A basal cell defect promotes budding of prostatic intraepithelial neoplasia.
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 α6β4 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 α6β4 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 α6β4 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. β4-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 (β4 integrin), laminin-332 or abnormal luminal expansion during HG-PIN progression.
Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
Mengdie
M
Wang
Department of Pathology, College of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA.
Raymond B
RB
Nagle
Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
Beatrice S
BS
Knudsen
Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA gcrogers@email.arizona.edu cress@email.arizona.edu.
Gregory C
GC
Rogers
Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA gcrogers@email.arizona.edu cress@email.arizona.edu.
Anne E
0000-0001-6194-0061
AE
Cress
D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009024:Morphogenesis; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D039161:Integrin alpha6beta4; D000097794:Kalinin
Integrin; Laminin; Neoplasia; Prostate; Spheroids