Expression of thrombospondin-1 in human pancreatic adenocarcinomas: Role in matrix metalloproteinase-9 production

Human pancreatic adenocarcinoma, an aggressive malignant disease, shows a strong desmoplastic reaction characterized by a remarkable proliferation of interstitial connective tissues. Thrombospondin-1 (TSP-1), a 450 kDa platelet and matrix glycoprotein, has been implicated in tumor invasion, angiogenesis and metastasis. TSP-1 and MMP-9 expression in pancreatic adenocarcinoma and control pancreas tissues was measured by immunohistochemistry. TSP-1 expression in pancreatic carcinoma cell lines, fibroblasts, and endothelial cells was measured by a competitive TSP-1 enzyme linked immunosorbent assay (ELISA). The effect of TSP-1 on MMP-9 production in pancreatic carcinoma cell lines was measured by zymography and Western blot analysis. Eighty five per cent (23/27) of cases of pancreatic adenocarcinoma showed increased TSP-1 staining in the desmoplastic stroma adjacent to tumor cells. No specific positive staining for TSP-1 was observed in the normal pancreatic tissues and the inflammatory areas. TSP-1 localized in tumor stroma surrounding the tumor cells expressing MMP-9. Using TSP-1 competitive ELISA, the secretion of TSP-1 by different pancreatic cancer cell lines into culture medium varied from 11.45 plus minus 14.08 to 275.82 plus minus 45.56 ng/10 6 cells/24 hours. The amounts of TSP-1 detected in both culture media and cell extracts from fibroblasts or endothelial cells were at least 2-3 fold higher than those from pancreatic cancer cells. TSP-1 augmented the production of matrix metalloproteinase-9, a matrix degrading enzyme, in pancreatic cancer cells in vitro. Stromally-derived TSP-1 up-regulates the production of MMP-9 by pancreatic adenocarcinoma. These data are consistent with the conclusion that TSP-1-rich stroma is involved in regulating matrix remodeling in tumor invasion.     

Instructions for Authors

Tissue remodeling is a key element in the local invasion and metastasis of malignant breast tumors. The degradation of extracellular matrix that is associated with this process is thought to be mediated by a number of Zn²⁺-dependent matrix metalloproteinases (MMPs). In most cases these enzymes are not produced by the malignant epithelium itself but by adjacent breast stroma, suggesting an important role for cell-cell interactions. We have analyzed Gelatinase A (MMP-2) and Gelatinase B (MMP-9) gene expression in a panel of six breast cancer cell lines and six primary cultures of stromal cells deriving from breast cancer biopsies. With one exception we did not detect MMP-2 or MMP-9 gene expression in any of the established tumor cell lines. Conversely, tumor stroma-derived fibroblasts expressed MMP-2 mRNA, although no MMP-9 mRNA was seen in RNase protection assays. When fibroblasts were cultured in the presence of media conditioned by MCF-7 tumor cells, MMP-2 enzyme production increased but MMP-9 activity remained undetectable. However, when fibroblasts and MCF-7 tumor cells were co-cultured together, MMP-9 was induced. These observations were confirmed by immunocytochemical analysis of co-cultures of MCF-7 and tumor-derived fibroblasts in which MMP-2 and MMP-9 protein expression was confined to stromal cells adjacent to MCF-7 tumor cells. No MMP-2 or MMP-9 staining was detected in monocultures of the two respective cell types. We conclude that MMP-2 expression is present in the stroma of malignant tumors and is increased by paracrine stimulation mediated by soluble factors. In contrast, MMP-9 expression tumor-derived fibroblasts requires direct contact with malignant tumor epithelium.     

Tumour-site-dependent expression profile of angiogenic factors in tumour-associated stroma of primary colorectal cancer and metastases

Background:

Tumour-associated stroma has a critical role in tumour proliferation. Our aim was to determine a specific protein expression profile of stromal angiogenic cytokines and matrix metalloproteinases (MMPs) to identify potential biomarkers or new therapy targets.

Methods:

Frozen tissue of primary colorectal cancer (n=25), liver (n=25) and lung metastases (n=23) was laser-microdissected to obtain tumour epithelial cells and adjacent tumour-associated stroma. Protein expression of nine angiogenic cytokines and eight MMPs was analysed using a multiplex-based protein assay.

Results:

We found a differential expression of several MMPs and angiogenic cytokines in tumour cells compared with adjacent tumour stroma. Cluster analysis displayed a tumour-site-dependent stromal expression of MMPs and angiogenic cytokines. Univariate analysis identified stromal MMP-2 and MMP-3 in primary colorectal cancer, stromal MMP-1, -2, -3 and Angiopoietin-2 in lung metastases and stromal MMP-12 and VEGF in liver metastases as prognostic markers (P>0.05, respectively). Furthermore, stroma-derived Angiopoietin-2 proved to be an independent prognostic marker in colorectal lung metastases.

Conclusion:

Expression of MMPs and angiogenic cytokines in tumour cells and adjacent tumour stroma is dependent on the tumour site. Stroma-derived MMPs and angiogenic cytokines may be useful prognostic biomarkers. These data can be helpful to identify new agents for a targeted therapy in patients with colorectal cancer.     

Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis

Cap43 has been identified as a nickel- and calcium-induced gene, and is also known as N-myc downstream-regulated gene 1 (NDRG1), Drg-1 and rit42. It is also reported that overexpression of Cap43 suppresses metastasis of some malignancies, but its precise role remains unclear. In this study, we asked how Cap43 could modulate the tumor growth of pancreatic cancer. Stable Cap43 cDNA transfectants of pancreatic cancer cells with Cap43 overexpression showed similar growth rates in culture as their control counterparts with low Cap43 protein level. By contrast, Cap43 overexpression showed a marked decrease in tumor growth rates in vivo. Moreover, a marked reduction in tumor-induced angiogenesis was observed. Gelatinolytic activity by matrix metalloproteinase-9 and invasive ability in Matrigel invasion activity were markedly decreased in pancreatic cancer cell lines with high Cap43 expression. Cellular expression of matrix metalloproteinase-9 and two major angiogenic factors, vascular endothelial growth factor and interleukin-8, were also significantly decreased in cell lines with Cap43 overexpression as compared with their parental counterparts. Immunohistochemical analysis of specimens from 65 patients with pancreatic ductal adenocarcinoma showed a significant association between Cap43 expression and tumor microvascular density (P = 0.0001) as well as depth of invasion (P = 0.0003), histopathologic grading (P = 0.0244), and overall survival rates for patients with pancreatic cancer (P = 0.0062). Thus, Cap43 could play a key role in the angiogenic on- or off-switch of tumor stroma in pancreatic ductal adenocarcinoma.     

Serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinases 2 (TIMP-2) in colorectal cancer patients

The objective of the study was the assessment of serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC). The study included 72 CRC patients and 68 healthy subjects. The serum levels of MMP-2 and TIMP-2 were measured using enzyme-linked immunosorbent assay (ELISA) method, whereas tissue expression of MMP-2 and TIMP-2 in cancer cells, interstitial inflammatory cells, and adjacent normal colorectal mucosa were examined by immunohistochemical staining of tumor samples. The serum levels of MMP-2 and TIMP-2 in cancer patients were significantly lower than those in control group, but the percentage of positive immunoreactivity of these proteins were higher in malignant and inflammatory cells as compared to normal tissue. There was a significant correlation between MMP-2 immunoreactivity in inflammatory cells and the presence of distant metastases and between TIMP-2 expression in inflammatory cells and tumor size, nodal involvement, and distant metastases. Area under receiver operating characteristic (ROC) curve (AUC) for serum MMP-2 was higher than for serum TIMP-2. Moreover, positive tissue expression of MMP-2 was a significant prognostic factor for CRC patients’ survival. Our findings suggest that MMP-2 and TIMP-2 might play a role in the process of colorectal cancer invasion and metastasis, but the significance of their interactions with tumor stroma and interstitial inflammatory infiltration in colorectal neoplasia require further elucidation.     

Evaluation of urinary plasminogen activator, its receptor, matrix metalloproteinase-9, and von Willebrand factor in pancreatic cancer.

PURPOSE: Pancreatic cancer remains a devastating problem with the majority of patients succumbing to death from this disease. A hallmark of pancreatic cancer is the loss of basement membrane that may be attributed to the action of urinary plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9). These enzymes are also implicated in angiogenesis. uPA and microvessel density have been shown to be good prognostic indicators for breast and colon cancer. MMP-9 and microvessel density have not been investigated in pancreatic cancer. We have therefore investigated by immunohistochemistry: (a) frequency of uPA expression and its receptor uPAR and the site of synthesis of uPA by in situ hybridization (ISH); (b) MMP-9 and its coexpression with uPA; (c) microvessel density as determined by von Willebrand factor staining and its relationship to uPA and MMP-9 expression; and (d) correlation of these parameters with survival. EXPERIMENTAL DESIGN: Archival paraffin sections of 27 pancreatic tumors were semiquantitatively investigated by immunohistochemistry using the following antibodies: (a) monoclonal antibodies (MAbs) uPA(1) and uPA(2) (3689 and 394, respectively); (b) MAb uPAR, (no. 3932); (c) MAb MMP-9 (no. 936); and (d) rabbit anti-F8RA/vWF. ISH was performed using a uPA cDNA. RESULTS: Both uPA antibodies revealed overexpression of uPA (93%) often with uniform staining of tumor cells. uPAR and MMP-9 showed focal staining in only 52 and 37% of tumors, respectively. Morphologically normal appearing ductal cells in close proximity to tumors overexpressed uPA in contrast to distally located normal cells (P = <0.001). uPA staining was also investigated in pancreatic intraepithelial neoplasia (PanIN) lesions. PanIN 1A/B staining for uPA was seen in 8 cases (30%), that for PanIN 2 in 19 cases (70%), and for PanIN3 in 12 cases (44%). Lumen of microvessels in the tumor stroma also revealed staining of uPA in 10 cases (37%). ISH experiments revealed the presence of uPA mRNA not only in the cytoplasm of tumor cells but also in adjacent normal appearing ducts as well as in PanIN lesions. Patients with overexpression of uPA, uPAR, or MMP-9 had a trend toward poorer survival than those who did not express it. Microvessel density did not show any significant relationship with uPA, uPAR, and MMP-9 expression and survival. CONCLUSIONS: We conclude that uPA and MMP-9 are potential prognostic indicators in pancreatic cancer, whereas microvessel density may not be one. This study confirms our previous observation that uPA is made by the tumor cells themselves. Presence of uPA in vessels of tumor stroma suggests that uPA is in circulation, and its measurement and that of MMP-9 in the blood of these patients may aid in prognosis. Patients showing overexpression of uPA and MMP-9 have a trend toward shorter survival time.     

The prognostic value of angiogenesis and metastasis-related genes for progression of transitional cell carcinoma of the renal pelvis and ureter.

PURPOSE: We reported previously that angiogenesis evaluated by intratumor microvessel density (MVD), expression of such angiogenic factors as vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF), and the matrix metalloproteinase-9:E-cadherin ratio (M:E ratio) could identify patients with advanced transitional cell carcinoma (TCC) of the bladder for whom chemotherapy and cystectomy will be unsuccessful. In the present study, we evaluated the significance of the M:E ratio as a predictor for prognosis for patients with TCC in the upper urinary tract (TCC-UUT). EXPERIMENTAL DESIGN: We evaluated MVD by immunohistochemistry and the expression of angiogenic and metastasis-related factors by in situ hybridization in 55 nephroureterectomy specimens from patients who received no neoadjuvant therapy. The expression of angiogenesis, angiogenic and metastasis-related factors, and clinicopathological characteristics were evaluated for their correlation with metastasis, recurrence, and disease prognosis. RESULTS: We found that tumor grade and pathological stage were important predictors for metastasis and survival in these patients. The expression level of matrix metalloproteinase type 9 (MMP-9) and type 2 (MMP-2) and the M:E ratio correlated with MVD. Increased MVD, elevated expression levels of MMP-9 and MMP-2, and a higher M:E ratio were associated with poor prognosis. Moreover, lower expression levels of E-cadherin were associated with fewer recurrences in the urinary bladder. Multivariate analysis indicated that the M:E ratio and E-cadherin expression were independent prognostic factors for disease progression and intravesical recurrence, respectively. CONCLUSION: We suggest that the M:E ratio and E-cadherin expression may be targets for novel therapeutic strategies.     

Expression and localization of matrix metalloproteinases and tissue inhibitors of metalloproteinases as a prognostic factor in advanced colorectal carcinomas

To clarify the usefulness of matrix metallo-proteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as prognostic factors in advanced colorectal carcinoma, the immunohistochemical expressions of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 and TIMP-2 were examined. Specimens were selected from 67 consecutive patients undergoing surgery for advanced colorectal carcinoma. The patterns of expression were compared with the prognoses of the patients. The patients with TIMP-2 expression in stroma adjacent to the tumor mass had better prognoses than those of the patients who had no TIMP-2 expression in normal stroma adjacent to the tumor (p<0.05), which probably acted as a block of cancer cell invasion. However, the expression of MMP-2, presumably acting as an antagonist to TIMP-2 was not related to the prognosis, and the MMP-1, MMP-2, MMP-3, MMP-9 and TIMP-1 expressions were not related to any clinicopathological factors examined.     

Colony-stimulating factor-1 antisense treatment suppresses growth of human tumor xenografts in mice

Matrix metalloproteinases (MMPs) foster cellular invasion by disrupting extracellular matrix barriers and thereby facilitate tumor development. MMPs are synthesized by both cancer cells and adjacent stromal cells, primarily macrophages. The production of macrophages is regulated by colony-stimulating factor-1 (CSF-1). Tissue CSF-1 expression increased significantly in embryonic and colon cancer xenografts. We, therefore, hypothesized that blocking CSF-1 may suppress tumor growth by decelerating macrophage-mediated extracellular matrix breakdown. Cells expressing CSF-1 and mice xenografted with CSF-1 receptor (c-fms)- and CSF-1-negative malignant human embryonic or colon cancer cells were treated with mouse CSF-1 antisense oligonucleotides. Two weeks of CSF-1 antisense treatment selectively down-regulated CSF-1 mRNA and protein tissue expression in tumor lysates. CSF-1 blockade suppressed the growth of embryonic tumors to dormant levels and the growth of the colon carcinoma by 50%. In addition, tumor vascularity and the expression of MMP-2 and angiogenic factors were reduced. Six-month survival was observed in colon carcinoma mice only after CSF-1 blockade, whereas controls were all dead at day 65. These results suggest that human embryonic and colon cancer cells up-regulate host CSF-1 and MMP-2 expression. Because the cancer cells used were CSF-1 negative, CSF-1 antisense targeted tumor stromal cell CSF-1 production. CSF-1 blockade could be a novel strategy in treatment of solid tumors.     

Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database

Traditionally, matrix metalloproteinases (MMPs) have been implicated in cancer invasion and metastasis. Because of their role in these processes, several MMPs have been investigated for potential prognostic value as well as targets for antimetastatic therapy. In this investigation, we used a publically available database to relate messenger RNA expression levels for 17 different MMPs to tumor characteristics and outcome in patients with breast cancer. Of the MMPs investigated, only MMP-1 was significantly increased in tumors >2 cm in size compared with those ≤2 cm while MMP-1, -9, -12 and -15 were significantly elevated in high-grade compared with low-grade tumors. Only MMP-10 was higher in lymph node-positive compared with lymph node-negative cancers. Using univariate analysis, high expressions of MMP-1, -9, -12, -14 and -15 were associated with poor overall survival. Of these five, only MMP-14 predicted outcome independent of tumor size, tumor grade and lymph node status. None of the MMPs investigated were associated with good outcome. We conclude that only a minority of MMPs, i.e. MMP-1, -9, -12, -14 and -15, are associated with adverse outcome in patients with breast cancer. These MMPs are likely to be involved in mediating breast cancer progression and may thus be good targets for designing specific MMP inhibitors for the treatment of breast cancer.     

Epithelial MMP-2 expression correlates with worse prognosis in pancreatic cancer

OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix and are involved in tumor invasion and metastasis in various cancers. In pancreatic cancer, MMP-2 expression is upregulated and correlates with tumor recurrence. The aim of this study was to evaluate the prognostic significance of MMP-2 in pancreatic ductal adenocarcinoma. METHODS: MMP-2 expression was assessed by immunohistochemistry in 127 patients operated on at Helsinki University Hospital from 1974 to 1998, with expression interpreted separately in epithelial and stromal samples. RESULTS: Epithelial MMP-2 expression was strong in 5%, moderate in 20%, weak in 25% and negative in 50% of the tumors, with high epithelial MMP-2 expression significantly associated in univariate survival analysis with advanced stage, poor grade and poor survival. Stromal MMP-2 expression was strong in 0%, moderate in 14%, weak in 70% and negative in 16% of the cases, and did not significantly correlate with patient survival. CONCLUSION: Epithelial MMP-2 correlates with advanced tumor stage and grade, but is not an independent predictor of survival.     

Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma

BALB-neuT mice expressing an activated rat c-erbB-2/neu transgene under the mouse mammary tumor virus long terminal repeat show enhanced hematopoiesis with hyperproduction of myeloid-derived suppressor cells (MDSC) because of vascular endothelial growth factor (VEGF) secreted by the tumor. Here, we show that both tumor and stromal cells express matrix metalloproteinase-9 (MMP-9), thereby increasing the levels of pro-MMP-9 in the sera of tumor-bearing mice. Treatment with amino-biphosphonates impaired tumor growth, significantly decreased MMP-9 expression and the number of macrophages in tumor stroma, and reduced MDSC expansion both in bone marrow and peripheral blood by dropping serum pro-MMP-9 and VEGF. We dissected the role of tumor-derived MMP-9 from that secreted by stromal leukocytes by transplanting bone marrow from MMP-9 knockout mice into BALB-neuT mice. Although bone marrow progenitor-derived MMP-9 had a major role in driving MDSC expansion, amino-biphosphonate treatment of bone marrow chimeras further reduced both myelopoiesis and the supportive tumor stroma, thus enhancing tumor necrosis. Moreover, by reducing MDSC, amino-biphosphonates overcome the tumor-induced immune suppression and improved the generation and maintenance of antitumor immune response induced by immunization against the p185/HER-2. Our data reveal that suppression of MMP-9 activity breaks the vicious loop linking tumor growth and myeloid cell expansion, thus reducing immunosuppression. Amino-biphosphonates disclose a specific MMP-9 inhibitory activity that may broaden their application above their current usage.     

Anti-angiogenic effects of somatostatin receptor subtype 2 on human pancreatic cancer xenografts.

Somatostatin receptor subtypes, especially subtype 2 (SSTR2), exert their antitumor (cytostatic and/or cytotoxic) and anti-angiogenic effects. Here we aimed to investigate the anti-angiogenic effect of SSTR2 gene transfer into pancreatic cancer cell line PC-3, and the mechanisms involved in this effect. The full-length human SSTR2 complementary DNA was introduced into pancreatic cancer cell line PC-3 by lipofectamine-mediated transfection, and stable expression of SSTR2 was detected by immunohistochemistry and RT-PCR. Athymic mice were separately xenografted with SSTR2-expressing cells (experimental group), vector control and mock control cells. Intratumoral microvessel density (MVD) was assessed by immunohistochemistry. Immunohistochemistry and RT-PCR were used to determine the expression of angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and matrix metalloproteinase (MMP)-2 in xenograft tumors. MVD was significantly lower in the experimental group (5.16 +/- 1.34) than that in the vector control (16.52 +/- 2.25) and mock control (15.32 +/- 2.53) (P < 0.05). The immunohistochemical assay showed a significant decrease in the expression of VEGF, bFGF and MMP-2 protein in the experimental group compared with the vector control and mock control, considering both the integral optical density and area of staining (P < 0.05). RT-PCR showed a significant reduction of VEGF, bFGF and MMP-2 mRNA expression in the experimental group compared with the vector control and mock control (P < 0.05). Thus, introduction of the SSTR2 gene, the expression of which is frequently lost in human pancreatic adenocarcinoma, exerts its anti-angiogenic effects by down-regulating the expression of the factors, which are involved in tumor angiogenesis and metastasis, suggesting SSTR2 gene transfer as a promising strategy of gene therapy for pancreatic cancer.     

Histopathological and immunohistochemical features associated with clinical response to neoadjuvant gefitinib therapy in early stage non-small cell lung cancer

Background

Matrix metalloproteinases (MMPs) are considered important players in angiogenesis and cancer progression. Several drugs developed for targeting MMPs have until now been without clinical efficacy. As both malignant cells and cells of the surrounding stroma contribute to tumor growth, we have explored the impact of MMP-2, -7 and -9 expression in both the tumor and stromal compartment of non-small-cell lung cancers (NSCLC).

Patients and methods

From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). Immunohistochemistry was used to detect the expression of MMP-2, -7 and -9 in tumor and stromal cells.

Results

In univariate analyses, high tumor cell MMP-7 expression (P = 0.029) and high stromal MMP-9 expression (P = 0.001) were positive prognostic factors. In the multivariate analysis, high tumor cell MMP-7 expression (HR 1.58, CI 1.08-2.32, P = 0.020) and high stromal MMP-9 expression (HR 1.92, CI 1.25-2.96, P = 0.003) were independent positive prognostic factors for disease-specific survival.

Conclusion

High levels of MMP-7 in tumor cells and high levels of MMP-9 in tumor associated stroma were independent positive prognostic factors in NSCLC patients.     

Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer

Strong expression of many matrix metalloproteinases (MMPs) has been related to poor survival of colorectal cancer (CRC) patients. The expression of tissue inhibitors of metalloproteinases (TIMPs) has been associated with both a beneficial and a poor outcome and there is thus a need to further clarify the significance of MMPs and TIMPs in CRC. The prognostic significance of 4 MMPs and TIMPs in CRC was evaluated. Formalin-fixed, paraffin-embedded tissue arrayed samples of 351 patients with primary colon or rectal cancer of Dukes' stages A-D were selected for immunohistochemical staining of MMP-1, -2, -7 and -13, and TIMP-1, -2, -3 and -4. High expression of MMP-2 in the malignant epithelium as well as in the surrounding stroma was associated with reduced survival of colon cancer patients. Strong epithelial and stromal cytoplasmic staining of TIMP-3 was associated with a longer survival in rectal cancer patients, and here the interobserver variation for evaluating the degree of staining was lower than for epithelial staining. Strong stromal cytoplasmic staining of TIMP-4 predicted longer survival of rectal cancer patients. Multivariate analysis showed that stromal cytoplasmic TIMP-3 staining was the only marker of independent prognostic value. MMP-2 might be a useful prognostic marker in colon cancer, and TIMP-3 and TIMP-4 in rectal cancer, but the findings associated with stromal staining should be interpreted with some caution. Different biologic behavior or different genetic development may explain the differences between colon and rectal cancers regarding the expression of MMP-2, TIMP-3 and TIMP-4.     

Angiogenesis and platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in endometrial cancer.

The object of this study was to clarify the association of angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (dThdPase) with clinicopathological factors including tumor angiogenesis and patient outcome in endometrial cancer. There was no correlation between the expression of PD-ECGF in cancer cells and any of the clinicopathological variables. Immunopositivity for PD-ECGF in stroma cells was significantly higher in poorly differentiated adenocarcinomas. The microvessel counts correlated with PD-ECGF positive stroma cells (p<0.0001). Disease-free survival was significantly worse in patients with marked PD-ECGF expression in stromal cells and high microvessel count. A multivariate analysis using Cox's proportional hazard model showed that high microvessel counts independently predicted disease-free survival as well as stage and myometrial invasion. The expression of PD-ECGF in stroma cells may play a crucial role in the promotion of angiogenesis. Tumor angiogenesis can be used to predict prognosis in patients with endometrial cancer.     

基质金属蛋白酶-9在胃癌中的表达及其预后价值

目的 探讨基质金属蛋白酶-9（MMP-9）在胃癌组织中的表达情况,分析其表达