ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Charafe-Jauffret, Emmanuelle; Ginestier, Christophe; Bertucci, François; Cabaud, Olivier; Wicinski, Julien; Finetti, Pascal; Josselin, Emmanuelle; Adélaı̈de, José; Nguyen, Tien-Tuan; Monville, Florence; Jacquemier, Jocelyne; Thomassin-Piana, Jeanne; Pinna, Guillaume; Jalaguier, Aurélie; Lambaudie, Éric; Houvenaeghel, Gilles; Xerri, Luc; Harel‐Bellan, Annick; Chaffanet, Max; Viens, Patrice; Birnbaum, Daniel

doi:10.1158/0008-5472.can-12-4704

Cited by 106 publications

(93 citation statements)

References 47 publications

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“…Numerous studies concur that, in breast cancer and in cancers from other tissues, ALDH activity and/or expression identifies the subpopulation with highest tumorigenicity and metastatic potential [12,21,45,46]. General agreement also exists that ALDH1A1 correlates with ER– status in breast cancers and is an independent predictor of poor clinical outcome [12,22,27,45].…”

Section: Discussionmentioning

confidence: 97%

Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium

et al. 2014

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IntroductionAlthough estrogen and progesterone play a key role in normal mammary development and in breast cancer, the potential for proliferation and lineage differentiation as well as origin of cells that express the estrogen receptor (ER) in normal breast epithelium are not known. Some evidence suggests that normal human mammary stem/progenitor cells are ER–, but the identity of these cells and the cellular hierarchy of breast epithelium are still subjects of controversy. It is likely that elucidation of these aspects will bring insight into the cellular origin of breast cancer subtypes.MethodsWe used fluorescence-activated cell sorting of primary human mammary epithelial cells along with in vitro and in vivo functional assays to examine the hierarchic relation between cells with aldehyde dehydrogenase enzymatic activity (ALDH+ cells) and ER+ cells in the normal human breast epithelium. We assessed the proliferation and lineage differentiation potential of these cells in vitro and in vivo. A gene reporter assay was used to separate live ER+ and ER– mammary epithelial cells. With shRNA-mediated knockdown, we investigated the role of ALDH isoforms in the functionality of mammary epithelial progenitor cells.ResultsWe describe a cellular hierarchy in the normal human mammary gland in which ER–/ALDH+ cells with functional properties of stem/progenitor cells generate ER+ progenitor cells, which in turn give rise to cells of luminal lineage. We show that the ALDH1A1 isoform, through its function in the retinoic acid metabolism, affects the proliferation and/or early differentiation of stem/progenitor cells and is important for branching morphogenesis.ConclusionsThis study presents direct evidence that ER+ cells are generated by ER–/ALDH+ stem/progenitor cells. We also show that ER+ cells are able to generate cell progeny of luminal lineage in vitro and in vivo. Loss of ALDH1A1 function impairs this process, as well as branching morphogenesis and clonogenicity in suspension culture. This latter effect is reversed by treatment with retinoic acid.

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Section: Discussionmentioning

confidence: 97%

Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium

et al. 2014

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“…Numerous preclinical studies have shown that expression of ALDH1 in tumor cells has been associated with stem-like characteristics, including innate chemoresistance and clonal capacity [17-20]. Moreover, expression of ALDH1 in surgically resected breast cancer is strongly associated with metastasis and poor survival [18,21].…”

Section: Introductionmentioning

confidence: 99%

Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer

et al. 2014

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IntroductionAlthough neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy.MethodsWomen with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher’s exact test while Kaplan-Meier method was used to calculate survival.ResultsA hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. ConclusionsALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells. Trial registrationACTRN12605000588695

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“…It is now well established that cancer stem-like cells (CSCs) can be identified within in vivo tumor bulks or in vitro cell cultures thanks to several markers [1, 2, 3]. Many studies have already reported the presence of CSCs in different solid tumors, such as breast, brain, prostate, lung, ovary, colon, pancreas, liver, melanoma, head and neck [4, 5, 6, 7].…”

Section: Introductionmentioning

confidence: 99%

“…This protein was first discovered on human hematopoietic stem cells and then identified in several cancers [4, 9]. Some studies also revealed that ALDH1, another common marker used for CSC identification, was also intimately correlated with tumorigenesis [1, 8, 15, 16]. …”

Section: Introductionmentioning

confidence: 99%

CD133-positive cancer stem cells from colo205 human colon adenocarcinoma cell line show resistance to chemotherapy and display a specific metabolomic profile

Zangiacomi¹,

Urakami²,

Maruyama³

et al. 2014

Genes Cancer

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During the past decade, cancer stem-like cells (CSCs) have drawn substantial interest in cancer research since they have been described as major targets to improve treatment of tumors and to prevent recurrence and metastasis. In this paper, we report on the search for CSCs within the Colo205 human adenocarcinoma cell line. We describe that CD133 (prominin) was the only reliable marker for the isolation and characterization of CSCs within a Colo205 cell population. CD133-positive cells displayed many CSC characteristics, such as tumorsphere formation ability, expression of early-stage development markers, high invasiveness, raised tumor initiation potential and resistance to cisplatin chemotherapy treatment. In vitro analyses also highlighted a specific metabolomic profile of CD133-positive cells and we concluded that the chemotherapy resistance of CSCs could be related to the quiescence of such cells associated with their reduced metabolism. Furthermore, in vivo metabolome analyses suggested that a high level of circulating glutathione molecules could also promote treatment resistance. From the perspective of metabolomics, we also discuss the controversial use of serum-free in vitro cultures for CSC enrichment prior to further phenotype characterization.

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ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Cited by 106 publications

References 47 publications

Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium

Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium

Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer

CD133-positive cancer stem cells from colo205 human colon adenocarcinoma cell line show resistance to chemotherapy and display a specific metabolomic profile

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