Castration-Resistant Luminal Cells Active for Wnt Signaling as Cells of Origin of Castration-Resistant Prostate Cancer
Abstract
Prostate cancer is a major epithelial solid tumor and the second most common cause of cancer-related death for men. Prostate cancer-related mortality is mainly caused by castration-resistant prostate cancer (CRPC) (i.e., cancer cells that survive androgen deprivation therapy). Thus, understanding how this advanced stage prostate cancer is developed is the key to developing a novel therapy to further reduce prostate cancer-related mortality. One mechanism for developing CRPC is that CRPC cells acquire this ability from normal prostate cells from which they are derived; the gene expression program of such normal cells has already been wired in a way so that they can naturally survive under a low androgen environment. The prostate gland is composed of a layer of secretory luminal cells and a second layer of basal cells. In mice, upon castration, many basal cells as well as a small portion of luminal cells can survive castration. Traditionally, it is believed that prostate basal cells have stem cell activity and can produce both basal cells and luminal cells. However, more recent studies suggest that prostate luminal cells are more likely maintained by their own stem cells and such luminal stem cells may be intrinsically resistant to castration. Recent studies also suggest that most prostate cancers may originate from luminal cells, rather than from basal cells. Therefore, it is of great interest and importance to identify and characterize such luminal stem cells. To address this, we dissected prostates from both castrated and uncastrated mice and isolated single prostate cells from them. We then measured expression levels of couple hundred genes of our interest in these individual prostate cells and compared their expression between castrated and uncastrated prostate cells. Interestingly, we found a subset of castration-resistant luminal cells upregulated expression of several genes belonging to a signaling pathway called Wnt signaling, which is a well-known pathway playing key roles in early development, stem cell function, tissue injury, and subsequent tissue repair. One of these upregulated Wnt pathway genes encodes a cell surface marker called Lgr5, which is a well-known marker for stem cells in the intestine. We hypothesize that these Lgr5-expressing castration-resistant luminal cells represent luminal stem cells that can regenerate the prostate luminal epithelial cell compartment upon restoration of testosterone (such cells can serve as the target cell population that give rise to more aggressive prostate cancer) and that Lgr5-expressing cells (that is, cells active for Wnt signaling) are also present in CRPC. We further hypothesize that Wnt signaling itself is required for the regenerative capacity of the Lgr5-expressing castration-resistant luminal cells, as well as for their roles in invasive prostate cancer and CRPC. By determining the unique molecular program in these Wnt signaling-active castration-resistant luminal cells, we expect to gain novel insights into how CRPC is developed, how CRPC can be treated and/or prevented, and how we can distinguish prostate lesions that will progress to CRPC from those that would not progress. To achieve this goal, we will use existing tools from mouse genetics that can allow us to visualize cells that express Lgr5 or allow us to permanently label Lgr5-expressing cells with a fluorescent protein marker so that such cells can be traced in mice either during tissue regeneration or during prostate cancer development. The ability to visualize such cells will allow us to isolate them and characterize their global gene expression pattern by a well-established technology called microarray. This will allow us to determine the unique molecular signatures in them, some of which may be translated into novel targets for treating and/or preventing CRPC. Taking advantage of the ability to trace the progression of these cells, we will determine whether these castration-resist
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510546
Entities
People
- Zhe Li
Organizations
- United States Army