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Abstract
<p class="first" id="P1">Breast cancer cell invasion is influenced by growth factor
concentration gradients
in the tumor microenvironment. However, studying the influence of growth factor gradients
on breast cancer cell invasion is challenging due to both the complexities of
<i>in vivo</i> models and the difficulties in recapitulating the tumor microenvironment
with defined
gradients using
<i>in vitro</i> models. A defined hyaluronic acid (HA)-based hydrogel crosslinked
with matrix metalloproteinase
(MMP) cleavable peptides and modified with multiphoton labile nitrodibenzofuran (NDBF)
was synthesized to photochemically immobilize epidermal growth factor (EGF) gradients.
We demonstrate that EGF gradients can differentially influence breast cancer cell
invasion and drug response in cell lines with different EGF receptor (EGFR) expression
levels. Photopatterned EGF gradients increase the invasion of moderate EGFR expressing
MDA-MB-231 cells, reduce invasion of high EGFR expressing MDA-MB-468 cells, and have
no effect on invasion of low EGFR-expressing MCF-7 cells. We evaluate MDA-MB-231 and
MDA-MB-468 cell response to the clinically tested EGFR inhibitor, cetuximab. Interestingly,
the cellular response to cetuximab is completely different on the EGF gradient hydrogels:
cetuximab decreases MDA-MB-231 cell invasion but increases MDA-MB-468 cell invasion
and cell number, thus demonstrating the importance of including cell-microenvironment
interactions when evaluating drug targets.
</p>