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    3D porous chitosan-alginate scaffold stiffness promotes differential T
    responses in prostate cancer cell lines
    Kailei Xua, Kavya Ganapathyb, Thomas Andlb, Zi Wanga, John A. Coplandc, Ratna Chakrabartib, Stephen J. Florczyka,b,*
    a Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, 32816-2455, USA
    b Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
    c Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
    • Three CA scaffold compositions were prepared with different scaffold stiffness.
    • PC-3, C4-2B, and 22Rv1 cell lines had stiffness independent growth in CA scaffolds.
    • Osteoblastic lines C4-2B and 22Rv1 mineralized, while osteolytic PC-3 line did not.
    Prostate cancer
    Tumor microenvironment
    Tumor model
    Polyelectrolyte complex 
    Prostate cancer (PCa) is a leading cause of death for men worldwide. Most PCa patients die from metastasis and bone is the most common metastatic site. Three dimensional (3D) porous chitosan-alginate (CA) scaffolds were developed for bone tissue engineering and demonstrated for culture of cancer Etoposide and enrichment of cancer stem cells. However, only a single scaffold composition was studied. Three compositions of 3D porous CA scaffolds (2, 4, and 6 wt%) were used to investigate the effect of scaffold stiffness on PCa cell response with PC-3, C4-2B, and 22Rv1 cell lines. The PC-3 cells formed cell clusters while the C4-2B and 22Rv1 cells formed mul-ticellular spheroids. The three cell lines demonstrated stiffness independent cell growth and expressed pheno-typic PCa biomarkers. The osteoblastic PCa lines C4-2B and 22Rv1 mineralized in basal media, while the os-teolytic PC-3 line did not, demonstrating that CA scaffold cultures revealed differences in PCa phenotypes. The CA scaffolds are a 3D culture platform that supports PCa growth and phenotypic expression with adjustable scaffold stiffness to mimic stages of metastatic progression. Further investigation of the scaffolds for co-culture of PCa cells with fibroblasts and primary PCa cell culture should be conducted to develop a platform for screening chemotherapies.
    1. Introduction
    Prostate cancer (PCa) is a leading cause of death for men; 1 out of 6 men over age 50 in the United States will be diagnosed with PCa and 1 out 33 will die from it [1]. Primary PCa is curable, while the fatal cases are typically recurrent and metastatic PCa. Metastasis is the process of cancer spreading from the primary tumor to other organs [2]. Ap-proximately 90% of PCa metastasis is to bone, which makes bone me-tastasis the predominant source of PCa mortality [3]. Based on Paget's ‘seed and soil’ theory of cancer metastasis [4], the bone micro-environment provides a fertile soil to PCa cells growth compared with other organs. PCa cells may be attracted to bone by stromal factors [5].
    PCa cells preferentially metastasize to cancellous bone, where the os-teoblastic (mineralizing) PCa cells and occasionally osteolytic PCa cells colonize in the vascular beds [6]. Two dimensional (2D) cell cultures are commonly used for in vitro studies evaluating cancer therapies. However, there are considerable differences in cell Etoposide response between 2D cultures and in vivo growth. 2D culture alters cell morphologies, metabolic pathways, gene expression, and proliferation rate compared to in vivo conditions and also reduces extracellular matrix protein production [7–9]. These differences be-tween 2D culture and in vivo growth lead to differential responses from cancer treatments in 2D cultures and patients, potentially resulting in drugs that appeared to be efficacious during preclinical screening to