High Expression of Heparanase is Significantly Associated with Dedifferentiation and Lymph Node Metastasis in Patients with Pancreatic Ductal Adenocarcinomas and Correlated to PDGFA and Via HIF1a to HB-EGF and bFGF

Inositol hexaphosphate (IP6) and inositol (Ins), naturally occurring carbohydrates present in most mammals and plants, inhibit the growth of numerous cancers both in vitro and in vivo. In this study, we first examined the anti-metastatic effects of IP6 and Ins using a liver metastasis model of colorectal cancer (CRC) in BALB/c mice. CT-26 cells were injected into the splenic capsule of 48 BALB/c mice. The mice were then randomly divided into four groups: IP6, Ins, IP6 + Ins and normal saline control (n = 12 per group). IP6 and/or Ins (80 mg/kg each, 0.2 mL/day) were injected into the gastrointestinal tracts of the mice on the second day after surgery. All mice were sacrificed after 20 days, and the tumor inhibition rates were determined. The results demonstrated that the tumor weights of liver metastases and the tumor inhibition rates were reduced in the experimental groups compared to the control group and that treatment with the combination of IP6 and Ins resulted in greater inhibition of tumor growth than treatment with either compound alone. These findings suggest that IP6 and Ins prevent the development and metastatic progression of colorectal cancer to the liver in mice by altering expression of the extracellular matrix proteins collagen IV, fibronectin and laminin; the adhesion factor receptor integrin-β1; the proteolytic enzyme matrix metalloproteinase 9; and the angiogenic factors vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor beta in the tumor metastasis microenvironment. In conclusion, IP6 and Ins inhibited the development and metastatic progression of colorectal cancer to the liver in BALB/c mice, and the effect of their combined application was significantly greater than the effect of either compound alone. This evidence supports further testing of the combined application of IP6 and Ins for the prevention of colorectal cancer metastasis to the liver in clinical studies.

Inositol Hexaphosphate and Inositol Inhibit Colorectal Cancer Metastasis to the Liver in BALB/c Mice

Cytoplasmic RAD23B interacts with CORO1C to synergistically promote colorectal cancer progression and metastasis.

Metastasis is the most devastating aspect of the tumor, being the main cause of morbidity and mortality in cancer patients. The events that lead to tumor invasion and metastasis depend fundamentally on the initial aquisition of a mesenchymal phenotype by the primary carcinoma, which provides the necessary machinary for invasion, intravasation, vascular transport, extravasation and tumor colonization. These events are orquestrated by different growth factors, proteoglycans and adhesion molecules, acting at the surface of cells. The anticoagulant heparin binds several of these molecules and can regulate the interactions that occur during tumor invasion and metastasis. For example, heparin modulates the binding of FGF-2 to its tyrosine kinase receptor during tumor proliferation, and the binding of growth factors involved in epithelial to mesenchymal transition during tumor invasion. It also binds P-selectin on activated platelets, preventing tumor cell-platelet interaction during hematogeneous metastasis. In this review, we discuss the role of sulfated glycosaminoglycans during tumor invasion and metastasis, and the possible therapeutic use of heparin analogs on cancer treatment.

Effect of sulfated glycosaminoglycans on tumor invasion and metastasis.

Triple-negative breast cancer (TNBC), which is characterized by inherently aggressive behavior and lack of recognized molecular targets for therapy, poses a serious threat to women's health worldwi ...

/pdf/heparanase-from-triple-negative-breast-cancer-and-platelets-hoadqzy7tj.pdf

Heparanase from triple-negative breast cancer and platelets acts as an enhancer of metastasis

Organ-specific tumor cell adhesion to extracellular matrix (ECM) components and cell migration into host organs often involve integrin-mediated cellular processes. Direct integrin-mediated cell adhesion to ECM components in the space of Disse appears to be required for the successful liver metastatic formation of colon cancer. In the present study, human colon cancer HT-29 cells were transfected by liposome with integrin-β1 antisense oligodeoxynucleotide (ASODN). The integrin-β1 gene expression in HT-29 cells was significantly down-regulated. The migration of HT-29 cells was assayed using transwell cell culture chambers in vitro. The number of migrating HT-29 cells in experimental group was far less than that in control group (P<0.05). The models of hepatic metastasis in nude mice were established by the intrasplenic injection of transfected HT-29 cells. Thirty days later, the nude mice were killed and the average number of hepatic metastases (4.00±0.93 per mouse), average volume (10.10±6.50 mm3 per mouse), average weight (0.0440±0.0008 g per mouse) in experimental group were remarkably reduced as compared with those in control group (P<0.05). Integrin-β1 expression in the hepatic metastasis was studied by immunohistochemistry (SP). Positive cell percentage of hepatic metastases in experimental group was markedly decreased as compared with that in control group (P<0.05). It was concluded that integrin-β1 may take part in hepatic metastasis, and down-regulation of integrin-β1 expression may play a key role in decreasing migration and hepatic metastasis of human colon carcinoma cells (HT-29).

Effects of down-regulation of integrin-β1 expression on migration and hepatic metastasis of human colon carcinoma

Extracellular matrix (ECM) degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic Heparanase (HPSE) is an endoglycosidase that specifically degrades heparin sulfate proteoglycans (HSPG), a chief component of ECM HPSE is not expressed in normal epithelial cells but can be detected in a variety of human carcinomas including pancreatic cancer In the present study, human pancreatic cancer cell line Panc-1 was transfected with HPSE antisense oligodeoxynucleotide (AS-ODN) in vitro, then the inhibitory effect of AS-ODN on HPSE gene expression and invasive ability of Panc-1 cells in vitro was examined The HPSE mRNA and protein expression of Panc-1 cells transfected with AS-ODN was significantly inhibited However, there were no marked inhibitory effects in Panc-1 cells treated with nonsense oligodeoxynucleotide (NS-ODN) Moreover, a modified Boyden chamber assay demonstrated that transfection with HPSE AS-ODN significantly inhibited invasive potential of Panc-1 cells in vitro after AS-ODN transfection This suggests that HPSE AS-ODN may contribute to the inhibition of HPSE mRNA and protein expression, and results in a decrease of the invasive ability of Panc-1 in vitro

Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro.

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Effects of down-regulation of integrin-β1 expression on migration and hepatic metastasis of human colon carcinoma

Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro.