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

• Published in: Cellular and molecular bioengineering 2018-10, Vol.11 (5), p.419-433
• Main Authors: Saini, Harpinder, Rahmani Eliato, Kiarash, Silva, Casey, Allam, Mayar, Mouneimne, Ghassan, Ros, Robert, Nikkhah, Mehdi
• Format: Article
• Language: English
• Subjects: Anticancer properties; Atomic force microscopy; Biological and Medical Physics; Biomaterials; Biomechanics; Biomedical Engineering and Bioengineering; Biomedical Engineering/Biotechnology; Biophysics; Breast cancer; Cancer; Cell Biology; Cell proliferation; Collagen; Collagen (type I); Combinatorial analysis; Density; Doxorubicin; Drug delivery; Drug efficacy; Drug resistance; Drugs; Engineering; Fibroblasts; Fibronectin; Fibrosis; Hydrogels; Invasiveness; Matrix protein; Mechanical properties; Modulus of elasticity; Proteins; Stiffness; Stromal cells; Three dimensional models; Tumors
• ISSN: 1865-5025; 1865-5033
• DOI: 10.1007/s12195-018-0544-9

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.