Stromal expression of ALDH1 in human breast carcinomas indicates reduced tumor progression

Bednarz‐Knoll, Natalia; Nastały, Paulina; Żaczek, Anna; Stoupiec, MaÅ Gorzata; Wikman, Harriet; Müller, Volkmar; Skokowski, Jarosław; Szade, Jolanta; Sejda, Aleksandra; Wełnicka-Jaśkiewicz, Marzena; Pantel, Klaus

doi:10.18632/oncotarget.4628

Cited by 21 publications

(34 citation statements)

References 48 publications

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“…Stromal positivity also indicated a longer time to BR and metastasis, and appeared even to be an independent predictor of good prognosis in the subgroup of d'Amico high risk patients. It is reasonable to conclude that ALDH1positive stromal cells might play a protective role in PCa, which is similar to the observation in breast cancer (2). ALDH1-positive stromal cells might hypothetically secrete retinoic acid and consequently in this way suppress tumor aggressiveness (2).…”

Section: Discussionsupporting

confidence: 74%

“…It is reasonable to conclude that ALDH1positive stromal cells might play a protective role in PCa, which is similar to the observation in breast cancer (2). ALDH1-positive stromal cells might hypothetically secrete retinoic acid and consequently in this way suppress tumor aggressiveness (2). Retinoic acid is known to induce tumor cell differentiation and inhibit tumor cell proliferation and migration (7)(8)(9).…”

Section: Discussionsupporting

confidence: 69%

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ALDH1-positive intratumoral stromal cells indicate epithelial differentiation and good prognosis in prostate cancer

Nastały

Filipska

Morrissey

et al. 2018

Preprint

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Aldehyde dehydrogenase 1 (ALDH1) characterizes tumor-initiating cells in solid tumors, however little is known about its expression in intratumoral stromal cells. Herein, we aimed to dissect its potential dual relevance in prostate cancer (PCa).ALDH1 expression was evaluated immunohistochemically in tumor and stromal cells in primary PCa and metastasis. It was correlated with clinico-pathological parameters, outcome of patients, and selected protein expression (CK5/6, CK14, CK8/18, CK19, EpCAM, Ki-67, E-cadherin, N-cadherin, and vimentin).ALDH1 protein was detected in tumor and stromal cells in 16% and 67% of 348 primary PCa, respectively. Tumor cell ALDH1 expression was associated with advanced tumor (T) status (p=0.009), higher Gleason score (p=0.016), shorter time to biochemical recurrence (BR) (p=0.010) and CK14 expression (p=0.023). Stromal cell ALDH1 expression correlated with lower T status (p=0.008), N0 status (p=0.017), lower Gleason score (p=0.016) and longer time to BR (p=0.017). In the subgroup of d’Amico high-risk patients it occurred even to be an independent predictor of good prognosis (multivariate analysis, p=0.050). ALDH1 was found in stroma of tumors characterized by CK8/18 (p=0.033) or EpCAM expression (p<0.001) and rarely by epithelial-mesenchymal transition defined as CK8/18(-)vimentin(+) phenotype (p=0.003). ALDH1 was detected in tumor cells and stroma of 33% and 41% of hormone naive lymph node metastases (n=63), 52% and 24% of castration resistant bone metastases, as well as 89% and 28% of castration resistant visceral metastases (n=21), respectively.We have determined that contrary to tumor cell ALDH1, the presence of stromal ALDH1 is associated with a more differentiated tumor epithelial phenotype in primary PCa, improved clinical outcome, and is less frequent in PCa metastases.AbbreviationsALDH1aldehyde dehydrogenase 1BRbiochemical recurrenceCKcytokeratinCRPCcastration resistant prostate cancerCSCcancer stem cellFFPEformalin fixed paraffin embedded tissueIHCimmunohistochemistryLNMlymph node metastasisOSoverall survivalPSAprostate specific antigenPTprimary tumorREMARKREporting recommendations for tumour MARKer prognostic studiesTMAtissue microarray

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 69%

ALDH1-positive intratumoral stromal cells indicate epithelial differentiation and good prognosis in prostate cancer

Nastały

Filipska

Morrissey

et al. 2018

Preprint

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“…Another study 49 indicated that ALDH1A1 expression was associated with good outcomes in TNBC. Sj€ ostr€ om et al 50 reported that stromal ALDH1A1 was associated with better distant disease-free survival in BC. A possible explanation of the survival discrepancy in mRNA expression is that the stromal expression of ALDH1A1 was not completely removed during tissue processing in the process of RNA extraction.…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance of ALDH1A1 expression in early invasive breast cancer

et al. 2020

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Aims Aldehyde dehydrogenase family 1 member A1 (ALDH1A1) is reportedly a key ALDH isozyme linked to the cancer stem cells (CSC) of many solid tumours, where it is involved in self‐renewal, differentiation and self‐protection. In this study, the prognostic significance of ALDH1A1 expression in early invasive breast cancer (BC) and its role as a BC stem cell (BCSC) were evaluated. Methods and results ALDH1A1 expression was assessed, using immunohistochemistry and tissue microarrays, in a large well‐characterised BC cohort. ALDH1A1 mRNA expression was also assessed at transcriptomic levels, utilising data from the Molecular Taxonomy of Breast Cancer International Consortium. The associations of ALDH1A1 with clinicopathological parameters, other stem cell markers and patient outcomes were determined. ALDH1A1 was expressed in 71% of BC cases at both the protein and mRNA levels. High ALDH1A1 expression was associated with poor prognostic features, including high grade, poor Nottingham Prognostic Index (NPI), lymph node metastasis and highly proliferative ER+ (luminal B) and triple‐negative (TNBC) subtypes. ALDH1A1 expression was positively correlated with the expression of CD44, CD24, TWIST, SOX9, EPCAM and CD133. The high immunoexpression of ALDH1A1 was significantly associated with poor BC‐specific survival (P < 0.001), and specifically in the luminal B and TNBC subtypes (P = 0.042 and P = 0.003, respectively). The immunoexpression of ALDH1A1 was an independent predictor of poor prognosis (P = 0.015). Conclusions ALDH1A1, as assessed using immunohistochemistry, seems to act as a BCSC marker associated not only with other BCSC markers but also with poor prognostic characteristics and poor outcomes, particularly in the luminal B and TNBC subtypes.

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“…A total of 411 breast cancer patients treated at the University Medical Center Hamburg-Eppendorf during 1999 -2006 were included in this study as described (10 ). The variable clinicopathologic and molecular parameters were documented (see Table 1 in the Data Supplement that accompanies the online version of this article at http://www.…”

Section: Clinical Materialsmentioning

confidence: 99%

Potential Involvement of Jagged1 in Metastatic Progression of Human Breast Carcinomas

et al. 2016

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BACKGROUND Jagged1, the ligand of Notch, has been shown to be involved in formation of bone metastases in an experimental study. Here, clinical relevance of Jagged1 expression in tumor progression was assessed in human breast carcinomas. METHODS Jagged1 expression was evaluated by immunohistochemistry in 228 tumor tissue samples and compared to clinicopathologic parameters and patients' outcomes. Furthermore, circulating tumor cells (CTCs) from peripheral blood of 100 unmatched metastatic cancer patients with progressive disease were enriched using Ficoll density gradient centrifugation and detected by pan-keratin/Jagged1/CD45 immunofluorescent staining. RESULTS Jagged1 expression was detected in 50% of 228 tumors. Jagged1 expression was correlated with higher tumor grade (P = 0.047), vascular invasion (P = 0.026), luminal B subtype (P = 0.016), overexpression of Her-2 (P = 0.001), high Ki-67 expression (P = 0.035), and aldehyde dehydrogenase 1 (ALDH1) positivity (P = 0.013). Jagged 1 expression indicated shorter disease-free survival (DFS) (P = 0.040) and metastasis-free survival (P = 0.048) in lymph node–negative breast cancer for which it was the only independent predictor of DFS (multivariate analysis, P = 0.046). Tumors characterized by the strongest Jagged1 staining intensity (7.5% of cases) correlated with lymph node positivity (P = 0.037), metastatic relapse (P = 0.049), and higher number of disseminated tumor cells in bone marrow aspirates (P = 0.041). Twenty-one unmatched metastatic breast cancer patients with progressive disease were positive for CTCs, and 85.7% of the CTCs also expressed Jagged1. The presence of Jagged1(+) CTCs was significantly associated with shorter progression-free survival in patients treated with bisphosphonates (P = 0.013). CONCLUSIONS Jagged1 expression characterizes more aggressive breast carcinoma and might be involved in tumor cell dissemination, metastatic progression, and resistance to bone-targeting therapy in breast cancer patients.

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Stromal expression of ALDH1 in human breast carcinomas indicates reduced tumor progression

Cited by 21 publications

References 48 publications

ALDH1-positive intratumoral stromal cells indicate epithelial differentiation and good prognosis in prostate cancer

ALDH1-positive intratumoral stromal cells indicate epithelial differentiation and good prognosis in prostate cancer

The prognostic significance of ALDH1A1 expression in early invasive breast cancer

Potential Involvement of Jagged1 in Metastatic Progression of Human Breast Carcinomas

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