Chemoprotection Across the Tumor Border: Cancer Cell Response to Doxorubicin Depends on Stromal Fibroblast Ratios and Interstitial Therapeutic Transport



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 µm/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.

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Human breast triple negative adenocarcinoma cell line (luminal)


Human breast triple negative invasive ductal carcinoma cell line (luminal)


Human breast ER+/PR+ adenocarcinoma cell line (basal)


Human dermal fibroblast


Tumor cell




Agent-based model


Tumor microenvironment


Tumor to stroma transition model


Interstitial fluid pressure




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The researchers would like to acknowledge Lynette Sequeira for her technical laboratory assistance, Charles Calderwood for statistical assistance. We also thank RC Cornelison, RP Pompano, SM Peirce-Cottler, and SS Blemker for helpful discussion. We would also like to acknowledge the Janes Lab at UVa for initial contribution of cell lines, the Advanced Microscopy Facility and the Biorepository and Tissue Research Facility. This research was funded in part through funding to JM Munson from the UVa Cancer Center through the NCI Cancer Center Support Grant P30 CA44579 and support from the Snell Endowment Fund and Commonwealth of VA, the School of Medicine, and funding to GF Beeghly from the Harrison Undergraduate Research Awards Center at UVa.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All human samples were acquired according to the ethical standards. No animal studies were performed in this work.

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Correspondence to Jennifer M. Munson.

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Jennifer M. Munson, Ph.D. is an Assistant Professor of Biomedical Engineering at the University of Virginia. Dr. Munson received her Bachelor of Science in Chemical Engineering and Neuroscience from Tulane University in 2006. She worked at Genentech in Process Engineering before pursuing graduate study at Georgia Tech with Ravi Bellamkonda, Ph.D. Supported by a National Science Foundation Graduate Research Award, she developed liposomal nanocarriers to deliver a novel anti-invasive therapeutic to glioblastoma. During her Ph.D. she was awarded a Fulbright Fellowship to Switzerland to pursue independent study on the glioma microenvironment at L’École Polytechnique Fédérale de Lausanne with Melody Swartz, Ph.D. After completing her Ph.D. in 2011, she returned to Switzerland as a Whitaker Scholar for postdoctoral training on the breast cancer microenvironment, focusing on changes that alter interstitial transport. Dr. Munson began her faculty career at the University of Virginia in 2014 and moved to Virginia Tech to the Department of Biomedical Engineering and Mechanics in 2017, pursuing research interests related to the cancer microenvironment, drug delivery, and transport in brain and breast cancers. Her work includes the development of tissue engineered systems for the study of interstitial flow and tissue transport as well as translation of these systems for patient-specific drug screening. She was awarded the Rita Schaffer Young Investigator Award by the Biomedical Engineering Society in 2016.

This article is part of the 2017 CMBE Young Innovators special issue.


Associate Editor Michael King oversaw the review of this article.

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Logsdon, D.K., Beeghly, G.F. & Munson, J.M. Chemoprotection Across the Tumor Border: Cancer Cell Response to Doxorubicin Depends on Stromal Fibroblast Ratios and Interstitial Therapeutic Transport. Cel. Mol. Bioeng. 10, 463–481 (2017).

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  • Tumor microenvironment
  • Drug delivery
  • Doxorubicin
  • Fibroblasts
  • Breast cancer
  • Interstitial flow
  • 3D cell culture