Vascular Endothelial Growth Factor (VEGF-C) Signaling Through KDR (VEGFR-2) and FLT- 4 (VEGFR-3) Mediates Leukemic Cell Proliferation and Survival
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- Category: Vol. 77, June 2009
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Vascular Endothelial Growth Factor (VEGF-C) Signaling Through KDR (VEGFR-2) and FLT- 4 (VEGFR-3) Mediates Leukemic Cell Proliferation and Survival,MANAL EL-MASRY, HANAN N. RASLAN, DINA RASHEED, NIHAL SALAH, MAI SHERIF and AHMAD AMIN
Abstract
VEGF, a key angiogenic molecule, is a multifunctional cytokine that acts both as a potent inducer of vascular perme-ability and as a specific endothelial cell mitogen. Because of its effects on endothelial cell growth and microvascular permeability, VEGF is believed to be an important mediator of tumor angiogenesis. Leukemic cells not only release VEGF but also express its receptors, resulting in the establishment of an autocrine loop that supports their migration and survival. VEGF-C may play an important role in the pathophysiology of hematopoietic malignancies by not only regulation of lymphangiogenesis in vivo, but also by promotion of angio-genesis, invasion of neoplastic cells into lymphatic vessels and enhancing lymphatic metastasis during tumor progression.
Although it is well established that growth in solid tumors is dependent on the formation of neovasculature, the role of angiogenesis in hematopoietic neoplasms has not been deter-mined. The present study was undertaken to identify whether VEGF-C and its receptors VEGFR-2 (KDR) and VEGFR-3 (FLT-4) were expressed in patients with denovo acute leukemia by RT-PCR and to evaluate the relationship between their expression and clinical, laboratory findings and prognosis.
Using reverse transcription polymerase chain reaction analysis (RT-PCR), 30 de novo acute leukemia patients (20 ALL patients and 10 AML patients) as well as 10 controls were tested for the expressions of VEGF-C, VEGFR-3 (FLT-4) and VEGFR-2 (KDR) genes.
In the current study, VEGF-C, FLT-4 and KDR were detected in 10% of control samples. In ALL patients VEGF-C was expressed in 65% of cases, FLT-4 in 70% of cases and KDR in 30% of cases. The expressions of VEGF-C, FLT-4 and KDR in ALL patients were associated with increased risk of leukemia (with OR 16.7 and 95% CI 1.7-160.4, OR 21.0 and 95% CI 2.2-204.6 and with OR 3.9 and 95% CI 0.4-37.6 respectively). In AML patients, VEGF-C was expressed in 60% of cases, FLT-4 in 70% of cases and KDR in 40% of cases. The expression of VEGF-C, FLT-4 and KDR in AML patients was associated with increased risk of leukemia (with OR 13.5 and 95% CI 1.2-152.2, OR 21.0 and 95% CI 1.8- 248.1 and OR 6.0 and 95% CI 0.5-67.7 respectively).
In the 6 followed-up ALL patients, 3 (50%) were in remission, three of them were VEGF-C negative, 2 were FLT-4 positive and 1 was KDR positive. 2 of the 6 ALL patients (33.3%) were resistant to treatment, both were VEGF-C positive, FLT-4 positive and 1 was KDR positive. One of the 6 ALL patients (16.6%) died during induction, this patient was VEGF-C positive and FLT-4 and KDR negative. In the 4 followed-up AML patients, 3 of them (75%) were in remis-sion, 1 of the 3 was VEGF-C positive and 2 were FLT-4 positive. One of the four AML patients (25%) was resistant to treatment, this patient was VEGF-C, FLT-4 and KDR positive. The number of VEGF-C positive patients with no treatment failure was lower than the number of VEGF-C positive patients with treatment failure. Also, the risk of failed induction, was found to be greater in VEGF-C positive patients than in VEGF-C negative patients, thus, the expression of VEGF-C and its receptors (FLT-4 and KDR) in ALL and AML patients was associated with increased risk of leukemia and unfavorable treatment outcome. VEGF-C and its receptors KDR (VEGFR-2) and FLT-4 (VEGFR-3) may play an impor-tant role in the pathophysiology of hematopoietic malignancies and may actually contribute to the development of leukemia. Also, owing to the importance of angiogenesis in tumor progression and the effects of VEGF-C, KDR and FLT-4 in chemotherapy-treated leukemias, inhibition of VEGF-C sig-naling represents an attractive cancer treatment.