UHN UT University of Toronto University Health Network


 

Tumor Biology

 

Lab Members: Aws Abdul-Wahid, Marzena Cydzik

 

1) Angiogenesis

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 ovarian cancer.

Angiogenesis

Selected References

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 J, 29(8):3493-505.

 

2) Cancer Vaccines and Metastasis

Metastatic 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).

Using 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).

In another 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).

 

Selected References

1) 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. 8(2): 337-350.Aws-2013

2) 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. Orava-2013

3) 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. Aws-2012

4) 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.

5) 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.

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