Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay

Abstract

The cell of origin for prostate cancer remains a subject of debate.Genetically engineered mouse models have demonstrated that both basal and luminal cells can serve as cells of origin for prostate cancer. Using a human prostate regeneration and transformation assay, our group previously demonstrated that basal cells can serve as efficient targets for transformation. Recently, a subpopulation of multipotent human luminal cells defined by CD26 expression that retains progenitor activity in a defined organoid culture was identified. We transduced primary human prostate basal and luminal cells with lentiviruses expressing c-Myc and activated AKT1 (myristoylated AKT1 or myrAKT1) to mimic the MYC amplification and PTEN loss commonly detected in human prostate cancer. These cells were propagated in organoid culture before being transplanted into immunodeficient mice. We found that c-Myc/myrAKT1-transduced luminal xenografts exhibited histological features of well-differentiated acinar adenocarcinoma, with strong androgen receptor (AR) and prostate-specific antigen (PSA) expression. In contrast, c-Myc/myrAKT1-transduced basal xenografts were histologically more aggressive, with a loss of acinar structures and low/absent AR and PSA expression. Our findings imply that distinct subtypes of prostate cancer may arise from luminal and basal epithelial cell types subjected to the same oncogenic insults. This study provides a platform for the functional evaluation of oncogenes in basal and luminal epithelial populations of the human prostate. Tumors derived in this fashion with defined genetics can be used in the preclinical development of targeted therapeutics.human prostate cancer | cells of origin | luminal cell | cancer differentiation | oragnoid culture

The Stem Cell Division Theory of Cancer

“…Theories primarily based on data from laboratory studies may be compromised by assumptions and experimental manipulations inherent to any experimental research. Laboratory data can demonstrate that a normal differentiated cell can be transformed into a tumorigenic cancer cell by inserting a set of mutations commonly found in human tumor samples [66,214,215]. However, this does not mean that human cancers occur because differentiated cells acquire such a set of mutations.…”

“…Currently, experimental data suggest that some cancers originate in stem cells and others in non-stem cells. For some common cancers, different experimental approaches have led to the identification of different cells of origin for cancer [60][61][62][63][64][65][66].…”

“…For example, because MYC amplification and PTEN loss are commonly detected in prostate cancers, the authors of a recent article [66] transduced primary human prostate basal and luminal cells with lentiviruses expressing c-Myc and activated AKT1 to mimic MYC amplification and PTEN inhibition. After propagation in organoid culture, the cells formed subcutaneous tumors in immunodeficient mice.…”

“…After propagation in organoid culture, the cells formed subcutaneous tumors in immunodeficient mice. The authors proposed that prostate cancers arise from both cell types, and that the distinct subtypes of prostate cancer may arise depending on which of these cells serves as the cell of origin of cancer [66].…”

“…The following analogy, based on the study mentioned above [66], may be useful to draw attention to the limitations of these strategies. Consider that we are investigating traffic accidents (prostate cancers) involving several vehicles (cell types) to identify which one causes the accidents (cell of origin in cancer).…”