Positive association of heparanase expression with tumor invasion and lymphatic metastasis in gastric carcinoma

Abstract

Tumor invasion and metastasis are the most common causes of death in gastric carcinoma. Human heparanase influences tumor invasiveness and angiogenesis. Analysis of its expression in gastric carcinoma has been hindered by our inability to procure pure cancer cells from heterogeneous tissue. In the present study, we analyzed heparanase expression in human primary and metastatic gastric carcinoma cells as well as in paired normal gastric epithelial cells by laser capture microdissection coupled with reverse transcriptionpolymerase chain reaction (RT-PCR). Tumor tissues, metastatic lymph nodes, and apparently uninvolved normal gastric tissues were collected from 30 patients who had undergone gastrectomy with radical lymph node dissection for gastric carcinoma without preoperative treatment. Bulk tissues and laser capture microdissected cell groups were separately subjected to RT-PCR analysis with heparanase-specific primers. For bulk tissues, heparanase-specific transcripts were detectable in all primary tumor tissues, metastatic lymph nodes, and almost all matching normal tissues. RT-PCR analysis after laser capture microdissection showed no detectable heparanase expression in matching normal epithelial cell groups. Of the laser capture microdissected primary gastric carcinoma cells, 47% (14/30) were heparanase positive. Expression was closely associated with greater tumor invasiveness, including Borrmann gross type and depth of wall infiltration. For metastatic cell groups dissected from lymph nodes, 95% showed clear heparanase expression. Furthermore, the extent of lymphatic spread was directly correlated to heparanase expression at the primary site. In conclusion, laser capture microdissection coupled with RT-PCR is a reliable approach for molecular analysis of heparanase expression in gastric carcinoma. Heparanase may facilitate invasion and metastasis of gastric carcinoma cells. Keywords: gastric carcinoma; laser capture microdissection; lymphatic metastasis; heparanase expression It is generally accepted that the invasion of the basement membrane and extracellular matrix is one of the critical steps for cancer cell metastasis. 1 Heparan sulfate proteoglycans, composed of a protein core covalently linked to heparan sulfate side-chains, represent a principal component of the extracellular matrix and, in particular, basement membranes. Cell surface heparan sulfate can also serve as coreceptors, along with the other cell surface molecules, to form functional receptor complexes that facilitate signal transduction. 2 Furthermore, heparan sulfate chains bind a large number of bioactive molecules and regulate their availability and function. These include growth factors, chemokines, cytokines, and enzymes that are essential for angiogenesis, cell adhesion, and locomotion. 3 Accordingly, enzymatic degradation of heparan sulfate may play a critical role in cancer cell invasion and metastasis. Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans at a limited number ...

MicroRNA-1258: An invasion and metastasis regulator that targets heparanase in gastric cancer

“…It is widely accepted that tumor metastasis begins with the degradation of the ECM and breakdown of the basement membrane (13). Our previous studies demonstrated an increased expression of HPSE in GC tissues and identified that HPSE facilitates invasion and metastasis of GC cells (13,14). However, the underlying molecular mechanism of the upregulation of HPSE in GC tissues remains unclear.…”

Stable knockdown of heparanase expression in gastriccancer cells in vitro

“…In highly metastatic B16-BL6 mouse melanoma cells, transfection of mouse HPA-specific siRNA resulted in a decrease in the invasiveness and metastasis of tumor cells [14] . Previous studies indicated that the expression of HPA was frequently obser ved in advanced gastric cancers, and the frequency was significantly correlated with histopathological parameters reflecting invasive and metastatic potentials and prognosis of gastric cancers [6,7] . Our studies also demonstrated the overexpression of HPA protein in advanced gastric cancer (data not shown).…”

“…Heparanase (HPA), a mammalian endo-beta-D-glucuronidase, is capable of degrading the heparan sulfate proteoglycans (HSPGs) in the ECM and BM, and is proposed to have a promoting role in cancer invasion, angiogenesis and metastasis [5] . In advanced gastric cancer, expression of HPA was frequently observed and correlated with histopathological parameters reflecting the invasiveness, metastatic potential and prognosis of gastric cancers [6,7] . Thus HPA may represent an important target for treatment of gastric cancer.…”

RhoA and RhoC -siRNA inhibit the proliferation and invasiveness activity of human gastric carcinoma by Rho/PI3K/Akt pathway

“…The RhoA and RhoC proteins comprise an important s u b s e t o f t h e R h o G T Pa s e f a m i l y t h a t h a s b een implicated in invasive gastric carcinomas, and is related to the PI3K/Akt signal pathway. To dissect the specific contributions of RhoA and RhoC in the behavior of invasive gastric carcinoma cells, we used RhoA and RhoC gene interference to inhibit proliferation and invasion of SGC7901 cells of gastric carcinoma [7,8] . We have used small interfering RNA (siRNA) approaches to interfere www.wjgnet.com the expression of the RhoA and RhoC isoforms in the SGC7901 cells.…”