Prostate cancer (PC) characterized by luminal cell expansion and the absence of basal cells is one of the most common cancer in men. Despite the success of identifying the rare prostate luminal stem cell as the cell of origin for PC under castration condition, it remains an open question which cell with defined markers is prostate epithelial stem/progenitor cells under the physiological conditions. There is a critical need for identifying the androgen-independent prostate luminal progenitor cells and determining the essential signaling that confers the capacity for androgen-independent survival to luminal cells.
In addition, with regard to the luminal histopathological characteristic of PC, it indeed highlights the need to identify the luminal stem/progenitor cells and to characterize their behaviors under various contexts. Prior work in prostate stem cells have focused on basal cells and luminal cells of the proximal prostate, both harboring increased stem characteristics such as in vitro colony formation and in vivo label retention.
However, in the context of normal prostate, the specific prostate luminal subpopulation that maintains prostate homeostasis and serves as the target for malignant transformation is largely unknown.
In a study published in Nature Genetics on August 17, a research team led by Dr. GAO Dong from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences found the Dist-Luminal-C cells as the luminal progenitor cell population in invagination tips.
Prostate cell types and their annotation are based on a small number of marker genes. To investigate the prostate cell types, the researchers analyzed the whole prostate cells and generated a comprehensive prostate cell atlas. They showed for the first time that prostate luminal cells divided into three types (Luminal-A/B/C cells), and will be a valuable resource to the entire field.
To investigate the prostate cell lineage hierarchy, the researchers analyzed the three prostate luminal cell types and identified Luminal-C cell population with stem/progenitor cell properties. Interestingly, they found that Luminal-C cells formed small clusters at the prostate glandular invagination tips in the prostate distal regions. Using the in vivo cell lineage tracing strategies, they have demonstrated that adult prostate luminal stem/progenitor cells (Luminal-C) are unipotent luminal progenitor cells through self-renewal and differentiation mechanism under physiological condition.
Knowing that prostate luminal cells are favor as cellular origin of PC led the researcher to their next question: Whether Luminal-A/B/C cells
have different abilities to generate prostate cancer?
In mouse models for the PC, they tested whether the different luminal cell types have different abilities to initiate PC. They randomly deleted Pten in the different luminal cell types. As expected, prostate tumors initiated by Luminal-A/B cells were similar to those originating from Luminal-C cells but developed more slowly, perhaps due to an intrinsic delay in the dedifferentiation of Luminal-C cells from Luminal-A/B cells.
Altogether, this work may also find one of the potential cellular origins of PC and it contributes pivotal new knowledge to the prostate stem cell research field that should provide novel models to do so.
Schematic diagram of the self-renewal of Dist-Luminal-C cells and their role as prostate cancer-initiating cells