The dual role of asporin in breast cancer progression

Simkova, Dana; Kharaishvili, Gvantsa; Korinkova, Gabriela; Oždian, Tomáš; Kleplová, Tereza Suchánková; Soukup, Tomáš; Křupka, Michal; Galandáková, Adéla; Džubák, Petr; Janíková, Mária; Navrátil, Jiří; Kahounová, Zuzana; Souček, Karel; Bouchal, Jan

doi:10.18632/oncotarget.10471

Cited by 24 publications

(31 citation statements)

References 60 publications

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“…While C57BL/6 mice have eight D-repeats interrupted by a single asparagine (N), the D-repeat length in humans is variable. Recent reports suggest that the D-repeat domain length may regulate cancer progression (21,29). Patients harboring germline allele(s) of ASPN D14 were more likely to develop metastatic prostate cancer, while homozygous germline ASPN D13 was associated with a reduced risk of metastatic prostate cancer (21).…”

Section: Discussionmentioning

confidence: 99%

“…ASPN has been shown to induce migration of scirrhous gastric (24,28) and pancreatic (25) cancer cells; nevertheless, ASPN expression in the tumor microenvironment may have a dual role in regulating cancer progression (21)(22)(23)(24)(25)29), possibly due to polymorphisms in the ASPN aspartic acid (D)-repeat domain length (21). ASPN expression in prostate reactive stromal cells is associated with adjacent local cancer aggressiveness and with worse oncologic outcomes (21,22).…”

Section: Introductionmentioning

confidence: 99%

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Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression

Hughes

Simons²,

Khan

et al. 2019

Cancer Research

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Tumor progression to metastasis is not cancer cell autonomous, but rather involves the interplay of multiple cell types within the tumor microenvironment. Here we identify asporin (ASPN) as a novel, secreted mesenchymal stromal cell (MSC) factor in the tumor microenvironment that regulates metastatic development. MSCs expressed high levels of ASPN, which decreased following lineage differentiation. ASPN loss impaired MSC self-renewal and promoted terminal cell differentiation. Mechanistically, secreted ASPN bound to BMP-4 and restricted BMP-4-induced MSC differentiation prior to lineage commitment. ASPN expression was distinctly conserved between MSC and cancer-associated fibroblasts (CAF). ASPN expression in the tumor microenvironment broadly impacted multiple cell types. Prostate tumor allografts in ASPN-null mice had a reduced number of tumor-associated MSCs, fewer cancer stem cells, decreased tumor vasculature, and an increased percentage of infiltrating CD8 þ T cells. ASPNnull mice also demonstrated a significant reduction in lung metastases compared with wild-type mice. These data establish a role for ASPN as a critical MSC factor that extensively affects the tumor microenvironment and induces metastatic progression. Significance: These findings show that asporin regulates key properties of mesenchymal stromal cells, including selfrenewal and multipotency, and asporin expression by reactive stromal cells alters the tumor microenvironment and promotes metastatic progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression

Hughes

Simons²,

Khan

et al. 2019

Cancer Research

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“…The detailed characterization of the human tumor samples was described previously (19) and is listed in Supporting Information Table S1. Fresh breast cancer tissue was obtained from patients at Masaryk Memorial Cancer Institute undergoing surgical breast tumor removal.…”

Section: Prostate and Breast Cancer Tissue Analysis And Fibroblasts Imentioning

confidence: 99%

“…The detailed characterization of the human tumor samples was described previously (19) and is listed in Supporting Information Table S1. Three fibroblast cell lines from fresh breast cancer tissues (BCaF3, BCaF4, and BCaF5) and two fibroblast cell lines from prostate cancer tissues (PCaF1 and PCaF2) were isolated according to a protocol kindly provided by Prof. Paola Chiarugi, University of Firenze, IT (20,21) as previously described (19). Briefly, samples of cancer tissue were cut into small pieces, and the pieces were put on a 100 mm tissue-culture dish.…”

Section: Prostate and Breast Cancer Tissue Analysis And Fibroblasts Imentioning

confidence: 99%

The fibroblast surface markers FAP, anti‐fibroblast, and FSP are expressed by cells of epithelial origin and may be altered during epithelial‐to‐mesenchymal transition

et al. 2017

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The identification of fibroblasts and cancer-associated fibroblasts from human cancer tissue using surface markers is difficult, especially because the markers used currently are usually not expressed solely by fibroblasts, and the identification of fibroblast-specific surface molecules is still under investigation. It was aimed to compare three commercially available antibodies in the detection of different surface epitopes of fibroblasts (anti-fibroblast, fibroblast activation protein α, and fibroblast surface protein). The specificity of their expression, employing fibroblast cell lines and tumor-derived fibroblasts from breast and prostate tissues was investigated. Both the established fibroblast cell line HFF-1 and ex vivo primary fibroblasts isolated from breast and prostate cancer tissues expressed the tested surface markers to different degrees. Surprisingly, those markers were expressed also by permanent cell lines of epithelial origin, both benign and cancer-derived (breast-cell lines MCF 10A, HMLE and prostate-cell lines BPH-1, DU 145, and PC-3). The expression of fibroblast activation protein α increased on the surface of previously described models of epithelial cells undergoing epithelial-to-mesenchymal transition in response to treatment with TGF-β1. To prove the co-expression of the fibroblast markers on cells of epithelial origin, we used freshly dissociated human prostate and breast cancer tissues. The results confirmed the co-expression of anti-fibroblast and fibroblast surface protein on CD31/CD45-negative/EpCAM-positive epithelial cells. In summary, our data support the findings that the tested fibroblast markers are not fibroblast specific and may be expressed also by cells of epithelial origin (e.g., cells undergoing EMT). Therefore, the expression of these markers should be interpreted with caution, and the combination of several epitopes for both positive (anti-fibroblast or fibroblast activation protein α) and negative (EpCAM) identification of fibroblasts from breast and prostate tumor tissues is advised. © 2017 International Society for Advancement of Cytometry.

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“…Importantly, induced ASPN expression in MDA-MB-468 cells significantly reduced their growth and metastatic capacity in a murine model 39 . During the publication process of this review, our original article on the dual role of asporin in breast cancer progression was accepted 65 . Briefly, according to our in silico search, high ASPN expression associated with significantly better relapse free survival (RFS) in patients with low-grade tumors but RFS was significantly worse in patients with grade 3 tumors.…”

Section: Cd34mentioning

confidence: 99%

Glycoprotein asporin as a novel player in tumour microenvironment and cancer progression

Simkova¹,

Kharaishvili²,

Slabáková³

et al. 2016

BIOMED PAP

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Background. Small leucine rich proteoglycans (SLRPs), major non-collagen components of the extracellular matrix (ECM), have multiple biological roles with diverse effects. Asporin, a member of the SLRPs class I, competes with other molecules in binding to collagen and affects its mineralization. Its role in cancer is only now being elucidated. Methods. The PubMed online database was used to search relevant reviews and original articles. Furthermore, altered asporin expression was analysed in publicly available genome-wide expression data at the Gene Expression Omnibus database. Results. Polymorphisms in the N-terminal polyaspartate domain, which binds calcium, are associated with osteoarthritis and prostate cancer. Asporin also promotes the progression of scirrhous gastric cancer where it is required for coordinated invasion by cancer associated fibroblasts and cancer cells. Besides the enhanced expression of asporin observed in multiple cancer types, such as breast, prostate, gastric, pancreas and colon cancer, tumour suppressive effects of asporin were described in triple-negative breast cancer. We also discuss a number of factors modulating asporin expression in different cell types relevant for alterations toing the tumour microenvironment. Conclusion. The apparent contradicting tumour promoting and suppressive effects of asporin require further investigation. Deciphering the role of asporin and other SLRPs in tumour-stroma interactions is needed for a better understanding of cancer progression and potentially also for novel tumour microenvironment based therapies.

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The dual role of asporin in breast cancer progression

Cited by 24 publications

References 60 publications

Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression

Asporin Restricts Mesenchymal Stromal Cell Differentiation, Alters the Tumor Microenvironment, and Drives Metastatic Progression

The fibroblast surface markers FAP, anti‐fibroblast, and FSP are expressed by cells of epithelial origin and may be altered during epithelial‐to‐mesenchymal transition

Glycoprotein asporin as a novel player in tumour microenvironment and cancer progression

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