The Role of Desmoplasia and Stromal Fibroblasts on Anti-cancer Drug Resistance in a Microengineered Tumor Model

Harpinder Saini, Kiarash Rahmani Eliato, Casey Silva, Mayar Allam, Ghassan Mouneimne, Robert Ros, Mehdi Nikkhah

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Introduction: Cancer associated fibroblasts (CAFs) are known to participate in anti-cancer drug resistance by upregulating desmoplasia and pro-survival mechanisms within the tumor microenvironment. In this regard, anti-fibrotic drugs (i.e., tranilast) have been repurposed to diminish the elastic modulus of the stromal matrix and reduce tumor growth in presence of chemotherapeutics (i.e., doxorubicin). However, the quantitative assessment on impact of these stromal targeting drugs on matrix stiffness and tumor progression is still missing in the sole presence of CAFs. Methods: We developed a high-density 3D microengineered tumor model comprised of MDA-MB-231 (highly invasive breast cancer cells) embedded microwells, surrounded by CAFs encapsulated within collagen I hydrogel. To study the influence of tranilast and doxorubicin on fibrosis, we probed the matrix using atomic force microscopy (AFM) and assessed matrix protein deposition. We further studied the combinatorial influence of the drugs on cancer cell proliferation and invasion. Results: Our results demonstrated that the combinatorial action of tranilast and doxorubicin significantly diminished the stiffness of the stromal matrix compared to the control. The two drugs in synergy disrupted fibronectin assembly and reduced collagen fiber density. Furthermore, the combination of these drugs, condensed tumor growth and invasion. Conclusion: In this work, we utilized a 3D microengineered model to tease apart the role of tranilast and doxorubicin in the sole presence of CAFs on desmoplasia, tumor growth and invasion. Our study lay down a ground work on better understanding of the role of biomechanical properties of the matrix on anti-cancer drug efficacy in the presence of single class of stromal cells.

Original languageEnglish (US)
JournalCellular and Molecular Bioengineering
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Drug Resistance
Fibroblasts
Tumors
Tumor
Cancer
Drugs
Doxorubicin
Tumor Growth
Pharmaceutical Preparations
Invasion
Neoplasms
Collagen
Model
Fibronectin
Growth
Hydrogel
Fibrosis
Cell proliferation
Stiffness matrix
Drug Combinations

Keywords

  • Cancer invasion
  • Doxorubicin
  • Matrix stiffness
  • Tranilast
  • Tumor microenvironment

ASJC Scopus subject areas

  • Modeling and Simulation
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

The Role of Desmoplasia and Stromal Fibroblasts on Anti-cancer Drug Resistance in a Microengineered Tumor Model. / Saini, Harpinder; Rahmani Eliato, Kiarash; Silva, Casey; Allam, Mayar; Mouneimne, Ghassan; Ros, Robert; Nikkhah, Mehdi.

In: Cellular and Molecular Bioengineering, 01.01.2018.

Research output: Contribution to journalArticle

Saini, Harpinder ; Rahmani Eliato, Kiarash ; Silva, Casey ; Allam, Mayar ; Mouneimne, Ghassan ; Ros, Robert ; Nikkhah, Mehdi. / The Role of Desmoplasia and Stromal Fibroblasts on Anti-cancer Drug Resistance in a Microengineered Tumor Model. In: Cellular and Molecular Bioengineering. 2018.
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AU - Ros, Robert

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AB - Introduction: Cancer associated fibroblasts (CAFs) are known to participate in anti-cancer drug resistance by upregulating desmoplasia and pro-survival mechanisms within the tumor microenvironment. In this regard, anti-fibrotic drugs (i.e., tranilast) have been repurposed to diminish the elastic modulus of the stromal matrix and reduce tumor growth in presence of chemotherapeutics (i.e., doxorubicin). However, the quantitative assessment on impact of these stromal targeting drugs on matrix stiffness and tumor progression is still missing in the sole presence of CAFs. Methods: We developed a high-density 3D microengineered tumor model comprised of MDA-MB-231 (highly invasive breast cancer cells) embedded microwells, surrounded by CAFs encapsulated within collagen I hydrogel. To study the influence of tranilast and doxorubicin on fibrosis, we probed the matrix using atomic force microscopy (AFM) and assessed matrix protein deposition. We further studied the combinatorial influence of the drugs on cancer cell proliferation and invasion. Results: Our results demonstrated that the combinatorial action of tranilast and doxorubicin significantly diminished the stiffness of the stromal matrix compared to the control. The two drugs in synergy disrupted fibronectin assembly and reduced collagen fiber density. Furthermore, the combination of these drugs, condensed tumor growth and invasion. Conclusion: In this work, we utilized a 3D microengineered model to tease apart the role of tranilast and doxorubicin in the sole presence of CAFs on desmoplasia, tumor growth and invasion. Our study lay down a ground work on better understanding of the role of biomechanical properties of the matrix on anti-cancer drug efficacy in the presence of single class of stromal cells.

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