Mitotic quiescence, but not unique "stemness," marks the phenotype of bone metastasis-initiating cells in prostate cancer.

Abstract

This study aimed to identify subpopulations of prostate cancer cells that are responsible for the initiation of bone metastases. Using rapidly dividing human prostate cancer cell lines, we identified mitotically quiescent subpopulations (<1%), which we compared with the rapidly dividing populations for patterns of gene expression and for their ability to migrate to the skeletons of athymic mice. The study used 2-photon microscopy to map the presence/distribution of fluorescently labeled, quiescent cells and luciferase expression to determine the presence of growing bone metastases. We showed that the mitotically quiescent cells were very significantly more tumorigenic in forming bone metastases than fast-growing cells (55 vs. 15%) and had a unique gene expression profile. The quiescent cells were not uniquely stem cell like, with no expression of CD133 but had the same level expression of other putative prostate stem cell markers (CD44 and integrins α2/β1), when compared to the rapidly proliferating population. In addition, mitotic quiescence was associated with very high levels of C-X-C chemokine receptor type 4 (CXCR4) production. Inhibition of CXCR4 activity altered the homing of quiescent tumor cells to bone. Our studies suggest that mitotic dormancy is a unique phenotype that facilitates tumor cell colonization of the skeleton in prostate cancer.

• Authors: Ning Wang, Freyja Docherty, Hannah K Brown, Kim Reeves, Anne Fowles, Michelle Lawson, Penelope D Ottewell, Ingunn Holen, Peter I Croucher, Colby L Eaton
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 8 Pg. 3141-50 (Aug 2015) ISSN: 1530-6860 [Electronic] United States
• PMID: 25888599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• AC133 Antigen
• Antigens, CD
• Biomarkers, Tumor
• Glycoproteins
• Hyaluronan Receptors
• Integrin alpha Chains
• Integrin beta Chains
• PROM1 protein, human
• Peptides
• Prom1 protein, mouse
• Receptors, CXCR4

Topics

• AC133 Antigen
• Animals
• Antigens, CD (metabolism)
• Biomarkers, Tumor (metabolism)
• Bone Neoplasms (metabolism, pathology)
• Glycoproteins (metabolism)
• Humans
• Hyaluronan Receptors (metabolism)
• Integrin alpha Chains (metabolism)
• Integrin beta Chains (metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitosis (physiology)
• Neoplastic Stem Cells (metabolism, pathology)
• Peptides (metabolism)
• Phenotype
• Prostatic Neoplasms (metabolism, pathology)
• Receptors, CXCR4 (metabolism)
• Tumor Cells, Cultured