Haematologica 2003 - Supplements

transducing component of the interleukin 6 (IL-6) receptor, to
cross-communicate with unrelated receptor systems (3-5).
The goal of this study, therefore, was to determine whether IL-6
signaling via gp130 interfaces with signals mediated through
other receptors expressed by myeloma cells. In this regard, we
have had a long-standing interest in interferon-alpha (IFN-α) and
insulin-like growth factor-I (IGF-I). IFN-α is a cytokine that
typically inhibits myeloma cell growth, and IGF-I is a growth
factor that can directly stimulate myeloma cell growth and in
some circumstances, synergistically enhance IL-6-stimulated
myeloma cell growth. We have made a number of interesting
observations which will be presented including novel evidence
for receptor cross-talk between gp130 and the IFN-α receptor
system in myeloma cells and the ability of IGF-IR levels to
influence the magnitude of IL-6 stimulated myeloma cell
proliferation. In conclusion, these studies suggest that atypical
receptor expression levels and accompanying unexpected
receptor interactions may be a common occurrence in multiple
myeloma and may underlie variable regulation of malignant
plasma cell growth and survival.
This work was supported by National Institutes of Health grants
CA62242 and CA62228.
References:
Hill, S. M. 1998. Receptor crosstalk: communication through cell
signaling pathways. Anat Rec 253:42-48.
Dumont, J. E., F. Pecasse, and C. Maenhaut. 2001. Crosstalk and
specificity in signalling. Are we crosstalking ourselves into
general confusion? Cellular Signaling 13:457-63.
Qiu, Y., L. Ravi, and H. J. Kung. 1998. Requirement of ErbB2
for signalling by interleukin-6 in prostate carcinoma cells. Nature
393:83-5.
Mitani, Y., A. Takaoka, S. H. Kim, Y. Kato, T. Yokochi, N.
Tanaka, and T. Taniguchi. 2001. Cross talk of the interferonalpha/beta
signalling complex with gp130 for effective
interleukin-6 signalling. Genes to Cells 6:631-40.
Grant, S. L., A. Hammacher, A. M. Douglas, G. A. Goss, R. K.
Mansfield, J. K. Heath, and C. G. Begley. 2002. An unexpected
biochemical and functional interaction between gp130 and the
EGF receptor family in breast cancer cells. Oncogene 21:460-74.
6. Role of microenvironment
P6.1
THE INFLUENCE OF THE TUMOR
MICROENVIRONMENT ON MYELOMA PROGRESSION
AND SURVIVAL
William S. Dalton, Yulia Nefedova, Melissa Alsina, Terry
Landowski, Kenneth Shain, and Lori Hazlehurst
H. Lee Moffitt Cancer Center and Research Institute At the
University of South Florida Tampa, Florida
Classically, studies of drug resistance in cancer have focused on
the molecular biology of single cancer cells. These types of
studies have provided important information regarding certain
drug resistance mechanisms, including mechanisms that reduce
intracellular drug accumulation, alter or repair drug-induced
damage, and reduce drug-induced apoptosis. While these cellular
mechanisms undoubtedly contribute to the overall phenomenon
of drug resistance, it is now evident that the tumor cell
microenvironment also influences how a tumor cell behaves and
responds to cytotoxic drugs or radiation. Two different forms of
tumor cell-environmental interaction may explain how some
myeloma cells survive initial drug exposure and eventually
express classical mechanisms of drug resistance. The first form
involves soluble mediators, such as interleukins, that are secreted
by non-tumor, stromal cells. Interleukin-6 (IL-6) is a classical
example of how a soluble mediator secreted by the tumor
microenvironment is capable of enhancing myeloma cell survival
and blocking apoptosis (Catlett-Falcone et al 1999). The second
form of tumor cell-environment interaction requires direct cell
contact and has been given the term cell adhesion mediated drug
resistance (CAM-DR). In this case, binding extracellular matrix
ligands in the tumor microenvironment may activate cell
adhesion molecules, such as the integrins, and these interactions
result in the activation of signal transduction pathways that block
drug-induced apoptosis. Interrupting the tumor cell-environment
interactions or the associated signal transduction pathways may
represent a new approach for the treatment of myeloma.
Our laboratory has shown that adhesion of myeloma cells to
fibronectin (FN) via β1 integrins contributes to a reversible denovo
drug resistance or CAM-DR (Damiano et al 1999). More
recently, we have extended this observation to myeloma cells
adhered to bone marrow stromal cells (Nefedova 2003). We have
also observed that, in addition to inhibiting intrinsic pathways of
apoptosis induced by cytotoxics, that myeloma cell adhesion to
FN blocks extrinsic pathways of apoptosis induced by CD95
(Shain etal 2002). Most recently, we have compared de novo and
acquired resistance to melphalan induced cell death in the human
myeloma cell line RPMI 8226. Our findings show that acquired
resistance to melphalan functionally correlates with reduced
melphalan interstrand crosslinks and a complex array of gene
expression changes involving DNA repair genes, transporters,
detoxifying molecules, and antiapoptotic genes. By comparison,
myeloma cells exhibiting a temporal melphalan resistance
following adhesion to FN are resistant to melphalan induced
mitochondrial perturbations and apoptosis compared to drug
sensitive cells despite no changes in melphalan induced DNA
damage. Changes in the transcriptisome when 8226 myeloma
cells were adhered to FN were less complex compared to cells
with acquired drug resistance; however, similar changes in gene
expression profiles were observed between cells with de novo
and acquired melphalan resistance. We propose that CAM-DR
induces reversible genomic changes that predispose cells to
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