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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 (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.
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 . 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 . Ap-proximately 90% of PCa metastasis is to bone, which makes bone me-tastasis the predominant source of PCa mortality . Based on Paget's ‘seed and soil’ theory of cancer metastasis , 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 .
PCa cells preferentially metastasize to cancellous bone, where the os-teoblastic (mineralizing) PCa cells and occasionally osteolytic PCa cells colonize in the vascular beds . Two dimensional (2D) cell cultures are commonly used for in vitro studies evaluating cancer therapies. However, there are considerable diﬀerences in cell 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