Aws Abdul-Wahid, Marzena Cydzik
Angiogenesis as a
mandatory phenomenon during a
number of physiological processes, is also associated with wound healing
and various pathologies, including autoimmune diseases and tumorigenesis.
Vascular neogenesis is tightly regulated by a number of stimuli, which
include soluble growth factors as well as dynamic changes in the
interaction between ECs and extracellular matrix (ECM) microenvironment.
Important cellular mechanisms contributing to the disease progression of
many types of cancer include cellular proliferation, adhesion, migration,
and invasion; all of which are influenced by the interaction between the
tumour cell and the extracellular matrix (ECM). .
Secreted Protein Acidic Rich in Cysteine (SPARC), a Ca2+-binding
ECM glycoprotein, was shown to display anti-angiogenic,
anti-proliferative and counter-adhesive activities. One mechanism by
which SPARC may exert its activity is by binding to Vascular Endothelial
Growth Factor (VEGF), known for its role in angiogenesis in ovarian
cancer, and preventing its interaction with cognate receptors.
Characterization of this molecular interaction holds the promise of
devising peptide mimetics capable of blocking VEGF binding to its cognate
receptors, thus inhibiting ovarian cancer cell proliferation and
invasion. We are presently characterizing the binding properties of VEGF
to SPARC and its peptide with a view to define a template for the design
of SPARC peptide-like anti-angiogenic and anticancer mimetics with
enhanced stability and activity . Antiangiogenic agents will be used in
conjunction with current chemotherapeutic drugs for treating advanced
1) Cydzik M, Abdul-Wahid A, Park S, Bourdeau A, Bowden K,
Prodeus A, Kollara A, Brown TJ, Ringuette MJ, Gariépy J. (2015) Slow
binding kinetics of SPARC-VEGF
interaction limit VEGF activation of
VEGF-R2 and attenuates angiogenesis. FASEB
Cancer Vaccines and Metastasis
cancers remain the primary cause of morbidity and mortality for cancer
patients despite significant advances in the treatment of localized
tumours. The prevention of metastasis combines early surgery (or
radiation therapy in some cases) as well as systemic therapy given before
or after surgery to target disseminated tumour cells that have detached
from primary tumours to engraft at distal sites, and/or were not detected
or accessible to surgical excision at the time of diagnosis. Tumor
metastasis is a complex phenomenon where intercellular and cell-matrix
adhesion events involving tumour cells lead to the formation as well as
expansion of metastatic foci. The carcinoembryonic antigen (CEA) is an
important pro-metastatic oncoprotein that is aberrantly over-expressed by
epithelial cancers including cancers of the gastrointestinal tract, breast,
lung, ovary and pancreas.
Our group is the
first to define the exact CEA domains responsible for its homotypic
cellular adherence and its interaction with the ECM protein fibronectin
(Fn). We showed that the CEA IgV-like N domain serves a key role in the
formation of at least two classes of binding events leading to cellular
engraftment and tumour foci formation. The first binding event involved
the direct association of CEA with Fn KD 16 + 3 nM),
independently of the presence of human α5β1 integrin. The second binding
event involved the formation of both cis-
[N-to-N] and trans-
[N-to-A3] homotypic complexes(KD 100 + 17nM as well as KD
18 + 3nM, respectively) (1).
this knowledge, we have devised DNA aptamers that can block homotypic as
well as heterotypic associations involving CEA (2). Importantly, we are
presently developing a preventive vaccine against metastatic cancer that
with generate immune responses able to block CEA-mediated tumour cell
implantation both in vitro and in vivo, and capable of killing of tumour
cells by complement - and antibody-dependent cellular cytotoxic
mechanisms (3, 4).
vaccine project, we have engineered a semi-synthetic tumour antigen
called the Tn antigen MUC1, which has been used recently in a Phase I/II
clinical trial in patients with castrate-resistant prostate cancer (5).
Abdul-Wahid A, Cydzik M, Prodeus A, Alwash M, Stanojcic M, Thompson M,
Huang EH, Shively JE, Gray-Owen SD, Gariépy J. (2016) Induction of
antigen-specific TH 9 immunity accompanied by mast cell activation blocks
tumor cell engraftment. Int J Cancer, 139(4):841-53.
2) Scheid E,
Major P, Bergeron A, Finn OJ, Salter RD, Eady R, Yassine-Diab B, Favre D,
Peretz Y, Landry C, Hotte S, Mukherjee SD, Dekaban GA, Fink C, Foster PJ,
Gaudet J, Gariepy J, Sekaly RP, Lacombe L, Fradet Y, Foley R. (2016)
Tn-MUC1 DC Vaccination of Rhesus Macaques and a Phase I/II Trial in
Patients with Nonmetastatic Castrate Resistant Prostate Cancer. Cancer Immunol Res, 4(10):881-892.
Abdul-Wahid A, Huang EH,
Cydzik M, Bolewska-Pedyczak E, Gariépy J. (2014) The carcinoembryonic
antigen IgV-like N domain plays a critical role in the implantation of
metastatic tumor cells. Mol Oncol.
4) Orava EW, Abdul-Wahid A, Huang EH, Mallick AI, Gariépy J.
(2013) Blocking the attachment of cancer cells in vivo with DNA aptamers
displaying anti-adhesive properties against the carcinoembryonic antigen.
Mol Oncol. 7(4):799-811.
5) Abdul-Wahid A, Huang EH, Lu H, Flanagan J, Mallick AI,
Gariépy J. (2012) A focused immune response targeting the homotypic
binding domain of the carcinoembryonic antigen blocks the establishment
of tumor foci in vivo. Int
J Cancer. 131(12):2839-2851.