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Leong H.S.,Translational Prostate Cancer Research Group | Robertson A.E.,Translational Prostate Cancer Research Group | Stoletov K.,University of Alberta | Leith S.J.,Translational Prostate Cancer Research Group | And 12 more authors.
Cell Reports | Year: 2014

Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation invivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively toinvadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin), maturation (Tks5), or function (Tks4) resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process. © 2014 The Authors. Source


Rohani R.,Lawson Health Research Institute | Figueredo R.,Cancer Research Laboratory Program | Bureau Y.,Lawson Health Research Institute | Bureau Y.,University of Western Ontario | And 10 more authors.
Molecular Imaging and Biology | Year: 2014

Purpose: The bacterial gene MagA imparts magnetic properties to mammalian cells and provides a basis for cell tracking by magnetic resonance imaging (MRI). In a mouse model of tumor growth from transplanted cells, we used repetitive MRI to demonstrate the in vivo imaging potential of MagA expression relative to a modified ferritin overexpression system, lacking regulation through iron response elements (HF + LF). Procedures: Subcutaneous tumor xenografts were monitored weekly from days 2 to 34 post-injection. Small animal MRI employed balanced steady-state free precession. Imaging was correlated with tumor histology using hematoxylin, Prussian Blue, Ki-67, and BS-1 lectin. Results: Tumor heterogeneity with respect to tissue morphology and magnetic resonance (MR) contrast was apparent within a week of cell transplantation. In MagA- and HF + LF-expressing tumors, MR contrast enhancement was recorded up to day 20 post-injection and 0.073-cm3 tumor volumes. MagA-expressing tumors showed increases in both quantity and quality of MR contrast as measured by fractional void volume and contrast-to-noise ratio, respectively. MR contrast in both MagA- and HF + LF-expressing tumors was maximal by day 13, doubling fractional void volume 1 week ahead of controls. Conclusions: MagA- and HF + LF-expressing tumor xenografts augment MR contrast after 1 week of growth. MagA expression increases MR contrast within days of cell transplantation and provides MR contrast comparable to HF + LF. MagA has utility for monitoring cell growth and differentiation, with potential for in vivo detection of reporter gene expression using MRI. © 2013 World Molecular Imaging Society. Source


Johnston J.,Cancer Research Laboratory Program | Johnston J.,University of Western Ontario | Ramos-Valdes Y.,Cancer Research Laboratory Program | Stanton L.-A.,University of Western Ontario | And 4 more authors.
Transgenic Research | Year: 2010

Stanniocalcin-1 (STC1) and -2 (STC2) are highly related, secreted, homodimeric glycoproteins that are significantly upregulated by different forms of stress including high phosphate levels. Transgenic mice that constitutively express either human STC1 or STC2 exhibit intra-uterine growth restriction and permanent post-natal growth retardation. STC1 is expressed in chondrocytic and osteoblastic cells during murine development and can enhance differentiation of calvarial cells in culture. Therefore, there is mounting evidence that stanniocalcins (STCs) modulate bone development in vivo. To further define the effects of stanniocalcins on skeletal development, we performed a series of measurements on components of the axial, appendicular, and cranial skeleton in transgenic and wildtype mice. We show that skeletal growth is retarded and that the intramembranous bones of the cranium exhibit a particularly severe delay in suture closure. The posterior frontal suture remains patent throughout the lifetime of human STC1 and STC2 transgenic mice. We did not observe significant effects on chondrogenesis: however, calvarial cells exhibited reduced viability, proliferation and delayed differentiation, indicating that developing osteoblasts are particularly sensitive to the levels of STCs. Given the evidence linking STC1 to cellular phosphate homeostasis, we assessed the expression of a variety of phosphate regulators in transgenic and wildtype calvarial cells and found significantly lower levels of Mepe, Dmp1, Sfrp4 in transgenic cells without a change in Pit1 or Pit2. Collectively these data support a direct regulatory role for STCs in osteoblasts and suggest that overexposure to these factors inhibits normal skeletal development without significant changes in patterning. © 2010 Springer Science+Business Media B.V. Source

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