Back to Search
Start Over
Deletion of the p16INK4a tumor suppressor and expression of the androgen receptor induce sarcomatoid carcinomas with signet ring cells in the mouse prostate
- Source :
- PLoS ONE, Vol 14, Iss 1, p e0211153 (2019), PloS one, vol 14, iss 1, PLoS ONE
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.
- Subjects :
- Male
0301 basic medicine
Carcinogenesis
medicine.disease_cause
Transgenic
Androgen
Mice
Prostate cancer
0302 clinical medicine
Adenocarcinomas
Signet ring cell carcinoma
Receptors
Medicine and Health Sciences
2.1 Biological and endogenous factors
Aetiology
Cancer
Staining
Prostatic Intraepithelial Neoplasia
Multidisciplinary
Signet ring cell
Prostate Cancer
Prostate Diseases
Retinoblastoma protein
Cell Staining
Animal Models
Signet Ring Cell
3. Good health
Experimental Organism Systems
Oncology
Receptors, Androgen
030220 oncology & carcinogenesis
Medicine
Anatomy
Research Article
Urologic Diseases
Epithelial-Mesenchymal Transition
General Science & Technology
Urology
Science
Mice, Transgenic
Mouse Models
Biology
Research and Analysis Methods
Carcinomas
03 medical and health sciences
Model Organisms
Exocrine Glands
Genetics
medicine
Animals
Humans
Neoplasm Invasiveness
Epithelial–mesenchymal transition
Sarcomatoid carcinoma
Immunohistochemistry Techniques
Cyclin-Dependent Kinase Inhibitor p16
Cell Proliferation
Carcinoma
Cancers and Neoplasms
Biology and Life Sciences
Prostatic Neoplasms
medicine.disease
Histochemistry and Cytochemistry Techniques
Genitourinary Tract Tumors
030104 developmental biology
Specimen Preparation and Treatment
Animal Studies
Immunologic Techniques
biology.protein
Cancer research
Prostate Gland
Cyclin-dependent kinase 6
Carcinoma, Signet Ring Cell
Gene Deletion
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....2941aa0e2bdf87cc6a1f863a4ac372ba