Opposing Effects of Heparanase and Heparanase-2 in Head &amp; Neck Cancer

Doweck, Ilana; Feibish, Nir

doi:10.1007/978-3-030-34521-1_37

Cited by 11 publications

(6 citation statements)

References 47 publications

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“…Substantial changes in Hpa2 staining intensities between normal and tumor lesions ( Fig. 1 ) [ 20 , 22 , 61 , 62 ] strongly suggest that Hpa2 expression is tightly regulated, but mechanisms that regulate Hpa2 expression have not been sufficiently elucidated yet. Zhang et al have reported that the Hpa2 gene is methylated, and gene methylation results in decreased Hpa2 expression [63] .…”

Section: Discussionmentioning

confidence: 99%

Role of heparanase 2 (Hpa2) in gastric cancer

Liu¹,

Knani²,

Gross-Cohen³

et al. 2021

Neoplasia

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Highlight We report that gastric cancer patients exhibiting high levels of heparanase 2 (Hpa2) survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to overexpress Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. These beneficial effects were found to associate with increased phosphorylation of AMP-activated protein kinase (AMPK) that play an instrumental role in cell metabolism and is situated at the center of a tumor suppressor network. 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, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, possibly leading to attenuation of gastric tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Role of heparanase 2 (Hpa2) in gastric cancer

Liu¹,

Knani²,

Gross-Cohen³

et al. 2021

Neoplasia

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“…The role of Hpa2 in cancer is largely unknown. In H&N cancer, high levels of Hpa2 were associated with prolonged patients' survival and decreased tumor cell dissemination to regional lymph nodes (13,14). Notably, overexpression of Hpa2 in H&N cancer cells resulted in a marked decrease in tumor growth, associating with a prominent reduction in tumor vascularity (15), and further supporting the notion that Hpa2 functions to attenuate H&N cancer.…”

Section: Introductionmentioning

confidence: 64%

“…Importantly, hypermethylation of Hpa2 was associated with poor prognosis of colorectal cancer patients (23), thus further supporting the notion that Hpa2 functions to suppress tumorigenesis. Moreover, we have reported that in head & neck (H&N) cancer high levels of Hpa2 are associated with prolonged patients' survival and decreased tumor cell dissemination to regional lymph nodes (13,14). Also, overexpression of Hpa2 in H&N cancer cells resulted in a marked decrease in tumor growth, associating with a prominent reduction in tumor vascularity (blood and lymph vessels) likely due to reduced Id1 expression (15), a transcription factor highly implicated in VEGF-A and VEGF-C gene regulation (24).…”

Section: Discussionmentioning

confidence: 99%

A Pro-Tumorigenic Effect of Heparanase 2 (Hpa2) in Thyroid Carcinoma Involves Its Localization to the Nuclear Membrane

et al. 2021

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Activity of the endo-beta-glucuronidase heparanase, capable of cleaving heparan sulfate (HS), is most often elevated in many types of tumors, associating with increased tumor metastasis and decreased patients’ survival. Heparanase is therefore considered to be a valid drug target, and heparanase inhibitors are being evaluated clinically in cancer patients. Heparanase 2 (Hpa2) is a close homolog of heparanase that gained very little attention, likely because it lacks HS-degrading activity typical of heparanase. The role of Hpa2 in cancer was not examined in detail. In head and neck cancer, high levels of Hpa2 are associated with decreased tumor cell dissemination to regional lymph nodes and prolonged patients’ survival, suggesting that Hpa2 functions to attenuate tumor growth. Here, we examined the role of Hpa2 in normal thyroid tissue and in benign thyroid tumor, non-metastatic, and metastatic papillary thyroid carcinoma (PTC) utilizing immunostaining in correlation with clinicopathological parameters. Interestingly, we found that Hpa2 staining intensity does not significantly change in the transition from normal thyroid gland to benign, non-metastatic, or metastatic thyroid carcinoma. Remarkably, we observed that in some biopsies, Hpa2 is accumulating on the membrane (envelop) of the nucleus and termed this cellular localization NM (nuclear membrane). Notably, NM localization of Hpa2 occurred primarily in metastatic PTC and was associated with an increased number of positive (metastatic) lymph nodes collected at surgery. These results describe for the first time unrecognized localization of Hpa2 to the nuclear membrane, implying that in PTC, Hpa2 functions to promote tumor metastasis.

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“…Substantial changes in Hpa2 staining intensities between normal and tumor lesions (Fig. 1) (19,49,50,53) strongly suggest that Hpa2 expression is tightly regulated, but mechanisms that regulate Hpa2 expression have not been elucidated yet. Here, we report for the rst time that Hpa2 expression is prominently induced by conditions of stress.…”

Section: Discussionmentioning

confidence: 99%

Role of heparanase 2 (Hpa2) in gastric cancer

Liu

Knani

Gross-Cohen

et al. 2021

Preprint

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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.

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Opposing Effects of Heparanase and Heparanase-2 in Head & Neck Cancer

Cited by 11 publications

References 47 publications

Role of heparanase 2 (Hpa2) in gastric cancer

Role of heparanase 2 (Hpa2) in gastric cancer

A Pro-Tumorigenic Effect of Heparanase 2 (Hpa2) in Thyroid Carcinoma Involves Its Localization to the Nuclear Membrane

Role of heparanase 2 (Hpa2) in gastric cancer

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