Aline Scandurro

Project:

Environmental Cues That Promote Recruitment of Mesenchymal Stem Cells Toward Tumor Angiogenesis

The potential therapeutic use of isolated stem cells to repair or regenerate diseased organs is a burgeoning field of research. Bone-marrow-derived mesenchymal stem cells (MSC) currently are being evaluated as a source of immature endothelial cells or angioblasts that can repair damaged vasculature. Hypoxia, or reduced oxygen tension, favors the differentiation of MSCs into cells capable of building new blood vessels. However, the classic hypoxia-induced angiogenic factors like vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are not fully capable of restoring this effect.

The hypoxia-regulated factor, erythropoietin (Epo), is known to mediate differentiation of erythroblasts into mature red blood cells. More recently, Epo was reported to induce a pro-angiogenic phenotype in human endothelial cells. Epo secretion has been implicated in tumor growth and angiogenesis of erythrocitic leukemia cells, hepatocellular carcinoma and several female breast and reproductive organ carcinomas.

Tumor angiogenesis is critical for tumor growth and survival. The goal of this project is to determine whether local Epo secretion following tissue exposure to hypoxia initiates a cascade of events in Epo-receptor-bearing MSCs and endothelial cells that lead to their differentiation and contribution to new blood vessel formation, facilitating malignant tumor development.

The project will evaluate the effects of environmental cues given by Epo and/or hypoxia on the induction of a pro-angiogenic phenotype of treated MSC and endothelial cells and will determine the cellular responses of Epo and/or hypoxia-treated MSC and endothelial cells. An animal model of Kaposi’s Sarcoma will be established as a tool to characterize in vivo the pro-angiogenic potential of mesenchymal stem cells and endothelial cells and their contribution toward tumor angiogenesis.

Defining these Epo-mediated events may lead to a better understanding of hypoxia-driven angiogenic processes and the identification of novel targets for the design of improved cancer therapy. MSCs currently are being evaluated as a source of immature endothelial cells or angioblasts that can target tumor vasculature. Human cells grown three-dimensionally (3-D) in NASA-engineered rotating wall vessels (RWVs) more closely resemble the parental tissues from which they originated, and proliferation assays and microscopic analyses revealed improved growth characteristics within the 3-D MSC compared to conventionally-grown MSCs, even after prolonged culture (>55 days). The 3-D MSC stem cells’ potential appears to remain intact following RWV culture as assessed by cartilage, adipocyte, bone and endothelial-like assays. The effect of hypoxia (1-5% O2) exposure on 3-D MSC culture was also investigated to recreate the bone marrow environmental origin of theses cells. Hypoxia exposure did not significantly affect viability.

Following establishment and characterization of the 3-D MSC model system, targeting of tumor vasculature with modified MSCs containing anti-cancer payloads will be explored.

Selected Publications:

Scandurro, A.B., McGary, E., Rondon, I.J., Wilson, R., and Beckman, B.S. (1995) Redox and heat shock protein HSP70 affect the binding of erythropoietin RNA binding protein to erythropoietin mRNA. Acta Hematologica 93: 216.

Scandurro, A.B., Rondon, I.J., Wilson R.B., Tennenbaum, S.A., Garry, R.F., and Beckman, B.S. (1997) Interaction of erythropoietin RNA binding protein with mRNA requires an association with heat shock protein 70. Kidney Int. 51(2): 579-584.

Mallia CM, Aguirre, V, McGary E, Tang Y, Scandurro AB, Liu C, Noguchi CT, Beckman B.S. (1998) Protein kinase C is an effector of hexamethylene bisacetamide-induced differentiation of friend erythroleukemia cells. Exp. Cell Res. 246:348-354.

Scandurro, A.B. and Beckman B.S. (1998) Common Proteins bind mRNAs encoding Erythropoietin, Tyrosine Hydroxylase and Vascular Endothelial Growth Factor. Biochem.Biophys.Res.Comm. 246:436-440.

Ohigashi T, Mallia CS, McGary E, Scandurro A.B., Rondon I, Fisher JW, Beckman BS (1999) Protein kinase C alpha protein expression is necessary for sustained erythropoietin production in human hepatocellular carcinoma (Hep3B) cells exposed to hypoxia. Biochim Biophys Acta 1450(2):109-18.

Scandurro, A.B., Weldon, C.W., Gutierrez, Y.I., Alam, J. and Beckman, B.S. (2001) Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells . Intl. J. Oncol. 19:129-135.

Weldon CB, Scandurro AB, Rolfe KW, Clayton JL, Elliott S, Butler NN, Melnik LI, Alam J, McLachlan JA, Jaffe BM, Beckman BS, Burow ME. (2002) Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray. Surgery. 132(2): 293-301.

Figueroa YG, Chan AK, Ibrahim R, Tang Y, Burow ME, Alam J, Scandurro AB, Beckman BS (2002) NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin gene expression. Exp Hematol. 30(12):1419-27.

Frigo DE, Tang Y, Beckman BS, Scandurro AB, Alam J, Burow ME, McLachlan JA. (2004) Mechanism of AP-1-mediated gene expression by select organochlorines through the p38 MAPK pathway.Carcinogenesis. Feb;25(2):249-61. Epub 2003 Nov 06.

Weldon CB, McKee A, Collins-Burow BM, Melnik LI, Scandurro AB, McLachlan JA, Burow ME, Beckman BS. (2005) PKC-mediated survival signaling in breast carcinoma cells: A role for MEK1-AP1 signaling. Int J Oncol. Mar;26(3):763-8.

Lamarca HL, Ott CM, Honer Zu Bentrup K, Leblanc CL, Pierson DL, Nelson AB, Scandurro AB, Whitley GS, Nickerson CA, Morris CA. (2005) Three-dimensional growth of extravillous cytotrophoblasts promotes differentiation and invasion. Placenta. 26(10):709-20. Epub 2005 Jan 25.

Lamarca HL, Nelson AB, Scandurro AB, Whitley GS, Morris CA. (2006) Human cytomegalovirus-induced inhibition of cytotrophoblast invasion in a first trimester extravillous cytotrophoblast cell line. Placenta. 27(2-3):137-47.

Weldon, C. B., A. McKee, B. M. Collins-Burow, L. I. Melnik, A. B. Scandurro, J. A. McLachlan, M. E. Burow, B. S. Beckman. 2005. PKC-mediated survival signaling in breast carcinoma cells: a role for MEK1-AP1 signaling. Int. J. Oncol. 26(3):763-8.

Elizabeth R. Abboud, Seth B. Coffelt, Yanira G. Figueroa, Kevin J. Zwezdaryk, Anne B. Nelson, Deborah E. Sullivan, Cindy B. Morris, Yan Tang, Barbara S. Beckman and Aline B. Scandurro. Integrin-Linked Kinase: A Hypoxia Induced Anti-Apoptotic Factor Exploited By Cancers. 2007. Int. J. Oncol. 30:113-122.

Seth B. Coffelt, Ruth S. Waterman, Luisa Florez, Kevin J. Zwezdaryk, Kerstin Honer zu Bentrup, Suzanne L. Tomchuck, Heather L. LaMarca, Yanira I. Gutierrez-Figueroa, Elizabeth S. Danka, and Aline B. Scandurro. hCAP-18/LL-37: A Novel Player in Cancers of the Ovary. Submitted to International Journal of Cancer May ’07.

Kevin J. Zwezdaryk, Seth B. Coffelt, Yanira G. Figueroa, Juliet Liu, Donald G. Phinney, Heather L. LaMarca, Luisa Florez, Cindy B. Morris, Gary W. Hoyle and Aline B. Scandurro. Erythropoietin a Hypoxia-Regulated Factor Elicits a Pro-Angiogenic Program in Human Mesenchymal Stem Cells. Experimental Hematology. 2007 Apr;35(4):640-52.

Suzanne L. Tomchuck, Kevin J. Zwezdaryk, Seth B. Coffelt, Ruth S. Waterman, and Aline B. Scandurro. Toll-Like Receptors on Human Mesenchymal Stem Cells Drive their Stress Signal Responses. Manuscript in preparation

Contact info: alibscan@tulane.edu