Current
Position
-
Career
Scientist, Cancercare Ontario, Northeastern
Ontario Regional Cancer Centre
-
Associate
Professor (Affiliated), Department of
Biology, Department of Chemistry and
Biochemistry, and Program in Biomolecular
Sciences, Laurentian University, Sudbury,
Ontario.
Education
and Training
1993-1997
Visiting Fellow,
Laboratory of Developmental Biology, National
Institute of Dental Research, National Institutes
of Health, Bethesda, Maryland.
1988-1994
Ph.D., Medical Science, McMaster
University, Hamilton, Ontario.
1996-1989
M.Sc., Medical Science, McMaster
University, Hamilton, Ontario.
1979-1984
B.Sc., Biochemistry, University
of British Columbia, Vancouver, British
Columbia.
External
Research Support
-
2003-2006
Canadian Institutes of Health Research
-
2003-2004
Canadian Cancer Etiology Research Network(Co-investigator,
PI - Dr. N Lightfoot, NEORCC)
-
2000-2003
Heart and Stroke Foundation of Ontario
-
1997-2000
Medical Research Council of Canada
-
1998-2000
Northern Ontario Heritage Fund Corporation
(Co-investigator, Dr. H Lee, Dr. R Lafrenie,
and Dr. A Parissenti)
-
1997-1999
Northern Cancer Research Foundation
- operating grant
Lab
Staff
|
Name |
Position |
E-mail |
| Mary
Bewick. |
Research
Technician |
|
| Lisa
Allen |
Graduate
Student |
|
|
Carly Buckner |
Graduate Student |
|
|
Peter Fairman |
Graduate Student |
|
| Mary-Ann
Harrison |
Graduate
Student |
|
|
Vanessa Wall |
Graduate Student |
|
Research
Interests
Cell adhesion alters
cellular signals and gene expression: implications
for carcinogenesis and differentiation.
One
of the defining characteristics of cancer
cells is their ability to grow in the absence
of adhesion. Most normal cells die in the
absence of adhesive stimuli. The adhesive
interaction of normal cells with extracellular
matrix are mediated primarily by integrin
cell surface receptors. Integrin-dependent
adhesion is an important component in regulating
cell growth and is central to differentiation
and to the regulation of gene expression
in a variety of cell models. We have shown
that integrin-dependent adhesion of cells
to extracellular matrix initiates cellular
signal transduction pathways and alters
the expression of several specific genes.
Continuing work in our laboratory is focused
on determining the role of the protein kinase
C and MAP kinase signaling cascades on the
expression of adhesion-responsive genes
and promotion of cellular differentiation.
We are also interested in determining the
role that adhesion-responsive genes play
in cellular differentiation. Preliminary
results suggest that this is a very complex
process and that different genes may be
regulated by adhesion to matrix via different
mechanisms.
Adhesion
of Monocytes to Extracellular Matrix and
Effects on Immune Function
Adhesion
of blood cells to components of extracellular
matrix is an important component in activation
of the inflammatory processes underlying
a wide variety of diseases including atheroslerosis,
rheumatoid arthritis, psoriasis, and various
fibrotic disorders. Monocyte adhesion to
extracellular matrix via cell surface integrin
adhesion molecules leads to significant
changes in the expression and synthesis
of a number of inflammatory mediators such
as cytokines and proteases. Work in the
laboratory is aimed at understanding the
mechanisms which underly changes in monocyte
gene expression following adhesion of monocytes
to extracellular matrix. We are currently
utilizing pharmacologic and genetic inhibitor
approaches to determine the role of the
MAP kinase pathway and protein kinase C
in the signals that mediate changes in monocyte
function and cytokine gene expression. Since
the process of monocyte adhesion is implicated
in a wide variety of diseases, it is possible
that the insights from this analysis may
provide clues to clinical treatments..
Prognostic
Indicators for Women with Breast Cancer
As part of a collaborative project with
members of the epidemiology and tumour biology
groups at the NEORCC, we have been attempting
to correlate the plasma and gene expression
levels of various immunological markers
with clinical outcome in patients with metastatic
breast cancer. This information could predict
the prognosis of patients with metastatic
breast cancer and identify a marker profile
which could assist the physician in deciding
the best treatment. We have already shown
that plasma levels of secreted cancer cell
products (HER-2), apoptotic markers (sFas),
inflammatory adhesion molecules (sE-selectin,
sICAM-1, sVCAM), and proinflammatory cytokines
(IL-1, IL-6, TNF-a) correlate with clinical
outcome. We are currenting assessing the
levels of gene expression in leukocytes
from patients with metastatic breast cancer
using cDNA microarray analysis and are performing
haplotype analysis using “single nucleotide
polymorphisms” in populations of patients
with cancer for comparison to the unaffected
population. We anticipate that these approaches
will identify prognostic markers that predict
responses to therapy and relative clinical
outcome of patients with metastatic breast
cancers.
Selected
Publications
Bewick,
MA, and Lafrenie, RM. Adhesion-dependent
signalling in the tumour microenvironment:
the future of drug targetting. Current Pharmaceutical
Design 2005, in press.
Lam,
K, Zhang, L, Bewick, M, and Lafrenie, RM.
HSG cells differentiated by culture on extracellular
matrix involves induction of S-adenosylmethionine
decarboxylase and ornithine decarboxylase.
J Cell Physiol 203: 353-361, 2005.
Bewick,
M, Conlon, M, Lee, H, Parissenti, AM, Zhang,
L, Gluck, S, and Lafrenie, RM. Evaluation
of sICAM-1 and sVCAM-1 and sE-selectin levels
in patients with metastatic breast cancer
receiving high dose chemotherapy. Stem Cells
and Development 13: 281-294, 2004.
Zhang,
L, M Bewick, M, and Lafrenie RM. Role of
Raf-1 and FAK in cell density-dependent
regulation of integrin-dependent activation
of MAP kinase. Carcinogenesis 23, 1251-1258,
2002.
Lafrenie,
RM, Lee SF, Hewlett, IK, Yamada, KM, and
Dhawan, S. Involvement of integrin alpha
v beta 3 in the pathogenesis of human immunodeficiency
virus type I infection in monocytes. Virology
297, 31-38, 2002.
Zhang,
L, Bewick, M, and Lafrenie, RM. EGFR and
ErbB2 differentially regulate Raf-1 translocation
and activation. Lab Invest 82, 71-78, 2002.
Bewick,
M., Conlon, M, Parissenti, AM, Lee, H, Zhang,
L, Gluck, S, and Lafrenie RM. Soluble Fas
(CD95) is a prognostic factor in patients
with metastatic breast cancer undergoing
high dose chemotherapy and autologous stem
cell transplantation. J. Hematotherapy and
Stem Cell Res 10, 759-768, 2001.
Lam,
K, Zhang, L, Yamada, K, and Lafrenie, RM.
Adhesion of epithelial cells to fibronectin
or collagen I induces alterations in gene
expression via a protein kinase C-dependent
mechanism. J. Cell. Physiol. 189, 79-90,
2001.
Bewick, M, Conlon, M, Gerard, S, Lee, H,
Parissenti, AM, Zhang, L, Gluck, S, and
Lafrenie, R. HER-2 expression is a prognostic
factor in patients with metastatic breast
cancer treated with a combination of high-dose
cyclophosphamide, mitozantrone, paclitaxel
and autologous blood stem cell support.
Bone Marrow Transplantation 27: 847-853,
2001.
Lafrenie,
RM, Wahl, LM, Epstein, JS, Hewlett, IK,
Yamada, KM, and Dhawan, S. Activation of
monocytes by HIV-Tat treatment is mediated
by cytokine expression. J. Immunol. 159:
4077-4083, 1997.
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