UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear. As activation of the epidermal growth factor receptor (EGFR) triggers mitogenic signaling in gastrointestinal mucosa, and its expression is also upregulated in colonic cancers and most neoplasms, we investigated whether PGs transactivate EGFR. Here we provide evidence that prostaglandin E2 (PGE2) rapidly phosphorylates EGFR and triggers the extracellular signal-regulated kinase 2 (ERK2)--mitogenic signaling pathway in normal gastric epithelial (RGM1) and colon cancer (Caco-2, LoVo and HT-29) cell lines. Inactivation of EGFR kinase with selective inhibitors significantly reduces PGE2-induced ERK2 activation, c-fos mRNA expression and cell proliferation. Inhibition of matrix metalloproteinases (MMPs), transforming growth factor-alpha (TGF-alpha) or c-Src blocked PGE2-mediated EGFR transactivation and downstream signaling indicating that PGE2-induced EGFR transactivation involves signaling transduced via TGF-alpha, an EGFR ligand, likely released by c-Src-activated MMP(s). Our findings that PGE2 transactivates EGFR reveal a previously unknown mechanism by which PGE2 mediates trophic actions resulting in gastric and intestinal hypertrophy as well as growth of colonic polyps and cancers.
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PMID:Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. 1187 1

There is general consensus that matrix metalloproteinases are involved in tumour progression. We show herein that inhibition of integrin alpha(v)beta6 expression in colon cancer cells suppresses MMP-9 secretion. This integrin-mediated event is dependent upon direct binding between the beta6 integrin subunit and extracellular signal-regulated kinase 2. Targetting either beta6 or its interaction with extracellular signal-regulated kinase in order to inhibit matrix metalloproteinase activity may offer a useful therapeutic approach in preventing growth and spread of colon cancer.
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PMID:Integrin alpha(v)beta6-associated ERK2 mediates MMP-9 secretion in colon cancer cells. 1217 7

The anti-metastatic efficacy of MMI-166, which is a selective matrix metalloproteinase (MMP) inhibitor, in combination with CPT-11 was examined using two metastasis models of human gastrointestinal cancer cells. In the liver metastasis model, C-IH human colon cancer cells were injected into the spleen of athymic BALB/c nude mice. Daily oral (p.o.) dosing of MMI-166 at 200 mg/kg starting 1 day after tumor inoculation led to a significantly prolonged survival effect by inhibiting liver metastasis of C-1H tumor cells. CPT-11 (5 or 20 mg/kg) was administered intraperitoneally (i.p.) three times on day 3, day 7 and day 11 and also improved the survival of tumor-inoculated mice compared with the vehicle control. When MMI-166 was combined with CPT-11, the anti-metastatic efficacy was significantly augmented. Moreover, long tumor-free survival was noted in two of eight mice that were given the combination therapy but not either MMI-166 or CPT-11 monotherapy. In the peritoneal dissemination model, TMK-1 human gastric cancer cells were injected i.p. into nude mice. While both MMI-166, administered daily p.o. from day 1 at 200 mg/kg, and CPT-11, administered intravenously (i.v.) three times, inhibited the tumor dissemination and growth, the combination therapy of MMI-166 plus CPT-11 showed a greater inhibitory effect than each monotherapy. A hematotoxicity study demonstrated that CPT-11 alone significantly decreased the number of white blood cells (WBC) and bone marrow cells (BMC) in the mice during treatment, while the daily administration of MMI-166 alone had no such effect. More importantly, the combination therapy of MMI-166 with CPT-11 did not augment the hematotoxicity caused by CPT-11. An in vitro cytotoxicity study showed that MMI-166 itself neither has direct cytotoxicity in C-1H and TMK-1 tumor cells, nor does it augment the cytotoxicity of SN-38, an active form of CPT-11. The findings indicate that the augmented anti-metastatic efficacy in combination treatment was not simply due to the augmentation of direct cytotoxic activity, but was rather an additive or synergistic effect of anti-metastatic activities with different mechanisms. In conclusion, we demonstrated that the anti-metastatic efficacy against C-1H colon cancer and TMK-1 gastric cancer were augmented by the combination therapy of MMI-166, an orally active MMP inhibitor, with CPT-11. However, the hematotoxicity caused by CPT-11 was not augmented in the combination with MMI-166. Thus, the combination therapy of MMI-166 and CPT-11 exhibited potent anti-metastatic efficacy without increased hematotoxicity. These results point to the clinical advantage of using MMI-166 in combination with CPT-11.
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PMID:Augmented anti-metastatic efficacy of a selective matrix metalloproteinase inhibitor, MMI-166, in combination with CPT-11. 1240 89

We previously reported that vessel count, vascular endothelial growth factor (VEGF) and platelet derived endothelial cell growth factor (PD-ECGF) expression are associated with metastasis formation in human colon cancer. This study was done to determine a stage of colon cancer progression where induction of these factors occurred (i.e. the angiogenic switch). We examined vessel count, VEGF, and matrix metalloproteinase (MMP)-7 expression in cancer cells and PD-ECGF expression in infiltrating cells in 25 adenomas, 35 mucosal cancers (Tis), 29 submucosal invasive cancers (T1) and 33 muscularis propria invasive cancers (T2) by immunostaining. The intensity of staining of VEGF and MMP-7 was evaluated blindly at the invasive edge and was confirmed by image analysis. Intensity of staining for these factors was graded on a scale of 0 to 3+, with 0 representing no detectable stain and 3+ representing the strongest stain. Intensites of PD-ECGF-positive infiltrating cells were similar on a scale 0 to 3+, as previous studies from our laboratory have demonstrated that PD-ECGF is expressed primarily in tumor infiltrating cells. The vessel density was 12.7+/-2.2 (SE) in adenoma, 11.8+/-1.7 in Tis, 35.0+/-6.5 in T1, and 35.2+/-5.3 in T2. There were significant differences in vessel densities between Tis and T1 (p<0.001). The intensities of VEGF expression were 0.6+/-0.1, 0.9+/-0.2, 1.7+/-0.3, and 1.8+/-0.3 for adenoma, Tis, T1 and T2, respectively, with significant differences between in Tis and T1 (p<0.001). There were also significant differences in the intensities of the expression of MMP-7 and PD-ECGF between Tis and T1. These results suggest that angiogenic switch may occur between Tis and T1, i.e. simultaneous to initiation of invasion, in the early development of colon cancer.
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PMID:The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. 1246 36

Overexpression of the matrix serine protease (MSP) trypsin has been implicated in tumour growth, invasion, and metastasis. The objective of this study was to clarify the clinicopathological and prognostic significance of trypsin expression in colorectal cancer. This study analysed the association between immunohistochemically detected trypsin expression in colorectal cancer and clinicopathological characteristics, and investigated whether trypsin is a predictor of recurrence and/or survival. Trypsin immunoreactivity was more intense at the invasive front than in the superficial part of the tumour. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 48 cases (48%), were judged to be positive for trypsin. Trypsin positivity was significantly correlated with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advanced pathological tumour-node-metastasis (TNM) stage, and recurrence. Patients with trypsin-positive carcinoma had significantly shorter overall and disease-free survival periods than did those with trypsin-negative carcinoma. Trypsin retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors. It is well known that trypsin activates matrilysin (matrix metalloproteinase-7), which plays an important role in colorectal cancer progression. Patients with concordant overexpression of trypsin and matrilysin at the invasive front, in which they were often co-localized, had the worst prognosis. Trypsinogen-1-transfected HCT116 colon cancer cells showed not only trypsin activity, but also active matrilysin activity and were more invasive in vitro than mock-transfected HCT116 cells. These results suggest that trypsin plays a key role in the progression of colorectal cancer. Detection of trypsin expression as well as matrilysin is useful for the prediction of recurrence in and poor prognosis of colorectal cancer patients.
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PMID:Association of trypsin expression with tumour progression and matrilysin expression in human colorectal cancer. 1253 30

Lysophosphatidic acid (LPA) is a lipid mediator with diverse effects on various cells. Here, we investigated the effects of LPA on human colon carcinoma DLD1 cells. Northern blot analysis revealed that DLD1 highly expressed LPA1/Edg-2 but showed only low expression of LPA2/Edg-4 and no expression of LPA3/Edg-7 at the mRNA level. Western blot analysis revealed that DLD1 cells highly expressed LPA1 at the protein level. Using the Boyden chamber assay, LPA markedly increased DLD1 cell migration at concentrations as low as 10 nM, with maximum stimulation at 100 nM (3.6-fold increase). Checkerboard analysis indicated that LPA stimulated both the chemotactic and chemokinetic migration of DLD1 cells. LPA induced a dose-dependent increase in the proliferation of DLD1 cells (3.2-fold increase at 20 microM). Furthermore, LPA stimulated DLD1 cell adhesion to collagen type I (2.0-fold increase at 10 microM) and also stimulated the secretion of both vascular endothelial growth factor (1.4-fold increase at 20 microM) and interleukin 8 (19-fold increase at 20 microM) by ELISA. In contrast, as for matrix metalloproteinase, LPA had no significant effect on pro-matrix metalloproteinase-2 secretion and its activation, as measured by Western blot analysis. Thus, LPA, at concentrations that are present physiologically, enhanced DLD1 cell migration, proliferation, adhesion, and secretion of angiogenic factors, all of which are crucial for cancer metastasis. In comparison, other human colon carcinoma cells (HT29 and WiDR) exclusively expressed LPA2. LPA enhanced their proliferation and secretion of angiogenic factors, whereas LPA did not enhance migration or adhesion. Our results suggest that LPA acts as a potent stimulator of colon cancer progression, although the binding to LPA1 and LPA2 induces slightly different responses.
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PMID:Lysophosphatidic acid (LPA) enhances the metastatic potential of human colon carcinoma DLD1 cells through LPA1. 1267 Sep 25

Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer.
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PMID:Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR-beta1 integrin complex in colon cancer cells. 1286 32

Expression of E1AF/PEA3 (ETV4), an ets family transcription factor, has been implicated in the invasive potential of several cancer cell lines through induction of matrix metalloproteinase (MMP) expression. The aim of this study was to examine E1AF mRNA expression and to determine whether it is correlated with progression of, and/or MMP expression in, human colorectal cancer. Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), 100 colorectal cancer tissues were analysed for E1AF mRNA expression. Expression of ER81 (ETV1) and ERM (ETV5), the other two members of the PEA3 subfamily, and Ets-1 and Ets-2 was also analysed. The results were correlated with clinicopathological characteristics and MMP expression. Immunohistochemical analysis and an in vitro invasion assay were also performed. E1AF mRNA expression was detected in 62% of the 100 colorectal cancer tissues, but was undetectable or only faintly detected in adjacent non-tumour tissues. E1AF mRNA was detected in all of the ten liver metastases from colorectal cancers. E1AF expression correlated significantly with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumour-node-metastasis stage, and recurrence. Patients with E1AF-positive tumours had significantly shorter overall and disease-free survival periods than did those with E1AF-negative tumours (p < 0.0001 and p < 0.0001, respectively). E1AF expression retained its significant predictive value for overall and disease-free survival in multivariate analysis that included conventional clinicopathological factors (p = 0.0066 and p = 0.0109, respectively). Among the MMPs analysed, expression of MMP-1 and matrilysin correlated significantly with E1AF expression. In contrast, expression of ER81 and ERM did not correlate with clinicopathological characteristics or the expression of these MMPs. Immunohistochemical expression of E1AF was predominantly observed at the invasive front, where the expression of MMP-1 and matrilysin and nuclear beta-catenin expression were often co-localized. Antisense E1AF-transfected HT-29 colon cancer cells expressed reduced levels of MMP-1 and matrilysin and were less invasive in vitro than neo-transfected HT-29 cells. The results of this study suggest that E1AF, the expression of which is closely correlated with the expression of MMP-1 and matrilysin, plays a key role in the progression of colorectal cancer.
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PMID:Association of ets-related transcriptional factor E1AF expression with tumour progression and overexpression of MMP-1 and matrilysin in human colorectal cancer. 1289 92

The present study describes the in vivo detection and imaging of tumour-associated MMP-7 (matrix metalloproteinase-7 or matrilysin) activity using a novel polymer-based fluorogenic substrate PB-M7VIS, which serves as a selective 'proteolytic beacon' (PB) for this metalloproteinase. PB-M7VIS is built on a PAMAM (polyamido amino) dendrimer core of 14.2 kDa, covalently coupled with an Fl (fluorescein)-labelled peptide Fl(AHX)RPLALWRS(AHX)C (where AHX stands for aminohexanoic acid) and with TMR (tetramethylrhodamine). PB-M7VIS is efficiently and selectively cleaved by MMP-7 with a k (cat)/ K (m) value of 1.9x10(5) M(-1).s(-1) as measured by the rate of increase in Fl fluorescence (up to 17-fold for the cleavage of an optimized PB-M7VIS) with minimal change in the TMR fluorescence. The K (m) value for PB-M7VIS is approx. 0.5 microM, which is approx. two orders of magnitude lower when compared with that for an analogous soluble peptide, indicating efficient interaction of MMP-7 with the synthetic polymeric substrate. With MMP-2 or -3, the k (cat)/ K (m) value for PB-M7VIS is approx. 56- or 13-fold lower respectively, when compared with MMP-7. In PB-M7VIS, Fl(AHX)RPLALWRS(AHX)C is a selective optical sensor of MMP-7 activity and TMR serves to detect both the uncleaved and cleaved reagents. Each of these can be visualized as subcutaneous fluorescent phantoms in a mouse and optically discriminated based on the ratio of green/red (Fl/TMR) fluorescence. The in vivo specificity of PB-M7VIS was tested in a mouse xenograft model. Intravenous administration of PB-M7VIS gave significantly enhanced Fl fluorescence from MMP-7-positive tumours, but not from control tumours ( P <0.0001), both originally derived from SW480 human colon cancer cells. Prior systemic treatment of the tumour-bearing mice with an MMP inhibitor BB-94 ([4-( N -hydroxyamino)-2 R -isobutyl-3 S -(thienylthiomethyl)-succinyl]-L-phenylalanine- N -methylamide), markedly decreased the Fl fluorescence over the MMP-7-positive tumour by approx. 60%. Thus PB-M7VIS functions as a PB for in vivo detection of MMP-7 activity that serves to light this optical beacon and is, therefore, a selective in vivo optical molecular imaging contrast reagent.
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PMID:Development of a novel fluorogenic proteolytic beacon for in vivo detection and imaging of tumour-associated matrix metalloproteinase-7 activity. 1455 51

Retinoids are natural and synthetic derivatives of vitamin A that have great promise for cancer therapy and chemoprevention. Of the retinoids developed so far, 4-(N-hydroxyphenyl)retinamide (4-HPR or fenretinide) appears to have the best therapeutic potential in vitro and in vivo and is currently being tested in clinical trials for cancer prevention and therapy. To develop other potentially potent antitumor agents, we synthesized 85 retinoid derivatives. In an initial screening of these synthetic retinoids using the HCT116 colon cancer cell line, we found that 4-amino-2-(butyrylamino)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,4,6,8-nonatetraenoate (ABPN or CBG41) induced the greatest growth inhibition, with an IC(50) value of 0.6 microM. Subsequent studies in other cancer cell lines indicated that ABPN was much more growth-inhibitory than all-trans retinoic acid or 4-HPR. Compared to 4-HPR, ABPN induced 5.5- to 70.0-fold more growth inhibition in most cancer cells, with the exception of gynecologic cancer cells. In these cells, the antiproliferative effect was only 1.5- to 2.8-fold more than 4-HPR. We examined the molecular mechanism underlying the difference in growth inhibition between 4-HPR and ABPN. DAPI staining, DNA fragmentation, FACS and Western blotting analyses suggest that ABPN induced apoptosis by activating caspase-3 and -8, which may result in increased PARP cleavage. Unlike 4-HPR, ABPN activated all 3 RAR isotypes to an extent similar to AtRA. In addition, ABPN significantly inhibited AP-1 transcriptional activity and thus greatly suppressed the expression of the matrix metalloproteinase -1, -2 and -3 genes, which are involved in tumor invasion. These results suggest that ABPN may be a promising retinoid derivative offering not only enhanced cytotoxicity, but also increased inhibition of tumor invasiveness.
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PMID:Novel retinoic acid derivative ABPN has potent inhibitory activity on cell growth and apoptosis in cancer cells. 1460 Oct 67

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