INTRODUCTION: Chemotherapeutic resistance is a topical question in longstanding treatment of cancer. Therefore, deciphering the basis of chemotherapeutic resistance of cancer cells has evident significance. The cellular response of cancer cells is pre-dominantly modulated by different cell types present in tumor-associated stroma and extra-cellular matrix [1, 2]. At the time of metastasis, cancer cells involve in remodeling the extra-cellular matrix; results in change in pore sizes, interconnectivity and stiffness of cancer stroma [3]. Hence, the critical role of individual cells and extra-cellular matrix in resistance of chemotherapeutics needs to be unwound. Mesenchymal stem cells are actively recruited by tumor-associated stroma [4]. Herein, we venture to explore the influence of human adipose derived stem cells (hASCs) on therapeutic response of human osteosarcoma (Saos 2) within 3D extra cellular environment created using silk fibroin and gellan gum.

METHODS: Silk fibroin – gellan gum based hydrogels with tunable mechanical properties were prepared by varying the blending ratio of gellan gum (GG) to silk to regulate the formation of spheroids of Saos 2 in presence of hASCs in an engineered 3D osteosarcoma model. The proliferation of cells within the spheroids was assessed by Alamar blue assay. For chemotherapeutic response studies, the spheroids were exposed to different dilutions of doxorubicin for 24 h and the viability of cells after treatment was assessed by MTT assay. The morphologies of both cells were examined under confocal and scanning electron microscopies.

RESULTS & DISCUSSION: The highest rates of cell proliferation, spheroid formation and collagen secretion were observed in less stiff hydrogels. It was also identified that the blending of silk with gellan gum enhanced cell survival and functionality possibly owing to biocompatibility of natural silk fibroin. When cultured in equal seeding ratio and treated with the model chemotherapeutic agent such as doxorubicin, the heterotypic culture exhibited different sensitivity compared to homotypic spheroid

CONCLUSIONS: The heterogeneity of the present model at structural and cellular level, recapitulates more closely the dynamic characteristics of physiological tumor stroma. This is anticipated to be useful in predicting the efficacy of cancer chemotherapeutics.

ACKNOWLEDGEMENTS: European Union Framework Programme for Research and Innovation Horizon 2020 (no 668983 —FoReCaST), Investigator FCT program IF/01214/2014 and IF/01285/2015

REFERENCES

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[3] Guzman A et al., Biomaterials 2014:35(25), 6954-63
[4] Roodhart JML et al., Cancer Cell 2011; 20(3):370–83.