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Open Access Research article

Blood vessel hyperpermeability and pathophysiology in human tumour xenograft models of breast cancer: a comparison of ectopic and orthotopic tumours

Karyn S Ho12, Peter C Poon1, Shawn C Owen12 and Molly S Shoichet123*

Author Affiliations

1 Department of Chemical Engineering & Applied Chemistry, 200 College Street, Toronto, ON, M5S 3E5, Canada

2 Institute of Biomaterials & Biomedical Engineering, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Room 514 – 160 College Street, Toronto, ON, M5S 3E1, Canada

3 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada

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BMC Cancer 2012, 12:579  doi:10.1186/1471-2407-12-579

Published: 5 December 2012

Abstract

Background

Human tumour xenografts in immune compromised mice are widely used as cancer models because they are easy to reproduce and simple to use in a variety of pre-clinical assessments. Developments in nanomedicine have led to the use of tumour xenografts in testing nanoscale delivery devices, such as nanoparticles and polymer-drug conjugates, for targeting and efficacy via the enhanced permeability and retention (EPR) effect. For these results to be meaningful, the hyperpermeable vasculature and reduced lymphatic drainage associated with tumour pathophysiology must be replicated in the model. In pre-clinical breast cancer xenograft models, cells are commonly introduced via injection either orthotopically (mammary fat pad, MFP) or ectopically (subcutaneous, SC), and the organ environment experienced by the tumour cells has been shown to influence their behaviour.

Methods

To evaluate xenograft models of breast cancer in the context of EPR, both orthotopic MFP and ectopic SC injections of MDA-MB-231-H2N cells were given to NOD scid gamma (NSG) mice. Animals with matched tumours in two size categories were tested by injection of a high molecular weight dextran as a model nanocarrier. Tumours were collected and sectioned to assess dextran accumulation compared to liver tissue as a positive control. To understand the cellular basis of these observations, tumour sections were also immunostained for endothelial cells, basement membranes, pericytes, and lymphatic vessels.

Results

SC tumours required longer development times to become size matched to MFP tumours, and also presented wide size variability and ulcerated skin lesions 6 weeks after cell injection. The 3 week MFP tumour model demonstrated greater dextran accumulation than the size matched 5 week SC tumour model (for P < 0.10). Immunostaining revealed greater vascular density and thinner basement membranes in the MFP tumour model 3 weeks after cell injection. Both the MFP and SC tumours showed evidence of insufficient lymphatic drainage, as many fluid-filled and collagen IV-lined spaces were observed, which likely contain excess interstitial fluid.

Conclusions

Dextran accumulation and immunostaining results suggest that small MFP tumours best replicate the vascular permeability required to observe the EPR effect in vivo. A more predictable growth profile and the absence of ulcerated skin lesions further point to the MFP model as a strong choice for long term treatment studies that initiate after a target tumour size has been reached.

Keywords:
Tumour xenograft models; Orthotopic transplantation; Ectopic transplantation; Enhanced permeability and retention; Breast cancer; Blood vessel hyperpermeability; Nanomedicine; Targeting