Characterization and Clinical Relevance of ALDHbright Populations in Prostate Cancer

Magnen, Clémentine Le; Bubendorf, Lukas; Rentsch, Cyrill A.; Mengus, Chantal; Gsponer, Joël; Zellweger, Tobias; Rieken, Malte; Thalmann, George N.; Cecchini, Marco; Germann, Markus; Bachmann, Alexander; Wyler, Stephen; Heberer, Michael; Spagnoli, Giulio C.

doi:10.1158/1078-0432.ccr-12-2857

Cited by 71 publications

(81 citation statements)

References 43 publications

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“…ALDH (aldehyde dehydrogenase) activity, often measured via ALDEFLUOR assay, has been successfully used as a marker to enrich CSC populations 11,[17][18][19][20][21][22] in a variety of cancers including human melanoma 23 and head and neck squamous cell cancer. 18 We characterized CSC-enriched populations in 2 histologically distinct murine tumors (melanoma D5 and squamous cell cancer SCC7) and evaluated their immunogenicity by administering CSC-based vaccines in 2 genetically different syngeneic immunocompetent hosts followed by tumor challenge.…”

Section: Introductionmentioning

confidence: 99%

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

et al. 2015

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Keywords: antitumor immunity, cancer stem cell, dendritic cell, metastasis, vaccine Abbreviations: ALDH, aldehyde dehydrogenase; CSC, cancer stem cell; CSC-DC, CSC lysate-pulsed dendritic cell; DC, dendritic cell; H-DC, heterogeneous, unsorted tumor cell lysate-pulsed dendritic cell; RT, radiation therapy; qRT-PCR, real time quantitative PCR.The inability to target cancer stem cells (CSC) may be a significant factor contributing to treatment failure. We have developed a strategy to target the CSC populations in melanoma and squamous cell carcinoma using CSC lysate-pulsed dendritic cells (DCs). The CSC-DC vaccine was administered in the adjuvant setting after localized radiation therapy of established tumors. Using mouse models we demonstrated that DCs pulsed with CSCs enriched by virtue of their expression of the CSC marker ALDH (termed CSC-DC) significantly inhibited tumor growth, reduced development of pulmonary metastases and prolonged survival. The effect was associated with downregulation of chemokine (C-C motif) receptors CCR7 and CCR10 in tumor cells and decreased expression of the chemokine (C-C motif) ligands CCL21, CCL27 and CCL28 in lung tissue. The CSC-DC vaccine significantly reduced ALDH high CSC frequency in primary tumors. Direct targeting of CSCs was demonstrated by the specific binding of IgG produced by ALDH high CSC-DC vaccineprimed B cells to ALDH high CSCs, resulting in lysis of these target CSCs in the presence of complement. These data suggest that the CSC-DC vaccine approach may be useful in the adjuvant setting where local and systemic relapse are high after conventional treatment of cancers.

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Section: Introductionmentioning

confidence: 99%

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

et al. 2015

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“…The first route is characterized by strong upregulation of the TGF-β receptor ALK1, which can be activated by various BMPs, in addition to TGF-β1 and TGF-β3 [41,42]. Inhibition of ALK1 in our model led to reduced phosphorylation of p38, downregulation of the EMT-markers VIM, MMP1, CDH2, and SNAI2, as well as reduced expression of ID1 and ID2, for which induction by ALK1 signaling is known [43].…”

Section: Discussionmentioning

confidence: 76%

“…ETS proteins can act as activator or repressor of transcription by regulating genes that are involved in cellular architecture, migration, invasion, and permeability. Therefore, ETS transcription factors play a role in embryogenesis, vasculogenesis, angiogenesis, haematopoiesis and neuronal development in a wide range of tissues [41]. During development, ERG is involved in the formation of the vascular system, the urogenital tract, in bone development, and in migration of embryonic neural crest cells [41].…”

Section: The Pathogenesis and Progression Of Prostate Cancermentioning

confidence: 99%

“…Therefore, ETS transcription factors play a role in embryogenesis, vasculogenesis, angiogenesis, haematopoiesis and neuronal development in a wide range of tissues [41]. During development, ERG is involved in the formation of the vascular system, the urogenital tract, in bone development, and in migration of embryonic neural crest cells [41]. In adult tissue, ERG expression is found in endothelial cells of various tissues maintaining vascular integrity and regulating vascular inflammatory response by regulating VE-cadherin, von Willebrand factor, endoglin, VEGF, IL8, ICAM-1, and VCAM [41].…”

Section: The Pathogenesis and Progression Of Prostate Cancermentioning

confidence: 99%

“…For example, JMJD1C, a histone demethylase also known as KDM3C, is involved in maintaining low H3K9me2 levels that are associated with activated target gene expression. JMJD1C has been described as coactivator for several transcription factors including AR [41,42]. A general interaction between Jmj-containing KDM proteins and ERG has been reported to lead to activation of the YAP1 proliferation pathway [43].…”

Section: Microarray Profiling Indicates Differentially Expressed Epigmentioning

confidence: 99%

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A Prominent Couple

Ratz¹

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Exploring the intratumoral heterogeneity of DNA ploidy in prostate cancer

Vlajnic,

Müller,

Ruiz

et al. 2023

Cancer Reports

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BackgroundProstate cancer is morphologically and molecularly heterogeneous. Genomic heterogeneity might be mirrored by variability in DNA ploidy. Aneuploidy is a hallmark of genomic instability and associated with tumor aggressiveness. Little attention has been paid to the biological significance of the diploid tumor cell population that often coexists with aneuploid populations. Here, we investigated the role of DNA ploidy in tumor heterogeneity and clonal evolution.MethodsThree radical prostatectomy specimens with intratumoral heterogeneity based on nuclear features on H&E were selected. DNA content of each subpopulation was determined by DNA image cytometry and silver in situ hybridization (SISH). Genomic evolution was inferred from array comparative genomic hybridization (aCGH). Additionally, immunohistochemistry was used to examine the stemness‐associated marker ALDH1A1.ResultsNuclear morphology reliably predicted DNA ploidy status in all three cases. In one case, aCGH analysis revealed several shared deletions and one amplification in both the diploid and the aneuploid population, suggesting that these populations could be related. In the other two cases, a statement about relatedness was not possible. Furthermore, ALDH1A1 was expressed in 2/3 cases and exclusively observed in their diploid populations.ConclusionsIn this proof‐of‐concept study, we demonstrate the feasibility to predict the DNA ploidy status of distinct populations within one tumor by H&E morphology. Future studies are needed to further investigate the clonal relationship between the diploid and the aneuploid subpopulation and test the hypothesis that the aneuploid population is derived from the diploid one. Finally, our analyses pointed to an enrichment of the stemness‐associated marker ALDH1A1 in diploid populations, which warrants further investigation in future studies.

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Characterization and Clinical Relevance of ALDHbright Populations in Prostate Cancer

Cited by 71 publications

References 43 publications

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells

A Prominent Couple

Exploring the intratumoral heterogeneity of DNA ploidy in prostate cancer

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