Cell interactions control the fate of malignant keratinocytes in an organotypic model of early neoplasia

• Verfasst von: Vaccariello, Michael [VerfasserIn]
• Verfasst von: Fusenig, Norbert [VerfasserIn]
• Titel: Cell interactions control the fate of malignant keratinocytes in an organotypic model of early neoplasia
• Verf.angabe: Michael Vaccariello, Ashkan Javaherian, Youai Wang, Norbert E. Fusenig, and Jonathan A. Garlick
• E-Jahr: 2015
• Jahr: 8 December 2015
• Jahr des Originals: 1999
• Umfang: 8 S.
• Fussnoten: Available online 8 December 2015 ; Elektronische Reproduktion der Druck-Ausgabe ; Gesehen am 11.02.2021
• Titel Quelle: Enthalten in: The journal of investigative dermatology
• Ort Quelle: Amsterdam : Elsevier, 1938
• Jahr Quelle: 1999
• Band/Heft Quelle: 113(1999), 3, Seite 384-391
• ISSN Quelle: 1523-1747
• DOI: doi:10.1046/j.1523-1747.1999.00701.x
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: intraepithelial neoplasia
• Sach-SW: organotypic culture
• Sach-SW: tumor suppression
• K10plus-PPN: 1748111396

Abstract

The role of cell interactions during early neoplastic progression in human skin is not well understood. We report that the fate and behavior of low-grade malignant cells in stratified epithelium is dependent on their interactions with neighboring cells and with extracellular matrix during the early events in neoplastic progression. We utilized an organotypic tissue model which mimics premalignancy to monitor malignant cells (II-4) genetically marked with β-gal and grown in the context of either normal human keratinocytes or the immortalized cell line HaCaT. HaCaT cells were permissive for clonal expansion of II-4 cells at ratios of 4:1, 12:1, and 50:1 (HAC:II-4) when compared with coculture with normal human keratinocytes. This II-4 cell expansion was associated with the failure of neighboring HaCaT cells to induce differentiation and cell cycle withdrawal of II-4, as had been seen in the context of normal human keratinocytes. When 12:1 mixtures (NHK:II-4) were stripped of all suprabasal cells and regrown, all β-gal cells were lost showing that these normal human keratinocyte-suppressed II-4 cells had been actively sorted to a suprabasal position where their clonal expansion was limited. These growth-suppressive effects of normal human keratinocytes were found to be conditional on direct cell-cell contact, as II-4 formed colonies when trypsinized from 12:1 (NHK:II-4) mixtures and grown at clonal density in submerged culture. The distribution and behavior of low-grade malignant cells was therefore dependent on the state of transformation of adjacent keratinocytes and on cell-matrix interactions. These results demonstrate that alterations in the cellular microenvironment are central to the induction of clonal expansion and early neoplastic progression in stratified epithelium.