Abstract
The development of a suitable three dimensional (3D) culture system for anticancer drug development remains an unmet need. Despite progress, a simple, rapid, scalable and inexpensive 3D-tumor model that recapitulates in vivo tumorigenesis is lacking. Herein, we report on the development and characterization of a 3D nanofibrous scaffold produced by electrospinning a mixture of poly(lactic-co-glycolic acid) (PLGA) and a block copolymer of polylactic acid (PLA) and mono-methoxypolyethylene glycol (mPEG) designated as 3P. Cancer cells cultured on the 3P scaffold formed tight irregular aggregates similar to in vivo tumors, referred to as tumoroids that depended on the topography and net charge of the scaffold. 3P scaffolds induced tumor cells to undergo the epithelial-to-mesenchymal transition (EMT) as demonstrated by up-regulation of vimentin and loss of E-cadherin expression. 3P tumoroids showed higher resistance to anticancer drugs than the same tumor cells grown as monolayers. Inhibition of ERK and PI3K signal pathways prevented EMT and reduced tumoroid formation, diameter and number. Fine needle aspirates, collected from tumor cells implanted in mice when cultured on 3P scaffolds formed tumoroids, but showed decreased sensitivity to anticancer drugs, compared to tumoroids formed by direct seeding. These results show that 3P scaffolds provide an excellent platform for producing tumoroids from tumor cell lines and from biopsies and that the platform can be used to culture patient biopsies, test for anticancer compounds and tailor a personalized cancer treatment.
Highlights
Potential anticancer drugs entering clinical development have the highest level of attrition (95%)[1] of any drugs in spite of the huge amounts (,1 billion dollars per drug) spent on their development and testing
Preparation and characterization of the 3P scaffold The 3P scaffolds were constructed by electrospinning a solution of the block co-polymer monomethoxypolyethylene glycol (mPEG)/LA and poly(lactic-co-glycolic acid) (PLGA) dissolved in appropriate organic solvents
We report on a novel 3P fibrous scaffold that induced the formation of a micrometastatic compact aggregate of tumor cells that we term a ‘tumoroid’
Summary
Potential anticancer drugs entering clinical development have the highest level of attrition (95%)[1] of any drugs in spite of the huge amounts (,1 billion dollars per drug) spent on their development and testing. Such a high failure rate has been partly attributed to the conventional two-dimensional (2D) monolayer cell-culture assays used for studying cancer cell biology, and screening and testing of potential anticancer drugs. 3D culture of cancer cells form multicellular aggregates termed spheroids that support anchorage-independent growth with functional and mass transport properties similar to those observed in micrometastases or poorly vascularized regions in solid tumors [17,18,19,20,21,22]. Developing a 3D tumor model that more closely mimics the in vivo tumor microenvironment (TME) remains a formidable challenge and unmet need
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