Chemoprotection Across the Tumor Border: Cancer Cell Response to Doxorubicin Depends on Stromal Fibroblast Ratios and Interstitial Therapeutic Transport
Authored by Daniel K Logsdon, Jennifer M Munson, Garrett F Beeghly
Date Published: 2017
DOI: 10.1007/s12195-017-0498-3
Sponsors:
Snell Endowment Fund
UVa Cancer Center
Platforms:
No platforms listed
Model Documentation:
Other Narrative
Mathematical description
Model Code URLs:
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Abstract
Increasing evidence suggests that the tumor microenvironment reduces
therapeutic delivery and may lead to chemotherapeutic resistance. At
tumor borders, drug is convectively transported across a unique
microenvironment composed of inverse gradients of stromal and tumor
cells. These regions are particularly important to overall survival, as
they are often missed through surgical intervention and contain many
invading cells, often responsible for metastatic spread. An
understanding of how cells in this tumor-border region respond to
chemotherapy could begin to elucidate the role of transport and
intercellular interactions in relation to chemoresistance. Here we
examine the contribution of drug transport and stromal fibroblasts to
breast cancer response to doxorubicin using in silico and in vitro
models of the tumor-stroma interface.
2D culture systems were utilized to determine the effects of modulated
ratios of fibroblasts and cancer cells on overall cancer cell viability.
A homogenous breast mimetic in vitro 3D collagen I-based hydrogel
system, with drug delivered via pressure driven flow (0.5 A mu m/s), was
developed to determine the effects of transport and fibroblasts on
doxorubicin treatment efficacy. Using a novel layered tumor
bulk-to-stroma transition in vitro 3D hydrogel model, ratios of
MDA-MB-231s and fibroblasts were seeded in successive layers creating
cellular gradients, yielding insight into region specific cancer cell
viability at the tumor border. In silico models, utilizing concentration
profiles developed in COMSOL Multiphysics, were optimized for time
dependent viability prediction and confirmation of in vitro findings.
In general, the addition of fibroblasts increased viability of cancer
cells exposed to doxorubicin, indicating a protective effect of
co-culture. More specifically, however, modulating ratios of cancer
cells (MDA-MB-231):fibroblasts in 2D co-cultures, to mimic the
tumor-stroma transition, resulted in a linear decrease in cancer cell
viability from 77\% (4:1) to 44\% (1:4). Similar trends were seen in the
breast-mimetic in vitro 3D collagen I-based homogenous hydrogel system.
Our in vitro and in silico tumor border models indicate that MDA-MB-231s
at the top of the gel, indicative of the tumor bulk, receive the
greatest concentration of drug for the longest time, yet cellular death
is lowest in this region. This trend is reversed for MDA-MB-231s alone.
Together, our data indicate that fibroblasts are chemoprotective at
lower density, resulting in less tumor death in regions of higher
chemotherapy concentration. Additionally, chemotherapeutic agent
transport properties can modulate this effect.
Tags
Agent-based model
Microenvironment
Chemotherapy
In-vitro
Drug-resistance
Extracellular-matrix
Breast-cancer
Fibroblasts
Solid tumors
Tumor microenvironment
Drug delivery
Doxorubicin
Breast
cancer
Interstitial flow
3d cell culture
Multidrug-resistance mdr
Fluid pressure