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The role of hypoxia in the migratory and metabolic activities of mesenchymal stem cells in the tumor microenvironment

by
Yanique Rattigan
B.S., 2005
University of Maryland Eastern Shore

Thesis Advisor: Debabrata Banerjee, Ph.D.

Graduate Program: Cellular and Molecular Pharmacology

CHINJ, Room 3101

Tuesday, January 12, 2010
2:00 pm


Abstract

Mesenchymal stem cells (MSCs) are a heterogeneous population of non-hematopoietic precursor cells predominantly found in the bone marrow. They have been recently reported to home towards the hypoxic tumor microenvironment in vivo, and support tumor growth. Solid tumors develop hypoxia as a result of inadequate O2 supply. Interestingly, tumor types with increased levels of hypoxia are known to have increased resistance to chemotherapy as well as increased metastatic potential. Cytokines are known to play an important role within the tumor milieu especially in tumor growth, immune modulation and response to drugs. Interleukin-6 (IL-6) is a multifunctional cytokine normally involved in the regulation of the immune and inflammatory response. In addition to its normal function, IL-6 signaling has been implicated in tumorigenesis.

A consequence of hypoxia within the solid tumor is enhanced production and secretion of lactate. Recent reports suggest that lactate produced by cancer cells may be taken up by stromal cells and recycled to regenerate pyruvate. Stromal cells can efflux pyruvate to serve as a power supply to sustain the metabolic needs of tumor cells. Therefore, the primary focus of our studies was to delineate the molecular mechanisms involved in the crosstalk between MSCs and hypoxic tumor cells lending to the recruitment of MSCs towards tumor sites to aid in tumor progression.

Here, we present evidence that under hypoxic conditions (1.5% O2) breast cancer cells secrete high levels of IL-6, which serve to activate and attract MSCs. We now report that secreted IL-6 acts in a paracrine fashion on MSCs stimulating the activation of both Stat3 and MAPK signaling pathways to enhance migratory potential and cell survival. Inhibition of IL-6 signaling utilizing neutralizing antibodies leads to attenuation of MSC migration. Specifically, increased migration is dependent on IL-6 signaling through the IL-6 receptor.

Furthermore, we show that MDA-MB-231 and MCF-7 breast cancer cell lines secrete enhanced levels of lactate (2-fold) under hypoxia (1.5% O2) as compared to normoxia (21% O2). Analysis of MSC migration, showed that 15mM lactate enhanced MSC migration over 3-fold compared to control medium. Lactate stimulation of MSCs induced expression of a functional monocarboxylate transporter MCT-1, one of the proteins involved in lactate transport, at both mRNA and protein levels. Furthermore, activation of Stat3 and downstream signaling pathways following lactate stimulation was observed, suggesting that lactate plays a role in the metabolic fate of cancer cells through the recruitment of MSCs. Delineating the interaction between MSCs, lactate and the hypoxic tumor microenvironment will be fundamental in understanding tumor cell metabolism and provide knowledge for the development of novel anticancer therapies.


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