significant difference of VEGF expression (p=0.576) between both diseases. Co-expression of VEGF and VEGFR-1
was significant in both nodular hyperplasia (p=0.016) and PTC (p=0.03), meanwhile no relevant relationship for VEGF
and VEGFR-2 expression (p>0.05). No significant association (p>0.05) between lymph node status and extrathyroid
extension with age groups, gender, VEGF and VEGFR expression. Conclusions: VEGF, VEGFR-1 and VEGFR-2
showed overexpression in both nodular hyperplasia and PTC. The expression of VEGFR-1 and VEGFR-2 are more
significant in PTC with relevant co-expression of VEGF and VEGFR-1. Therefore, the inhibition of VEGFR offers a
promising prospect for tumour management in thyroid carcinoma.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1/metabolism
Fulltext Soluble Flt-1 gene delivery in acute myeloid leukemic cells mediating a nonviral gene carrier

Amini R, Azizi Jalilian F, Veerakumarasivam A, Abdullah S, Abdulamir AS, Nadali F, et al.

Biomed Res Int, 2013;2013:752603.
PMID: 23509773 DOI: 10.1155/2013/752603

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in angiogenesis-mediated progression of acute myeloid leukemia (AML). Studies have reported the role of soluble form of fms-like tyrosine kinase (sFlT-1) delivery as an antitumor agent by inhibiting VEGF. This study investigates the outcome of delivery of a VEGF165 antagonist, soluble vascular endothelial growth factor receptor, namely sFLT-1, mediating lipofectamine 2000 in acute myeloid leukemic cells. A recombinant plasmid expressing sFLT-1 was constructed and transfected into the K562 and HL60 cells using lipofectamine 2000 transfection reagent. sFLT-1 expression/secretion in pVAX-sFLT-1 transfected cells was verified by RT-PCR and western blot. MTS assay was carried out to evaluate the effect of sFLT-1 on human umbilical vein endothelial cells and K562 and HL60 cells in vitro. Treatment with pVAX-sFLT-1 showed no association between sFLT-1 and proliferation of infected K562 and HL60 cells, while it demonstrated a significant inhibitory impact on the proliferation of HUVECs. The results of the current study imply that the combination of nonviral gene carrier and sFLT-1 possesses the potential to provide efficient tool for the antiangiogenic gene therapy of AML.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1/genetics*
Fulltext Periodic assessment of plasma sFlt-1 and PlGF concentrations and its association with placental morphometry in gestational hypertension (GH) - a prospective follow-up study

Jeevaratnam K, Nadarajah VD, Judson JP, Nalliah S, Abdullah MF

BMC Pregnancy Childbirth, 2010;10:58.
PMID: 20920154 DOI: 10.1186/1471-2393-10-58

Hypertensive disorders in pregnancy contributes to about 12% of maternal deaths in Malaysia and similarly worldwide. Early detection and adequate management are preventable strategies. Biochemical markers of abnormal angiogenesis would be more specific in early detection than routine blood pressure and proteinuria measurements. The aim of this study was to estimate maternal plasma PlGF and sFlt-1 levels in pregnant women with gestational hypertension at three intervals of pregnancy and correlate these biomarker levels with placental morphometry.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1/blood*
Vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and genistein-induced changes in the vascular reactivity of rat's aorta

Fernandez AR, Husain R

J Obstet Gynaecol Res, 2015 Feb;41(2):277-82.
PMID: 25255906 DOI: 10.1111/jog.12511

During preeclampsia (PE), the excessive circulation of soluble fms-like tyrosine kinase 1 (sFLT1) hinders the vasodilatory effect of vascular endothelial growth factor (VEGF). This effect has been proven in vitro in the renal artery of rats. The endothelium of the blood vessels is also said to be dysfunctional in PE. Genistein has shown the ability to antagonize the vascular contractions caused by a wide range of contractile agents. We conducted vascular reactivity studies to demonstrate the effect of: (i) sFLT1 on the vasodilatory effect of VEGF; and (ii) genistein on the vasodilatory effect of VEGF and its effects on denuded blood vessels (dysfunctional endothelium).

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1
Fulltext Microvessel density and vascular endothelial growth factor receptors in breast carcinoma under the influence of rapamycin and platelet factor 4

Muhammad Sakri MS, Abdul Rahman WFW, Tengku Din TADA, Idris FM, Jaafar H

Indian J Pathol Microbiol, 2020 4 23;63(2):205-209.
PMID: 32317516 DOI: 10.4103/IJPM.IJPM_496_19

Background: Vascular endothelial growth factor receptors (VEGFRs) are major endothelial growth factor receptors that influence the growth of a tumor. Microvessel density.
(: MVD) is the quantification method of various aspects of tumor vasculature that indicates angiogenic activity. This study aims to analyze the correlation between MVD to the expression of VEGFRs on breast cancer tissue.
Materials and Method: A total of 60 N-methyl-N-nitrosourea (MNU)-induced breast carcinomas in rats were suppressed by using antiangiogenic drugs. The rats were then sacrificed, and the tumor was fixed in 10% formalin, paraffin embedded, and immunohistochemistry stained using VEGFRs and CD34.
Result: One-way ANOVA test showed a significant difference in all markers that have been used (P < 0.05) on MNU-breast tumor treated with rapamycin (M= 90.1664, SD= 7.4487), PF4 (M= 93.7946, SD= 7.1303) and rapamycin + PF4 (M= 93.6990, SD= 1.8432). We obtained a significant reduction of MVD count on breast carcinoma for rapamycin group (M= 25.6786, SD= 9.7075) and rapamycin + PF4 group (M= 30.5250, SD= 13.6928) while PF4 group (M=47.7985, SD=4.8892) showed slightly increase compared to control (M= 45.1875, SD= 4.4786). There was a moderately strong, positive correlation between angiogenic markers; Flt-1 (r= 0.544, n=60, P < 0.005) and Flt-4 (r= 0.555, n= 60, P < 0.005) while Flk-1 (r= 0.797, n= 60, P < 0.005) showed a strong, positive correlation with MVD.
Conclusion: MVD was strongly correlated to the VEGFRs expression on breast carcinoma.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1/genetics
Gene expression profiling of giant fibroadenomas of the breast

Yin Lee JP, Thomas AJ, Lum SK, Shamsudin NH, Hii LW, Mai CW, et al.

Surg Oncol, 2021 Jun;37:101536.
PMID: 33677364 DOI: 10.1016/j.suronc.2021.101536

INTRODUCTION: Fibroadenomas of the breast present as two phenotypic variants. The usual variety is 5 cm or less in diameter and there is another large variant called giant fibroadenoma which is greater than 5 cm in diameter. Despite of its large size, it is not malignant. The aim of our study is to determine whether this large variant is different from the usual fibroadenoma in terms of its biological pathways and biomarkers.
METHODS: mRNA was extracted from 44 fibroadenomas and 36 giant fibroadenomas, and transcriptomic profiling was performed to identify up- and down-regulated genes in the giant fibroadenomas as compared to the fibroadenomas.
RESULTS: A total of 40 genes were significantly up-regulated and 18 genes were significantly down-regulated in the giant fibroadenomas as compared to the fibroadenomas of the breast. The top 5 up-regulated genes were FN1, IL3, CDC6, FGF8 and BMP8A. The top 5 down-regulated genes were TNR, CDKN2A, COL5A1, THBS4 and BMPR1B. The differentially expressed genes (DEGs) were found to be associated with 5 major canonical pathways involved in cell growth (PI3K-AKT, cell cycle regulation, WNT, and RAS signalling) and immune response (JAK-STAT signalling). Further analyses using 3 supervised learning algorithms identified an 8-gene signature (FN1, CDC6, IL23A, CCNA1, MCM4, FLT1, FGF22 and COL5A1) that could distinguish giant fibroadenomas from fibroadenomas with high predictive accuracy.
CONCLUSION: Our findings demonstrated that the giant fibroadenomas are biologically distinct to fibroadenomas of the breast with overexpression of genes involved in the regulation of cell growth and immune response.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1
Fulltext Vascular Endothelial Growth Factor A (VEGF-A) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) as Potential Biomarkers for Oral Squamous Cell Carcinoma: A Sri Lankan Study

Edirisinghe ST, Weerasekera M, De Silva DK, Devmini MT, Pathmaperuma S, Wijesinghe GK, et al.

Asian Pac J Cancer Prev, 2023 Jan 01;24(1):267-274.
PMID: 36708576 DOI: 10.31557/APJCP.2023.24.1.267

BACKGROUND: The incidence of oral squamous cell carcinoma (OSCC) is very high in South Asia and Vascular endothelial growth factor (VEGF) is one of the key factors essential for cancer growth. The importance of VEGF-A and VEGF Receptor 2(VEGFR-2) in oral cancer pathophysiology is yet to be decided. Vascular Endothelial Growth Factor A (VEGF-A) is the main factor concerned in angiogenesis in tumors, but its role in Oral Squamous Cell Carcinoma (OSCC) is still debatable. Our study aimed to determine the role of VEGF-A and VEGFR-2 in OSCC.
METHODS: Blood from 30 patients with primary OSCC and 1:1 age-sex-matched controls was subjected to qPCR and ELISA to detect VEGF-A gene expression and serum level. Tumors of the 30 patients were investigated for VEGF Receptor-2 (VEGFR-2) expression and were analyzed using Image J software version 1.52 for DAB percentage (DAB-P) area and optical density (OD).
RESULTS: VEGF-A relative gene expression among patients was 2.43-fold higher compared to the healthy control group. Well-differentiated had a 1.98-fold increment, while poorly differentiated had a 3.58-fold increment. Serum VEGF-A was significantly elevated among the patients compared to controls (458.7 vs 253.2, p=0.0225). Poorly differentiated had a higher serum VEGF concentration (1262.0±354.7pg/ml) compared with other two. Mean VEGFR-2 DAB-P level in OSCC was 42.41±5.61(p=0.15). Well-differentiated had a DAB-P of 41.20±5.32 while poorly differentiated had DAB-P 46.21±3.78. The mean OD in OSCC was 0.54±0.16. VEGFR-2 OD in well and poorly differentiated OSCC were 0.48±0.12 and 0.68±0.17, respectively.
CONCLUSIONS: VEGF-A gene expression, serum levels, and tissue VEGFR-2 levels correlated linearly with the stage and grade of the tumor. This study justifies the value of VEGF-A as a potential biomarker in OSCC in early detection of OSCC. More studies are needed to accept the use of VEGF-A.

Matched MeSH terms: Vascular Endothelial Growth Factor Receptor-1