Heparanase promotes myeloma stemness and in vivo tumorigenesis

Tripathi, Kaushlendra; Ramani, Vishnu C.; Bandari, Shyam; Amin, Rada; Brown, Elizabeth E.; Ritchie, Joseph P.; Stewart, Mark; Sanderson, Ralph D.

doi:10.1016/j.matbio.2019.11.004

Cited by 26 publications

(29 citation statements)

References 54 publications

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“…Therefore, mechanistic understanding of myeloma constitutes the key to identifying novel specific therapies to improve patient prognosis and outcome. Heparanase plays a major role in promoting myeloma progression, resistance to chemotherapy and maintenance of cancer cell stemness [12][13][14]. In the present work, we investigated the role of nuclear heparanase in regulating myeloma behavior.…”

Section: Introductionmentioning

confidence: 98%

Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Amin

Tripathi

Sanderson

2020

Cells

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Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.

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Section: Introductionmentioning

confidence: 98%

Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Amin

Tripathi

Sanderson

2020

Cells

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“…It was also demonstrated that the tumor cells express a much higher level of heparanase upon relapse among patients with multiple myeloma following high-dose chemotherapy than was present prior to therapy 17 . In addition, the involvement of heparanase in myeloma resistance to drug therapy was found to be dependent upon its ability to increase stemness properties 18 .…”

Section: Introductionmentioning

confidence: 99%

Heparanase: a potential marker of worse prognosis in estrogen receptor-positive breast cancer

et al. 2021

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Heparanase promotes tumor growth in breast tumors. We now evaluated heparanase protein and gene-expression status and investigated its impact on disease-free survival in order to gain better insight into the role of heparanase in ER-positive (ER+) breast cancer prognosis and to clarify its role in cell survival following chemotherapy. Using pooled analysis of gene-expression data, we found that heparanase was associated with a worse prognosis in estrogen receptor-positive (ER+) tumors (log-rank p < 10−10) and predictive to chemotherapy resistance (interaction p = 0.0001) but not hormonal therapy (Interaction p = 0.62). These results were confirmed by analysis of data from a phase III, prospective randomized trial which showed that heparanase protein expression is associated with increased risk of recurrence in ER+ breast tumors (log-rank p = 0.004). In vitro experiments showed that heparanase promoted tumor progression and increased cell viability via epithelial–mesenchymal transition, stemness, and anti-apoptosis pathways in luminal breast cancer. Taken together, our results demonstrated that heparanase is associated with worse outcomes and increased cell viability in ER+ BC.

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“…One of the first steps in tumour cell invasion and secondary spread is the breakdown of connections between cells and between cells and the extracellular matrix (ECM) at the primary site of the tumour. Local remodelling of the basement membrane (BM) also facilitates this process [ 10 , 11 ]. Heparanase is an endo-β(1,4)-D-glucuronidase able to hydrolyse heparan sulphate (HS) side chains into 5 to 7 kDa fragments found in the BM and ECM [ 4 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Heparanase exerts its action via enzymatic and non-enzymatic ways. Interestingly, both heparanase activities are equally involved in cancer invasion and dissemination, allowing neoplastic cells to invade the tumour site locally and spread to distant sites [ 10 , 11 ]. By cleaving ECM proteins, heparanase can release and thus activate several latent growth factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF) attached at this site, which leads to the promotion of proliferation, migration, invasion, and cancer cell spread.…”

Section: Introductionmentioning

confidence: 99%

“…Heparanase over-secretion is observed in several solid tumours, sarcomas, haematological neoplasms, and is associated with aggressive tumour behaviour, a worse prognosis, and chemo-resistance [ 10 , 13 ]. According to our previous study, we suggest that patients considered low risk of relapse based on their pre-treatment heparanase values may better respond to adjuvant treatment [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Impact of Adjuvant Treatment on Heparanase Concentration in Invasive, Unilateral Breast Cancer Patients: Results of a Prospective Single-Centre Cohort Study

Ruszkowska-Ciastek

Bielawski

Zarychta

et al. 2021

JCM

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Background: In recent years, great progress has been made in the treatment of breast cancer, but it is still one of the ten leading causes of death in women. The aim of the study was to evaluate the heparanase concentration of invasive breast cancer (IBrC) patients, before and after cancer adjuvant treatment. Methods: Eighty patients with stage IA to IIB IBrC receiving adjuvant treatment were included prospectively in this study. The heparanase concentrations were determined by an enzyme-linked immunosorbent assay. A univariate analysis was used to estimate the factors influencing the low or high pre-treatment concentration of heparanase and the low or high numerical decrease in heparanase concentration after completion of adjuvant treatment. Results: Treatment reduced the concentration of heparanase by almost four times in the general IBrC cohort. Higher levels of pre- and post-treatment heparanase were noted in oestrogen receptor-negative cancers than in positive ones. A higher post-treatment concentration of heparanase was found in patients with a triple-negative tumour compared to patients with a luminal B HER2 negative type of IBrC. Overweight IBrC subjects and those with a tumour diameter of ≥2 cm demonstrated a lower chance of a lower pre-treatment heparanase concentration. Interestingly, a pre-treatment heparanase concentration is the main predictor of the changes in heparanase concentration after adjuvant treatment. Follow-up revealed significantly lower progression-free survival (PFS) rates in IBrC patients with a pre-treatment concentration of heparanase higher than 181.46 pg/mL (PFS = 80%). Conclusions: Our findings provide supporting evidence that IBrC therapy reduced the heparanase levels, regardless of treatment patterns and a pre-treatment concentration of heparanase may serve as a prognostic indicator for future outcomes.

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Heparanase promotes myeloma stemness and in vivo tumorigenesis

Cited by 26 publications

References 54 publications

Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Heparanase: a potential marker of worse prognosis in estrogen receptor-positive breast cancer

Impact of Adjuvant Treatment on Heparanase Concentration in Invasive, Unilateral Breast Cancer Patients: Results of a Prospective Single-Centre Cohort Study

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