Breast
tumor development is regulated in part by cues from the local microenvironment,
including interactions with neighboring nontumor cells as well as the ECM.
Studies using homogeneous populations of breast cancer cell lines cultured in
3D ECM have shown that increased ECM stiffness stimulates tumor cell invasion.
However, at early stages of breast cancer development, malignant cells are
surrounded by normal epithelial cells, which have been shown to exert a
tumor-suppressive effect on cocultured cancer cells. Here we explored how the
biophysical characteristics of the host microenvironment affect the
proliferative and invasive tumor phenotype of the earliest stages of tumor
development, by using a 3D microfabrication-based approach to engineer ducts
composed of normal mammary epithelial cells that contained a single tumor cell.
We found that the phenotype of the tumor cell was dictated by its position in
the duct: proliferation and invasion were enhanced at the ends and blocked when
the tumor cell was located elsewhere within the tissue. Regions of invasion
correlated with high endogenous mechanical stress, as shown by finite element
modeling and bead displacement experiments, and modulating the contractility of
the host epithelium controlled the subsequent invasion of tumor cells.
Combining microcomputed tomographic analysis with finite element modeling
suggested that predicted regions of high mechanical stress correspond to
regions of tumor formation in vivo. This work suggests that the mechanical tone
of nontumorigenic host epithelium directs the phenotype of tumor cells and
provides additional insight into the instructive role of the mechanical tumor
microenvironment.
Source:
Host epithelial geometry regulates breast cancer cell invasiveness.
Boghaert E, Gleghorn JP, Lee K, Gjorevski N, Radisky DC, Nelson CM (celesten@princeton.edu). Proc Natl
Acad Sci U S A. 2012 Nov 12.
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