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2016 ; 33
(ä): 13-24
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Extracellular matrix mediators of metastatic cell colonization characterized
using scaffold mimics of the pre-metastatic niche
#MMPMID26844426
Aguado BA
; Caffe JR
; Nanavati D
; Rao SS
; Bushnell GG
; Azarin SM
; Shea LD
Acta Biomater
2016[Mar]; 33
(ä): 13-24
PMID26844426
show ga
Metastatic tumor cells colonize the pre-metastatic niche, which is a complex
microenvironment consisting partially of extracellular matrix (ECM) proteins. We
sought to identify and validate novel contributors to tumor cell colonization
using ECM-coated poly(?-caprolactone) (PCL) scaffolds as mimics of the
pre-metastatic niche. Utilizing orthotopic breast cancer mouse models,
fibronectin and collagen IV-coated scaffolds implanted in the subcutaneous space
captured colonizing tumor cells, showing a greater than 2-fold increase in tumor
cell accumulation at the implant site compared to uncoated scaffolds. As a
strategy to identify additional ECM colonization contributors, decellularized
matrix (DCM) from lungs and livers containing metastatic tumors were
characterized. In vitro, metastatic cell adhesion was increased on DCM coatings
from diseased organs relative to healthy DCM. Furthermore, in vivo implantations
of diseased DCM-coated scaffolds had increased tumor cell colonization relative
to healthy DCM coatings. Mass-spectrometry proteomics was performed on healthy
and diseased DCM to identify candidates associated with colonization.
Myeloperoxidase was identified as abundantly present in diseased organs and
validated as a contributor to colonization using myeloperoxidase-coated scaffold
implants. This work identified novel ECM proteins associated with colonization
using decellularization and proteomics techniques and validated candidates using
a scaffold to mimic the pre-metastatic niche. STATEMENT OF SIGNIFICANCE: The
pre-metastatic niche consists partially of ECM proteins that promote metastatic
cell colonization to a target organ. We present a biomaterials-based approach to
mimic this niche and identify ECM mediators of colonization. Using murine breast
cancer models, we implanted microporous PCL scaffolds to recruit colonizing tumor
cells in vivo. As a strategy to modulate colonization, we coated scaffolds with
various ECM proteins, including decellularized lung and liver matrix from
tumor-bearing mice. After characterizing the organ matrices using proteomics,
myeloperoxidase was identified as an ECM protein contributing to colonization and
validated using our scaffold. Our scaffold provides a platform to identify novel
contributors to colonization and allows for the capture of colonizing tumor cells
for a variety of downstream clinical applications.