Heparanase and Chemotherapy Synergize to Drive Macrophage Activation and Enhance Tumor Growth

Bhattacharya, Udayan; Gutter-Kapon, Lilach; Kan, Tal; Boyango, Ilanit; Barash, Uri; Yang, Shiming; Liu, Jingjing; Gross-Cohen, Miriam; Sanderson, Ralph D.; Shaked, Yuval; Ilan, Neta; Vlodavsky, Israël

doi:10.1158/0008-5472.can-19-1676

Cited by 36 publications

(55 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To examine the signaling associated with cell adhesion to heparanase/Hpa2, cells were plated in the absence or presence of heparin (50 µg/ml) or the indicated anti-Hpa2 monoclonal antibody (30 µg/ml). For biochemical analyses, cell extracts were prepared and subjected to immunoblotting with the indicated antibody or were fixed with cold methanol and subjected to immunofluorescent staining, as described (14,28).…”

Section: Cell Adhesionmentioning

confidence: 99%

See 1 more Smart Citation

Elucidating the Consequences of Heparan Sulfate Binding by Heparanase 2

et al. 2021

Self Cite

View full text Add to dashboard Cite

Unlike the intense research effort devoted to exploring the significance of heparanase in human diseases, very little attention was given to its close homolog, heparanase 2 (Hpa2). The emerging role of Hpa2 in a rare autosomal recessive congenital disease called urofacial syndrome (UFS), clearly indicates that Hpa2 is not a pseudogene but rather a gene coding for an important protein. Hpa2 lacks the heparan sulfate (HS)-degrading activity typical of heparanase, yet exhibits high affinity to HS, affinity that is 10-fold higher than that of heparanase. The consequences of this high-affinity interaction of Hpa2 with plasma membrane HSPG has not been explored yet. Here, we used highly purified Hpa2 protein to examine this aspect. We provide evidence that cells adhere to and spread on dishes coated with Hpa2. We also show that cell migration is attenuated markedly by exogenous addition of Hpa2 to primary and transformed cells, a function that agrees with the anti-cancer properties of Hpa2. Interestingly, we found that exogenous addition of Hpa2 also disrupts the morphology of cell colonies, resulting in cell scattering. This implies that under certain conditions and experimental settings, Hpa2 may exhibit pro-tumorigenic properties. We further developed a panel of anti-Hpa2 monoclonal antibodies (mAb) and show that these properties of Hpa2 are prevented by some of the newly-developed mAb, thus providing new molecular tools to better appreciate the significance of Hpa2 in health and disease.

show abstract

Section: Cell Adhesionmentioning

confidence: 99%

“…Negative control was incubated without the primary antibody. Cells were then washed 3 times with the above washing buffer and incubated as above with 488-conjugated secondary antibody, washed, and analyzed using a CyAn fluorescent activated cell sorter (Beckman coulter) and Summit software, as described (28,29).…”

Section: Flow Cytometrymentioning

confidence: 99%

Elucidating the Consequences of Heparan Sulfate Binding by Heparanase 2

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cell lysates and protein blotting. Preparation of cell lysates and protein blotting were carried out essentially as described (24,29).…”

Section: Methodsmentioning

confidence: 99%

Role of heparanase 2 (Hpa2) in gastric cancer

Liu

Knani

Gross-Cohen

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundHeparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate (HS) and, consequently, remodel the extracellular matrix (ECM) underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks HS-degrading activity typical of heparanase. MethodsWe combined clinical, in vivo and in vitro studies to reveal the role of Hpa2 in gastric cancer. ResultsHere, we report that gastric cancer patients exhibiting high levels of Hpa2 survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to over-express Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. This was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), a kinase that is situated at the center of a tumor suppressor network known to attenuate the growth of various types of cancer including gastric cancer. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, and AMPK was found to induce the expression of Hpa2, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, leading to attenuation of gastric tumorigenesis. ConclusionsThese results indicate that high levels of Hpa2 in some tumors but not in others are due to stress conditions that tumors often experience due to their high rates of cell proliferating, high metabolic demands, and changes in the tumor microenvironment. This increase in Hpa2 levels by the stressed tumors appears critically important for the patient's outcome.

show abstract

“…Macrophages are activated upon expression of the cytokine macrophage inflammatory protein-2 (MIP-2), but this process is impaired in macrophages from HPSE-KO cells [130]. Interestingly, certain chemotherapeutics can stimulate macrophage activation and polarization into an M2 (pro-tumorigenic) phenotype in an HPSE-dependent mechanism [131].…”

Section: Role Of Hpse In Macrophage Activationmentioning

confidence: 99%

Heparanase, cell signaling, and viral infections

Koganti

Suryawanshi

Shukla

2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Heparanase (HPSE) is a multifunctional protein endowed with many non-enzymatic functions and a unique enzymatic activity as an endo-β-d-glucuronidase. The latter allows it to serve as a key modulator of extracellular matrix (ECM) via a well-regulated cleavage of heparan sulfate side chains of proteoglycans at cell surfaces. The cleavage and associated changes at the ECM cause release of multiple signaling molecules with important cellular and pathological functions. New and emerging data suggest that both enzymatic as well as non-enzymatic functions of HPSE are important for health and illnesses including viral infections and virally induced cancers. This review summarizes recent findings on the roles of HPSE in activation, inhibition, or bioavailability of key signaling molecules such as AKT, VEGF, MAPK-ERK, and EGFR, which are known regulators of common viral infections in immune and non-immune cell types. Altogether, our review provides a unique overview of HPSE in cell-survival signaling pathways and how they relate to viral infections.

show abstract

Heparanase and Chemotherapy Synergize to Drive Macrophage Activation and Enhance Tumor Growth

Cited by 36 publications

References 60 publications

Elucidating the Consequences of Heparan Sulfate Binding by Heparanase 2

Elucidating the Consequences of Heparan Sulfate Binding by Heparanase 2

Role of heparanase 2 (Hpa2) in gastric cancer

Heparanase, cell signaling, and viral infections

Contact Info

Product

Resources

About