Basal cells in a simple secretory epithelium adhere to the extracellular matrix (ECM), providing contextual cues for ordered repopulation of the luminal cell layer. Early high-grade prostatic intraepithelial neoplasia (HG-PIN) tissue has enlarged nuclei and nucleoli, luminal layer expansion and genomic instability. Additional HG-PIN markers include loss of alpha 6 beta 4 integrin or its ligand laminin-332, and budding of tumor clusters into laminin-511-rich stroma. We modeled the invasive budding phenotype by reducing expression of alpha 6 beta 4 integrin in spheroids formed from two normal human stable isogenic prostate epithelial cell lines (RWPE-1 and PrEC 11220). These normal cells continuously spun in culture, forming multicellular spheroids containing an outer laminin-332 layer, basal cells (expressing alpha 6 beta 4 integrin, high-molecular-weight cytokeratin and p63, also known as TP63) and luminal cells that secrete PSA (also known as KLK3). Basal cells were optimally positioned relative to the laminin-332 layer as determined by spindle orientation. beta 4-integrin-defective spheroids contained a discontinuous laminin-332 layer corresponding to regions of abnormal budding. This 3D model can be readily used to study mechanisms that disrupt laminin-332 continuity, for example, defects in the essential adhesion receptor (beta 4 integrin), laminin-332 or abnormal luminal expansion during HG-PIN progression.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/622647 |
| Date | 01 January 2017 |
| Creators | Wang, Mengdie, Nagle, Raymond B., Knudsen, Beatrice S., Rogers, Gregory C., Cress, Anne E. |
| Contributors | Univ Arizona, Ctr Canc, Coll Med, Dept Cellular & Mol Med, Univ Arizona, Ctr Canc, Dept Pathol, Coll Med |
| Publisher | COMPANY OF BIOLOGISTS LTD |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | Article |
| Rights | © 2017. Published by The Company of Biologists Ltd |
| Relation | http://jcs.biologists.org/lookup/doi/10.1242/jcs.188177 |
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