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VEGF/PLGF induces leukemia cell migration via P38/ERK1/2 kinase pathway, resulting in Rho GTPases activation and caveolae formation

Leukemia volume 21, pages 1590–1594 (2007)Cite this article

Similar to solid tumors, acute leukemia growth induces neo-vascularization (angiogenesis) within the bone marrow (BM) microenvironment. Several studies have shown that acute myeloid leukemia (AML) cells release angiogenic growth factors such as vascular endothelial growth factor (VEGF) within the BM. In turn, AML growth and expansion involves the activation of BM vessels, resulting in a paracrine stimulation of leukemia, similar to what is seen in solid neoplasms. In addition, we and others have shown that subsets of acute leukemias also express VEGF receptors; in these cases, autocrine stimulation of leukemia cells by VEGF may result in proliferation, migration and resistance to chemotherapy.1, 2, 3 Therefore, exposure of the BM microenvironment to increased VEGF levels may in fact contribute toward leukemia expansion via paracrine or autocrine stimulation of subsets of leukemia cells.

More recently, we have shown that acute lymphocytic leukemia expansion and the onset of extramedullary disease involved migration of leukemia cells, within the BM microenvironment and into the peripheral circulation.4 This migration was induced at least partly due to VEGF/PLGF (placental derived growth factor) stimulation of leukemia cells within the BM. However, the molecular mechanisms involved in this migration were not characterized, and are the subject of the present study.

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Acknowledgements

This study was supported by FCT (Portuguese Government) fellowships (SFRH/BPD/5683/2001, attributed to CC, SFRH/BD/14162/2003, attributed to RF) and FCT Project grant (POCTI 39381/2001, Sérgio Dias). We thank other members of the Angiogenesis laboratory for their critical reading of the manuscript. We are also grateful to Isabel Marques of Institute Gulbenkian of Science for the search of caveolin-binding domains in FLT-1 human sequence.

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Authors and Affiliations

  1. Angiogenesis Laboratory, Centro de Investigação em Patobiologia Molecular (CIPM), Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal

    C Casalou, R Fragoso & S Dias

  2. Pathology Laboratory, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal

    J F M Nunes

  3. Angiogenesis Laboratory, Instituto Gulbenkian Ciência, Oeiras, Portugal

    S Dias

  4. CIPM, Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisboa, Portugal

    S Dias

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  1. C Casalou
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  2. R Fragoso
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  4. S Dias
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Correspondence to S Dias.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Casalou, C., Fragoso, R., Nunes, J. et al. VEGF/PLGF induces leukemia cell migration via P38/ERK1/2 kinase pathway, resulting in Rho GTPases activation and caveolae formation. Leukemia 21, 1590–1594 (2007). https://doi.org/10.1038/sj.leu.2404668

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