Luminal Cells Are Favored as the Cell of Origin for Prostate Cancer

Wang, Zhu A.; Toivanen, Roxanne; Bergren, Sarah K.; Chambon, Pierre; Shen, Michael M.

doi:10.1016/j.celrep.2014.08.002

Cited by 121 publications

(121 citation statements)

References 37 publications

(62 reference statements)

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“…Hi basal cell 1,000 21 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Intriguingly, human basal-and luminal-derived tumors demonstrate histologically distinct phenotypes when challenged with the same oncogenes, MYC and AKT1. Tumors derived from basal cells are of a higher grade than tumors derived from luminal cells.…”

Section: Discussionmentioning

confidence: 99%

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

Park

Lee

Phillips

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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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

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Section: Discussionmentioning

confidence: 99%

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

Park

Lee

Phillips

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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“…It has been reported that by loss of tumor suppressor genes, both P-bSCs and P-lSCs can give rise to prostate cancer (12,13). Therefore, understanding how to manipulate the two populations of P-SCs to either remain silent in a dormant state or undergo terminal differentiation should provide new avenues to retrain prostate cancer progression and relapse.…”

Section: Discussionmentioning

confidence: 99%

Prostate Sphere-forming Stem Cells Are Derived from the P63-expressing Basal Compartment

Huang

Hamana

Liu

et al. 2015

Journal of Biological Chemistry

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Background: Different methods are established for identifying prostate stem cells (P-SCs). However, the relationship of these P-SCs is not fully clear. Results: Sphere-forming cells were from the basal compartment and also formed organoids. However, organoid-derived P-SCs cannot form prostaspheres. Conclusion:The basal P-SCs represent more primitive P-SCs than luminal P-SCs. Significance: The finding helps define the hierarchy of P-SCs.

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“…Luminal cells are generally accepted as the cells of origin for human PC 26,29 and human pathologists diagnose the disease based on the absence of basal cell markers. 42 Evidence from the mouse implicates both luminal cells 18,39,41 and basal cells 22,25,38 39 Alternatively, neoplastic transformation may commence in differentiated progenitor cells (intermediate cells) that co-opt self-renewal programs form tissue stem cells. 5 Finally, even mature differentiated postmitotic prostatic luminal cells could be reprogrammed by oncogenic pressure into tumor-initiating cells.…”

Section: Discussionmentioning

confidence: 99%

Different Growth Patterns of Canine Prostatic Carcinoma Suggests Different Models of Tumor-Initiating Cells

Akter

Lean

et al. 2015

Vet Pathol

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Controversies remain regarding the cell type from which human prostate cancer originates, and many attempts have been made to identify the cellular origin of canine prostate cancer but without definitive proof. This study aims to evaluate the expression of luminal (androgen receptor [AR], cytokeratin [CK]8/18) and basal (CK14, CK5) cell markers in different histologic subtypes of canine prostatic carcinoma (PC) and to suggest the most likely tumor-initiating cells. Normal prostates (n ¼ 8) were characterized by ARþCK8/18þ luminal cells and few CK5þ basal cells, while CK14 was absent. Similar pattern was observed in all 35 prostates with benign prostatic hyperplasia, except few scattered CK14þ basal cells in 13 samples (37.14%). AR was localized in the nucleus of both normal and hyperplastic cells. In 34 samples of PC, the following growth patterns were identified: cribriform (44.12%), solid (32.35%), small acinar/ductal (20.59%), and micropapillary (2.94%). Most PCs expressed AR and CK8/18, while CK5 and CK14 expression was observed in 25% and 20% of cases, respectively. AR revealed a variable intracellular distribution, both nuclear and cytoplasmic. Solid PC was characterized by an undifferentiated or aberrant phenotype with a reduced expression of AR and CK8/18, increased number of CK14þ cells, and 7 antigen expression patterns. This study demonstrated a predominance of differentiated luminal cell types in canine prostatic tumors, although the role of basal cells in prostate carcinogenesis should also be considered. Moreover, few scattered CK5þ cells in ARþCK8/18þ tumors identified the existence of intermediate cells, from which neoplastic transformation may alternatively commence.

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Luminal Cells Are Favored as the Cell of Origin for Prostate Cancer

Cited by 121 publications

References 37 publications

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

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

Prostate Sphere-forming Stem Cells Are Derived from the P63-expressing Basal Compartment

Different Growth Patterns of Canine Prostatic Carcinoma Suggests Different Models of Tumor-Initiating Cells

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