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51.
Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells 总被引:6,自引:0,他引:6
Thant AA Nawa A Kikkawa F Ichigotani Y Zhang Y Sein TT Amin AR Hamaguchi M 《Clinical & experimental metastasis》2000,18(5):423-428
Cell adhesion to the extracellular matrix appears to trigger a cascade of intracellular signalings. We have previously shown
that treatment of ovarian cancer cells, NOM1, with fibronectin (FN) stimulated matrix metalloproteinase (MMP)-9 secretion
and thereby activated the invasiveness of cells via the FAK/Ras signaling pathway. By use of chemical inhibitors, we investigated
the downstream effectors critical for FN-dependent secretion of MMP-9. Treatment of cells with MEK1 inhibitors, U0126 and
PD98059, dramatically suppressed the secretion of MMP-9 activated by FN. Similarly, PI-3 kinase inhibitors, Wortmannin and
LY294002, strongly suppressed the FN-dependent secretion of MMP-9 together with the inhibition of Akt activation. In contrast,
a specific PKC inhibitor (GF109203X) showed no inhibitory effect on the FN-dependent MMP-9 secretion. Moreover, we found that
both the MEK1 inhibitor and the PI3-K inhibitor, but not the PKC inhibitor, strongly suppressed the invasiveness of NOM1 cells.
Taken together, our results suggest that activation of dual signaling pathways, MEK1-MAPK and PI3K-Akt, is required for the
FN-dependent activation of MMP-9 secretion. Our results suggest the importance of these signaling molecules as a chemotherapeutic
target for cancer.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
52.
Massimo Pignatelli Tareq W. Ansari Pat Gunter Dan Liu Shinji Hirano Masatoshi Takeichi Günter Klppel Nicholas R. Lemoine 《The Journal of pathology》1994,174(4):243-248
Epithelial cadherin (E-cadherin) is a Ca2+-dependent cell-cell adhesion molecule that connects cells via homotypic interactions. Its function is critical in the induction and maintenance of cell polarity and differentiation, and its loss of downregulation is associated with an invasive and poorly differentiated phenotype in colon and other tumours. We have used an avidin-biotin immunoperoxidase technique to localize E-cadherin in microwave-treated, paraffin-embedded sections from 36 patients with pancreatic adenocarcinomas. E-cadherin was expressed by normal ductal and acinar cells with typical membranous staining at the intercellular junctions. Loss of normal surface E-cadherin expression was found in 19/36 (53 per cent) tumours compared to the adjacent normal ductal cells. Abnormal E-cadherin expression was found more frequently in poorly differentiated (grade III) (6/7, 86 per cent) than in well-differentiated tumours (grade I) (4/14, 28 per cent) (P=0·012). Membranous E-cadherin expression was also lost more frequently in primary tumours with lymph node (stage III) (14/23, 61 per cent) and distant metastasis (stage IV) (2/2, 100 per cent) compared with 3/11 (27 per cent) lymph node-negative tumours (stage I) (P=0·043). In conclusions, our data indicate that loss of membranous E-cadherin expression is associated with high grade and advanced stage in pancreatic cancer. 相似文献
53.
Junya Yoneda Ikuo Saiki Hideji Fujii Fuminori Abe Yutaka Kojima Ichiro Azuma 《Clinical & experimental metastasis》1992,10(1):49-59
We have investigated the effect of the immunomodulator ubenimex (hereafter referred to as bestatin) on the enzymatic degradation
of the extracellular matrix by human renal cell carcinoma SN12M cells during the invasive process. The invasion of SN12M cells
into reconstituted basement membrane (Matrigel) was inhibited by the presence of bestatin in a concentration-dependent manner.
However, bestatin did not have any effect on tumor cell adhesion and migration to the extracellular matrices which may be
involved in tumor cell invasion. Bestatin inhibited the degradation of type IV collagen by tumor cells, but not by tumor-conditioned
medium (TCM), in a concentration-dependent manner. We also found that bestatin inhibited hydrolysing activities towards substrates
of aminopeptidases in SN12M cells. Since bestatin was found to inhibit aminopeptidase activity, the inhibition of tumor invasion
by bestatin is likely to be associated with its action as an enzyme inhibitor. Bestatin only slightly inhibited tumor cell
plasmin activity, which can lead to the conversion of the latent collagenase to the active form, but this slight effect was
not significant. The zymography of TCM from SN12M cells showed that the treatment of tumor cells with bestatin resulted in
the disappearance of the 68 kDa type IV collagenase-enzyme level (active form) and slight reduction of the 72 kDa type IV
collagenase-enzyme level (latent form). These results indicated that bestatin may inhibit tumor cell invasion through a mechanism
involving its inhibitory action on aminopeptidases in tumor cells, suggesting that the aminopeptidase may partly be associated
with the conversion of a latent form of type IV procollagenase to an active form or the secretion of the collagenases from
tumor cells. 相似文献
54.
Adhesion polypeptides are useful for the prevention of peritoneal dissemination of gastric cancer 总被引:3,自引:0,他引:3
Tasuku Matsuoka Kosei Hirakawa-YS Chung Masakazu Yashiro Shigehiko Nishimura Tetsuji Sawada Ikuo Saiki Michio Sowa 《Clinical & experimental metastasis》1998,16(4):381-388
We examined the effect of adhesion polypeptides on the adhesion and invasiveness of gastric cancer cell lines. We previously reported the establishment of an extensively peritoneal-seeding cell line, OCUM-2MD3, from a poorly seeding human scirrhous gastric carcinoma cell line, OCUM-2M. Both 21 and 31 integrin expression was markedly increased on OCUM-2MD3 cells compared with OCUM-2M cells, and the ability of OCUM-2MD3 cells to bind to the extracellular matrix (ECM) was also significantly higher than that of OCUM-2M cells. The adhesion polypeptides, YIGSR and RGD, and two RGD derivatives significantly inhibited the adhesion of OCUM-2MD3 cells to the submesothelial ECM, while not inhibiting the adhesiveness of OCUM-2M cells and two well differentiated human gastric cell lines, MKN-28 and MKN-74. The YIGSR and RGD peptides also significantly inhibited the invasiveness of OCUM-2MD3 cells. The survival of nude mice with peritoneal dissemination given YIGSR sequenc e intraperitoneally was obviously longer than that of untreated mice. The survival of mice treated with RGD was also improved, and this effect was increased using the RGD derivatives, poly(CEMA-RGDS) and CM-chitin RGDS. These polypeptides appear to block the binding of integrins, which are expressed on OCUM-2MD3 cells, to the submesothelial ECM, and consequently inhibit peritoneal implantation. The peritoneal injection of adhe-sion polypeptides may be a new therapy against the dissemination of scirrhous gastric cancer, and may be useful for the prevention of dissemination in high-risk patients. © Rapid Science Ltd. 相似文献
55.
Ohnishi T Hiraga S Izumoto S Matsumura H Kanemura Y Arita N Hayakawa T 《Clinical & experimental metastasis》1998,16(8):729-741
In order to clarify the role of fibronectin in glioma invasion in vivo, we analyzed the relationship between fibronectin-stimulated cell migration and adhesion in 14 primary glioma cells and the expression of fibronectin and the fibronectin receptor in the corresponding tumor tissues. The tumors comprised nine glioblastomas (GB) and five anaplastic gliomas (AG) consisting of two astrocytomas, two oligoastrocytomas and one ependymoma. All glioma cells tested in the primary cell culture were found to migrate to fibronectin in a dose-dependent manner. The extent of cell migration to fibronectin was not significantly different for the GB and AG groups. On the other hand, cell adhesion to fibronectin in the AG was much stronger than that in the GB group. Immunohistochemistry demonstrated that fibronectin positively stained in the extra-cellular matrix (ECM) in eight cases and that the fibronectin receptor was positive in tumor cell membranes in 10 cases. In addition, cellular fibronectin isoforms containing ED-A and ED-B sequences were found to be immunolocalized in the tumor cells and the ECM of GB. These isoforms were also specifically expressed in tumor vessels within tumor tissues, but not in those within normal brain tissues. Cell migration tended to be expressed more strongly by glioma cells derived from tumor tissues in which fibronectin was posi-tively immunolocalized in the ECM than from tissues with negative fibronectin in the ECM. Four glioma cells derived from GB whose tumor cells did not positively stain for fibronectin receptors migrated much less extensively to fibronectin than other glioma cells whose tissues showed positive staining for the fibronectin receptor. Of these four GB, two had loss of heterozygosity in the locus of fibronectin receptor b1 gene. These results suggest that fibronectin deposited in the extracellular matrix of tumors, which can be derived from both plasma and the tumor cell itself, strongly promotes the migration of glioma cells, and that expression of the fibronectin receptor may play a critical role in the biological behavior of the tumor cells, particularly in fibronectin-stimulated cell migration in vivo.© Kluwer Academic Publishers 1998 相似文献
56.
Molecular determinants of human uveal melanoma invasion and metastasis 总被引:19,自引:0,他引:19
Seftor EA Meltzer PS Kirschmann DA Pe'er J Maniotis AJ Trent JM Folberg R Hendrix MJ 《Clinical & experimental metastasis》2002,19(3):233-246
The molecular analysis of cancer has benefited tremendously from the sequencing of the human genome integrated with the science
of bioinformatics. Microarray analysis technology has the potential to classify tumors based on the differential expression
of genes. In the current study, a collaborative, multidisciplinary approach was utilized to study the molecular determinants
of human uveal melanoma invasion and metastasis. Uveal melanoma is considered the most common primary intraocular cancer in
adults, resulting in the death of approximately 50% of patients affected. Unfortunately, at the time of diagnosis, many patients
already harbor microscopic metastases, thus underscoring a critical need to identify prognostic markers indicative of metastatic
potential. The investigative strategy consisted of isolating highly invasive vs. poorly invasive uveal melanoma cells from
a heterogeneous tumor derived from cells that had metastasized from the eye to the liver. The heterogeneous tissue explant
MUM-2 led to the derivation of two clonal cell lines: MUM-2B and MUM-2C. Further morphological and functional analyses revealed
that the MUM-2B cells were epithelioid, interconverted (expressing mesenchymal and epithelial phenotypes) highly invasive,
and demonstrated vasculogenic mimicry. The MUM-2C cells were spindle-like, expressed only a vimentin mesenchymal phenotype,
poorly invasive, and were incapable of vasculogenic mimicry. The molecular analysis of the MUM-2B vs. the MUM-2C clones resulted
in the differential expression of 210 known genes. Overall, the molecular signature of the MUM-2B cells resembled that of
multiple phenotypes – similar to a pluripotent, embryonic-like genotype. Validation of select genes that were upregulated
and down-regulated was conducted by semiquantitative RT-PCR measurement. This study provides a molecular profile that will
hopefully lead to the development of new molecular targets for therapeutic intervention and possible diagnostic markers to
predict the clinical outcome of patients with uveal melanoma.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
57.
c-erbB-2、VEGF和组织蛋白酶D在胃癌中的表达及其相关性 总被引:7,自引:1,他引:7
目的:探讨癌基因c-erbB-2、血管内皮生长因子(VEGF)和组织蛋白酶D(Cath-D)在胃癌中的表达及其与胃癌生物学行为的关系。方法:采用免疫组织化学(S-P)法,检测了102例胃癌手术标本中c-erbB-2、VEGF及Cath-D的表达,同时观察了网状纤维分布与c-erbB-2、Cath-D之间的关系,并将检测结果与跟踪随访资料进行了综合分析。结果:102例胃癌组织中c-erbB-2表达阳性率为38.24%(39/102),与胃癌浸润深度(P<0.05)、淋巴结转移(P<0.05)密切相关;VEGF表达阳性率为50%(51/102),与胃癌浸润深度(P<0.01)、生长方式(P<0.01)、淋巴结转移(P<0.01)密切相关;Cath-D表达阳性率为81.37%(83/102),与胃癌浸润深度(P<0.05)、生长方式(P<0.05)、淋巴结转移(P<0.05)及脉管内有无癌栓(P<0.05)有关。对生存期分析显示:Cath-D、VEGF、c-erbB-2阳性患者预后差,5年生存率低于阴性表达患者。结论:c-erbB-2、VEGF及Cath-D与胃癌的生长、浸润、转移、预后有密切关系,可作为判断胃癌生物学行为和预后的重要指标。 相似文献
58.
自发性高血压大鼠的微血管改变及其与血管内皮细胞损伤的关系 总被引:7,自引:1,他引:7
目的:探讨自发性高血压大鼠(SHR)的微血管改变与血管内皮细胞(VEC)损伤的关系。方法:以10只成年Wistar-Kyoto大鼠(WKY)为正常对照组(WKY组)。观察、计数10只成年SHR的肠壁微动脉管径和分支数,同时测定血浆亚硝酸根(NO2-)和内皮素(ET)并与WKY组对照。结果:SHR组的肠壁各级微动脉管径较WKY组变细(P<0.01~0.001)、各级微动脉总条数较WKY组减少(P<0.001~0.0001);SHR组的血浆NO2-水平和K值[10g(NO2-/ET)」较WKY组低(P<0.05~0.001),而ET较WKY组高(P<0.05)。血压和K值分别与肠壁微动脉管径和条数呈负相关和正相关(P<0.005~0.001)。结论:高血压的微血管结构异常与VEC损伤有密切的关系。 相似文献
59.
60.
Thomas Hoelting Andreas Zielke Allan E. Siperstein Orlo H. Clark Quan -Yang Duh 《Clinical & experimental metastasis》1994,12(4):315-323
The aggressiveness of follicular thyroid cancer (FTC) varies widely, and metastasis is the primary cause of death. Uncontrolled proliferation of cancer cells may be associated with loss of growth factor control. We investigated the effects of stimulating (epidermal growth factor [EGF]; thyreotropin [TSH] in low concentrations) and inhibiting growth factors (transforming growth factor beta 1 [TGF beta 1]; TSH in high concentrations) on invasion and growth of FTC cell lines from the thyroid tumor (FTC133) and from the lymph node (FTC236) and lung (FTC238) metastases of the same patient. Invasion—penetration through an 8m pore membrane, covered by Matrigel (basement membrane)—and growth were measured using the MTT-method. EGF (10 ng/ml) and TSH in low concentrations (1 mU/ml) stimulated invasion and growth of all FTC cell lines, but the amplitude of stimulation differed significantly. The parental cell line FTC133 was considerably more responsive to growth factor stimulation than the metastatic clones. Invasion of FTC133 was enhanced by 42% (EGF;p<0.02) and 21% (TSH;p<0.01), invasion of FTC236 by 8% (EGF;p<0.02) and 8% (TSH;p<0.01), and invasion of FTC238 by 9% (EGF;p<0.02) and 8% (TSH;p<0.01). Conversely, invasion and growth of FTC133 were significantly more inhibited by TGF beta 1 (10 ng/ml) and supraphysiologic concentrations of TSH (100 mU/ml) than the cell lines from the lymph node and lung metastases. At day 7, invasion of FTC133 was inhibited by 32% (TGF beta 1;p<0.02) and 21% (TSH;p<0.01), invasion of FTC236 by 18% (TGF beta 1;p<0.02) and 11% (TSH;p<0.01), and invasion of FTC238 by 16% (TGF beta 1;p<0.02) and 12% (TSH;p<0.01). Moreover, we analyzed growth factor independence in minimally supplemented or unsupplemented medium. Growth, but no invasion was evident when cells were cultured completely unsupplemented over 7 days. These results suggest that metastatic FTCs may have developed by escaping from the normal control of TSH and other growth factors. 相似文献