Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways

Chéry, Lisly; Lam, Hung; Coleman, Ilsa M.; Lakely, Bryce; Coleman, Roger; Larson, Sandy; Aguirre‐Ghiso, Julio A.; Xia, Jing; Gulati, Roman; Nelson, Peter S.; Montgomery, Bruce; Lange, Paul H.; Snyder, Linda A.; Vessella, Robert L.; Morrissey, Colm

doi:10.18632/oncotarget.2480

Cited by 92 publications

(108 citation statements)

References 30 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…Culture of PCa cells with NE demonstrated a decrease in expression of both p27 and p21 (Figure 3A–C). Previous reports have demonstrated that an increased ratio of p-ERK 1/2 to p-p38 MAPK is associated with re-activation from dormancy in prostate and other cancers (7,9,31). Thus, we also evaluated p-ERK and p-p38 levels following exposure to NE (Figure 3D–E).…”

Section: Resultsmentioning

confidence: 95%

Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

Decker

Jung

Cackowski

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

Clinical observations have identified an association between psychological stress and cancer relapse; suggesting that the sympathetic nervous system/norepinephrine (NE) plays a role in reactivation of dormant disseminated tumor cells (DTCs) in the bone marrow niche. Here, the mechanism by which NE regulates prostate cancer (PCa) DTCs in the marrow is explored. NE directly stimulated PCa cell proliferation through β2-adrenergic receptors (ADRB2). NE also altered PCa proliferation in the marrow niche by indirectly by downregulating the secretion of the dormancy inducing molecule growth arrest specific-6 (GAS6) expressed by osteoblasts. These observations were confirmed in co-cultures of PCa cells expressing the fluorescent ubiquitination-based cell cycle reporters (FUCCI) and osteoblasts isolated from GAS6-deficient (GAS6−/−) animals. A novel ex vivo model system, using femurs harvested from GAS6+/+ or GAS6−/− mice, was used to confirm these results. As in co-culture, when PCa cells were injected into the marrow cavities of GAS6+/+ femurs, NE altered the PCa cell cycle. However, NE had less of an impact on PCa cells in femur explants isolated from GAS6−/− mice. Together, this study demonstrate that NE reactivates PCa cell-cycling through both a direct action on PCa cells and indirectly on adjacent niche cells

show abstract

Section: Resultsmentioning

confidence: 95%

Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

Decker

Jung

Cackowski

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Hypoxia activates an unfolded protein response (UPR) that results in the attenuation of translation initiation and the induction of cell cycle arrest genes [4,109,110]. Intriguingly, the UPR was found in dormant cancer cells in experimental models [111] and transcripts for speci c UPR genes were also found to be upregulated in dormant DTCs isolated from BM of prostate cancer patients [112]. These genes could also be turned on in DTCs in the target organ by the fact that they carry a signature epigenetically imprinted in the primary tumors (i.e., the DTCs carry a remodeled chromatin in response to hypoxia in the primary site) [7,113].…”

Section: Routes By Which Hypoxia Affects Dtc Fatementioning

confidence: 99%

The Different Routes to Metastasis via Hypoxia-Regulated Programs

Nobre

Entenberg

Wang

et al. 2018

Trends in Cell Biology

Self Cite

View full text Add to dashboard Cite

Hypoxia is linked to metastasis; however, how it affects metastatic progression is not clear due to limited consensus in the literature. We posit that this lack of consensus is due to hypoxia being studied using different approaches, such as in vitro, primary tumor, or metastasis assays in an isolated manner. Here, we review the pros and cons of in vitro hypoxia assays, highlight in vivo studies that inform on physiological hypoxia, and review the evidence that primary tumor hypoxia might influence the fate of disseminated tumor cells (DTCs) in secondary organs. Our analysis suggests that consensus can be reached by using in vivo methods of study, which also allow better modeling of how hypoxia affects DTC fate and metastasis.

show abstract

“…The culprits for the recurrent disease are the small number of residual cells that are disseminated from the primary tumor prior to treatment (4). Even patients with asymptomatic disease or no evidence of primary disease progression are known to often harbor cancer cells at distant organs such as bone, and they can be isolated from the bone marrow aspirate (5). These cells include quiescent cancer stem cells (CSCs) 2 and may reacquire clonogenic growth in a favorable environment and cause recurrent disease, which is evident in 20 -50% of patients who were treated for localized primary disease (6).…”

mentioning

confidence: 99%

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

Sharma

Xing

Yin

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prostate cancer is known to frequently recur in bone; however, how dormant cells switch its phenotype leading to recurrent tumor remains poorly understood. We have isolated two syngeneic cell lines (indolent and aggressive) through in vivo selection by implanting PC3mm stem-like cells into tibial bones. We found that indolent cells retained the dormant phenotype, whereas aggressive cells grew rapidly in bone in vivo, and the growth rates of both cells in culture were similar, suggesting a role of the tumor microenvironment in the regulation of dormancy and recurrence. Indolent cells were found to secrete a high level of secreted protein acidic and rich in cysteine (SPARC), which significantly stimulated the expression of BMP7 in bone marrow stromal cells. The secreted BMP7 then kept cancer cells in a dormant state by inducing senescence, reducing "stemness," and activating dormancy-associated p38 MAPK signaling and p21 expression in cancer cells. Importantly, we found that SPARC was epigenetically silenced in aggressive cells by promoter methylation, but 5-azacytidine treatment reactivated the expression. Furthermore, high SPARC promoter methylation negatively correlated with disease-free survival of prostate cancer patients. We also found that the COX2 inhibitor NS398 down-regulated DNMTs and increased expression of SPARC, which led to tumor growth suppression in bone in vivo. These findings suggest that SPARC plays a key role in maintaining the dormancy of prostate cancer cells in the bone microenvironment.

show abstract

Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways

Cited by 92 publications

References 30 publications

Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

The Different Routes to Metastasis via Hypoxia-Regulated Programs

Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone

Contact Info

Product

Resources

About