Heparanase contributes to pancreatic carcinoma progression through insulin-dependent glucose uptake

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor, which is highly resistant to existing therapies and characterized by one of the lowest survival rates known for solid cancers. Among the reasons for this poor prognosis are unique pathophysiological features of PDAC, such as dense extracellular matrix [ECM] creating barriers to drug delivery, as well as systemically-deregulated glucose metabolism manifested by diabetic conditions (i.e., hyperinsulinemia/hyperglycemia) occurring in the majority of PDAC patients. Moreover, in addition to systemically deregulated glucose homeostasis, intracellular metabolic pathways in PDAC are rewired toward increased glucose uptake/anabolic metabolism by the tumor cells. While the role of oncogene-driven programs in governing these processes is actively studied, mechanisms linking metabolic dysregulation and ECM enzymatic remodeling to PDAC progression/therapy resistance are less appreciated. The aim of the current study was to investigate the action of heparanase (the predominant mammalian enzyme that degrades heparan sulfate glycosaminoglycan in the ECM), as a molecular link between the diabetic state and the intracellular metabolic rewiring in PDAC pathogenesis. Here we show that in PDAC elevated levels of heparanase, coupled with diabetic conditions typical for PDAC patients, promote growth and chemotherapy resistance of pancreatic carcinoma by favoring insulin receptor signaling and GLUT4-mediated glucose uptake into tumor cells. Collectively, our findings underscore previously unknown mechanism through which heparanase acts at the interface of systemic and intracellular metabolic alterations in PDAC and attest the enzyme as an important and potentially modifiable contributor to the chemo-resistance of pancreatic tumors

Heparanase Accelerates Obesity-Associated Breast Cancer Progression

Contains fulltext : 209950.pdf (publisher's version ) (Closed access

Syndecan-1 deficiency promotes tumor growth in a murine model of colitis-induced colon carcinoma

<div><p>Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family, highly expressed by epithelial cells in adult organisms. Sdc1 is involved in the regulation of cell migration, cell-cell and cell-matrix interactions, growth-factor, chemokine and integrin activity, and implicated in inflammatory responses and tumorigenesis. Gastrointestinal tract represents an important anatomic site where loss of Sdc1 expression was reported both in inflammation and malignancy. However, the biological significance of Sdc1 in chronic colitis-associated tumorigenesis has not been elucidated. To the best of our knowledge, this study is the first to test the effects of Sdc1 loss on colorectal tumor development in inflammation-driven colon tumorigenesis. Utilizing a mouse model of colitis-related colon carcinoma induced by the carcinogen azoxymethane (AOM), followed by the inflammatory agent dextran sodium sulfate (DSS), we found that Sdc1 deficiency results in increased susceptibility to colitis-associated tumorigenesis. Importantly, colitis-associated tumors developed in Sdc1-defficient mice were characterized by increased local production of IL-6, activation of STAT3, as well as induction of several STAT3 target genes that act as important effectors of colonic tumorigenesis. Altogether, our results highlight a previously unknown effect of Sdc1 loss in progression of inflammation-associated cancer and suggest that decreased levels of Sdc1 may serve as an indicator of colon carcinoma progression in the setting of chronic inflammation.</p></div

Macrophages Upregulate Estrogen Receptor Expression in the Model of Obesity-Associated Breast Carcinoma

Breast cancer (BC) and obesity are two heterogeneous conditions with a tremendous impact on health. BC is the most commonly diagnosed neoplasm and the leading cause of cancer-related mortality among women, and the prevalence of obesity in women worldwide reaches pandemic proportions. Obesity is a significant risk factor for both incidence and worse prognosis in estrogen receptor positive (ER+) BC. Yet, the mechanisms underlying the association between excess adiposity and increased risk/therapy resistance/poorer outcome of ER+, but not ER&minus;negative (ER&minus;), BC are not fully understood. Tumor-promoting action of obesity, predominantly in ER + BC patients, is often attributed to the augmented production of estrogen in &lsquo;obese&rsquo; adipose tissue. However, in addition to the estrogen production, expression levels of ER represent a key determinant in hormone-driven breast tumorigenesis and therapy response. Here, utilizing in vitro and in vivo models of BC, we show that macrophages, whose adverse activation by obesogenic substances is fueled by heparanase (extracellular matrix-degrading enzyme), are capable of upregulating ER expression in tumor cells, in the setting of obesity-associated BC. These findings underscore a previously unknown mechanism through which interplay between cellular/extracellular elements of obesity-associated BC microenvironment influences estrogen sensitivity&mdash;a critical component in hormone-related cancer progression and resistance to therapy

Syndecan-1 deficiency exacerbates colonic chronic inflammation in DSS treated mice.

<p><b>(A)</b> WT and Sdc1-KO mice (n = 14 mice) were treated with three cycles of DSS as described in Methods and weight changes were measured. <b>(B)</b> Blinded histological scoring of inflammation in colonic mucosa of mice was performed as described in Methods. Error bars represent mean ± SE. *<i>P</i> < 0.05, **P < 0.01, **P < 0.001 by Student’s t test for mass change and Mann-Whitney U test for inflammation score.<b>(C)</b> Representative histopathologic sections of colon from WT and Sdc1-KO mice. Hyperplastic/dysplastic glands (lower panel—black arrowheads) were more frequent in Sdc1-KO than WT mice. Scale bar, 100 μm. <b>(D)</b> Representative immunoreactive staining (brown) for IL-6 (top panel) and phospho-STAT3 (middle panel) in colons of WT and Sdc1-KO mice. Scale bar, 100 μm. Lower panel: Representative negative controls (NEG) in which normal IgG was used in place of primary antibody.</p

Elevated expression of pro-tumorigenic target genes of STAT3 in Syndecan-1 KO mice compared to WT.

<p><b>(A)</b> Quantitative RT-PCR analysis revealed increased levels of Cyclin D1 (left), CCL-2 (middle) and Myc (right) in AOM-DSS induced colonic tumors derived from Sdc1-KO as compared to WT mice (n = 5). <b>(B)</b> Representative immunoreactive staining (brown) for Cyclin D1 in AOM-DSS induced colonic tumors (day 61) of WT and Sdc1-KO mice. Scale bar, 100 μm. <b>(C)</b> Quantification of average numbers of Cyclin D1 positive cells per high power field (X400) in ≥ 12 fields of each slide from 3 mice of each group. Error bars represent mean ± SE. *P < 0.05, ***P < 0.001 by Student’s t test. (D) Immunostaining for cMyc (brown) revealed increased levels of cMyc protein in AOM-DSS induced colonic tumors derived from Sdc1-KO vs. WT mice. Of note, cytoplasmic localization of cMyc was previously reported in several pathophysiological settings, including tumors of diverse origins (reviewed in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0174343#pone.0174343.ref070" target="_blank">70</a>]).</p

Increased activation of STAT3 in colonic tumors of Syndecan-1 KO mice compared to WT mice.

<p><b>(A)</b> Representative immunoreactive staining (brown) for phospho-STAT3 in AOM-DSS induced colonic tumors (day 61) of WT and Sdc1-KO mice. Scale bar, 100 μm. <b>(B)</b> Quantification of average numbers of phospho-STAT3 positive cells per high power field (X400) in ≥ 12 fields of each slide from 4 mice of each group. Error bars represent mean ± SE. **<i>P</i> < 0.01 by Student’s t test.</p

Syndecan-1 deficiency increases susceptibility to colitis-associated tumors in AOM/DSS-treated mice.

<p><b>(A)</b> Schematic representation of the mouse model of AOM/DSS-induced colitis–associated carcinoma performed as described in Methods. <b>(B)</b> Representative immunostaining (reddish) for Sdc-1 in normal colonic tissue and tumor tissue samples derived from the colons of WT and Sdc1-KO mice. Original magnification X200. <b>(C)</b> Quantification of average tumor size, and <b>(D)</b> tumor number/colon in WT and Sdc1-KO mice on day 61 of AOM-DSS–induced colon cancer (n = 6). Error bars represent mean ± SE. *<i>P</i> < 0.05 by Student’s t test. <b>(E)</b> Representative histopathologic sections of colon adenocarcinomas from WT and Sdc1-KO mice. (F) Representative immunostaining for beta-catenin in tumor tissue samples derived from the colons of WT and Sdc1-KO mice. Original magnification X1000.</p

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

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.SCOPUS: ar.jinfo:eu-repo/semantics/publishe