Abstract
Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate[1]. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina—features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These “Super-Lo-MYC” mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a “paradoxical” increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.
Highlights
Prostate cancer proceeds through a morphological progression consisting of the development of prostatic intraepithelial neoplasia (PIN), invasive adenocarcinoma, distant metastatic disease, and androgen refractory metastatic disease [2,3,4,5]
Together with the findings that overexpression of MYC in the mouse prostate causes PIN [1,32] that progresses to adenocarcinoma[1], and that MYC can transform isolated human prostate epithelial cells into tumorigenic cells when mixed with urogenital sinus mesenchyme [33], these results suggest MYC overexpression may be a critical factor contributing to prostatic adenocarcinoma initiation
Since all PIN lesions showed marked nucleolar enlargement, similar to human high grade PIN, we propose to refer to these lesions as high grade PIN and we submit that Lo-MYC and Hi-MYC mice do not develop low grade PIN
Summary
Prostate cancer proceeds through a morphological progression consisting of the development of prostatic intraepithelial neoplasia (PIN), invasive adenocarcinoma, distant metastatic disease, and androgen refractory metastatic disease [2,3,4,5]. We have postulated that atrophic epithelial cells, that often occur in large numbers in regions of inflammation (e.g. proliferative inflammatory atrophy/ PIA), are often the target cells for transformation This hypothesis is based upon morphological transitions of atrophy to PIN, and at times directly to micro-invasive adenocarcinoma, and rare molecular alterations such as methylation of GSTP1 [23] and telomere shortening [24]. Another possibility was recently revealed by Wang et al, who showed that rare cells within the luminal compartment of the mouse prostate, that express Nkx3.1 in an androgen independent fashion (referred to as castrate resistant Nkx3.1 expressing cells or CARNs), possess stem cell characteristics and can be a target of neoplastic transformation[25]. How do these aberrantly proliferating atrophic cells, or other luminal-like cells in non-atrophic epithelium, undergo transformation? The answer, at least in a significant fraction of cases, may relate to MYC expression (Note that the official gene name for what is commonly referred to as C-MYC is MYC)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
