Upregulated osterix promotes invasion and bone metastasis and predicts for a poor prognosis in breast cancer

Yao, Bing; Wang, Jue; Qu, Shuang; Liu, Yang; Jin, Yuci; Lu, Jiajia; Bao, Qianyi; Li, Lingyun; Yuan, Hongyan; Ma, Chao

doi:10.1038/s41419-018-1269-3

Cited by 25 publications

(24 citation statements)

References 38 publications

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“…Our study demonstrates that a transcription factor required for osteoblast differentiation, Osterix, marks pro-tumorigenic stromal cells infiltrating extra-skeletal tumors. A possible role of Osx in tumorigenesis is emerging from human studies as well showing that presence of Sp7 in the tumor is associated with poor patient survival ( Yao et al, 2019 ). Our own analysis of published gene microarray data of breast cancer stroma ( Finak et al, 2008 ), reveals higher Sp7 expression in tumor stroma relative to healthy tissue from the same subject, corroborating the notion that Osx+ stromal cells regulate tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics

Ricci

Tycksen

Celik

et al. 2020

eLife

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Cancer-associated fibroblasts (CAFs) are a heterogeneous population of mesenchymal cells supporting tumor progression, whose origin remains to be fully elucidated. Osterix (Osx) is a marker of osteogenic differentiation, expressed in skeletal progenitor stem cells and bone-forming osteoblasts. We report Osx expression in CAFs and by using Osx-cre;TdTomato reporter mice we confirm the presence and pro-tumorigenic function of TdTOSX+ cells in extra-skeletal tumors. Surprisingly, only a minority of TdTOSX+ cells expresses fibroblast and osteogenic markers. The majority of TdTOSX+ cells express the hematopoietic marker CD45, have a genetic and phenotypic profile resembling that of tumor infiltrating myeloid and lymphoid populations, but with higher expression of lymphocytic immune suppressive genes. We find Osx transcript and Osx protein expression early during hematopoiesis, in subsets of hematopoietic stem cells and multipotent progenitor populations. Our results indicate that Osx marks distinct tumor promoting CD45- and CD45+ populations and challenge the dogma that Osx is expressed exclusively in cells of mesenchymal origin.

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Section: Discussionmentioning

confidence: 99%

Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics

Ricci

Tycksen

Celik

et al. 2020

eLife

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“…Osterix, a zinc finger-containing transcription factor, decreases chemosensitivity and enhances anti-apoptosis by upregulating GALNT14 38 . Osterix has also important roles in facilitating breast cancer invasion 39 . In our study, treated CSCs acquired a phenotype closer to non-treated non-CSCs.…”

Section: Discussionmentioning

confidence: 99%

Glycosphingolipid expression at breast cancer stem cells after novel thieno[2,3-b]pyridine anticancer compound treatment

Marijan

Markotić

Mastelić

et al. 2020

Sci Rep

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Glycosphingolipid expression differs between human breast cancer stem cells (CSC) and cancer non-stem cells (non-CSC). We performed studies of viability, type of cell death, cancer stem cell percent and glycosphingolipid expression on CSC and non-CSC after treatment of MDA-MB-231 and MDA-MB-453 triple-negative breast cancer cells with a newly developed thienopyridine anticancer compound (3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, 1). Compound 1 was cytotoxic for both breast cancer cell lines and the majority of cells died by treatment-induced apoptosis. The percent of cancer stem cells and number of formed mammospheres was significantly lower. Glycosphingolipids IV 6 Neu5Ac-nLc 4 Cer and GalNAc-GM1b (IV 3 Neu5Ac-Gg5Cer) not reported previously, were identified in both CSCs and non-CSCs. IV 6 Neu5Ac-nLc 4 Cer had increased expression in both CSCs and non-CSCs of both cell lines after the treatment with 1, while GM3 (II 3 Neu5Ac-LacCer) had increased expression only on both cell subpopulations in MDA-MB-231 cell line. GalNAc-GM1b, Gb 4 Cer (GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer) and GM2 (II 3 Neu5Ac-GalNAcβ1-4Galβ1-4Glcβ1-1Cer) were increased only in CSCs of both cell lines while GD3 was decreased in CSC of MDA-MB-231 cell line. Due to its effect in reducing the percentage of cancer stem cells and number of mammospheres, and its influence upon several glycosphingolipid expressions, it can be concluded that compound 1 deserves attention as a potential new drug for triple-negative breast cancer therapy. The thieno[2,3-b]pyridines were initially discovered as potential inhibitors of phospholipase C (PLC) isoforms by virtual high throughput screen (vHTS) 1. Recently, we described glycoconjugate GM3 and CD15s expression in MDA-MB-231 triple negative breast cancer stem cell subpopulation cultured with 3-amino-5-oxo-N-naphthyl-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, which was developed as a putative PLC inhibitor. A close structural analogue of 3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide, or compound 1 2 was chosen for this study due to its enhanced potency against the MDA-MB-231 cell line and its mechanism of action has been investigated 3,4. Due to their ability to self-renew and to regenerate the primary tumour phenotypic heterogeneity, cancer stem cells are important therapeutical targets 5. CSCs are defined with their CD44 + /CD24 − or CD133 + phenotype 6. It is believed that CSCs are involved in therapy resistance in various cancers, including triple-negative breast cancers, i.e., breast cancers that do not express the genes for estrogen receptor, progesterone receptor and the human epidermal growth factor receptor-2 7. Glycosphingolipids (GSLs), consisting of a hydrophobic ceramide and hydrophilic carbohydrate residues, are an important component of cell plasma membranes. They regulate numerous cellular processes like adhesion, proliferation, apoptosis, recognition, modulation of signal transduct...

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“…Despite several factors, proteins, and mechanisms that lead to high expression of IL-8, it was also seen that metastatic breast cancer cells treated with the miR-520/373 family [24] or knockdown for LMW-PTP and its slow isoform [67] showed a decrease level of IL-8 expression in breast cancer cells [24,67]. In addition, similar results were observed in vivo using a nude mice model injected into the tibia with metastatic breast cancer cells and treated via neutralizing IL-8 [52] or knockdown of osterix [29], a zinc finger-containing transcription factor essential for osteoblast differentiation and bone formation, suggesting a novel and attractive target for the control of bone metastasis of breast cancers [29].…”

Section: Il-8mentioning

confidence: 68%

“…Injection of MDA-MB-231 GFP, MDA-MB-231 IV, MDA-MB-231 IL-1B+, or MDA-MB-231 IL-1R1+ cells into tail vein of BALB/c nude mice or following intra-ductal injection of E0771 into mammary ducts of IL-1B-KO or fl/fl. [29] IL-8 Breast cancer cells Evaluate the knockdown of Osx in breast cancer bone metastasis.…”

Section: Il-1β Breast Cancer Cells Macrophagesmentioning

confidence: 99%

What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence

Salamanna

Borsari

Contartese

et al. 2019

Cancers

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Breast cancer cells produce stimulators of bone resorption known as interleukins (ILs). However, data on the functional roles of ILs in the homing of metastatic breast cancer to bone are still fragmented. A systematic search was carried out in three databases (PubMed, Scopus, Web of Science Core Collection) to identify preclinical reports, and in three clinical registers (ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, European Union (EU) Clinical Trials Register) to identify clinical trials, from 2008 to 2019. Sixty-seven preclinical studies and 11 clinical trials were recognized as eligible. Although preclinical studies identified specific key ILs which promote breast cancer bone metastases, which have pro-metastatic effects (e.g., IL-6, IL-8, IL-1β, IL-11), and whose inhibition also shows potential preclinical therapeutic effects, the clinical trials focused principally on ILs (IL-2 and IL-12), which have an anti-metastatic effect and a potential to generate a localized and systemic antitumor response. However, these clinical trials are yet to post any results or conclusions. This inconsistency indicates that further studies are necessary to further develop the understanding of cellular and molecular relations, as well as signaling pathways, both up-and downstream of ILs, which could represent a novel strategy to treat tumors that are resistant to standard care therapies for patients affected by breast cancer bone disease.An initial literature search found 905 references, of which 151 articles were recognized using the PubMed database, 481 articles were recognized using Scopus, and 273 articles were found in the Web of Science Core Collection. Subsequently, the resulting references were submitted to a public reference manager (Mendeley 1.17.11) to eliminate duplicate articles, obtaining 666 articles. From the 666 articles obtained, after exclusion, 116 full-text articles were evaluated, of which 67 met the inclusion criteria. The 560 studies excluded from this review were excluded because they were meeting reports, reviews, book chapters, and case reports, and/or because they reported IL roles in primary breast tumor, as well as in lung, liver, and pulmonary metastasis, leukemia, osteosarcoma, ovarian tumor, melanoma, prostate cancer, autoimmune arthritis related to breast cancer, and other pathological conditions; however, they did not reveal the favorable development of bone metastases from breast cancer. In addition, we excluded studies where IL profiling was derived from breast cancer metastatic patients that were not grouped/analyzed based on the site of metastasis, and where breast cancer bone metastases were evaluated, but no IL roles/functions were examined. Finally, we also eliminated studies where responses to specific therapy (not IL-based) for breast cancer bone metastasis were analyzed, studies that evaluated the contributions of the sensory signaling pathways to neuropathic pain induced by breast cancer bone metastases, and studies on chronic s...

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Upregulated osterix promotes invasion and bone metastasis and predicts for a poor prognosis in breast cancer

Cited by 25 publications

References 38 publications

Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics

Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics

Glycosphingolipid expression at breast cancer stem cells after novel thieno[2,3-b]pyridine anticancer compound treatment

What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence

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