Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer

Seetoo, Da-Qiang; Crowe, Philip; Russell, Pamela J.; Yang, Jialin

doi:10.1002/jso.10210

Cited by 66 publications

(58 citation statements)

References 22 publications

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“…32 Activation of uPA is associated with a poor prognosis, distant metastasis, and local recurrence. 32 Protein expression of uPA is observed predominantly at the invasive tumor front and is correlated strongly with IHC expression of nuclear b-catenin, implicating uPA in Wnt pathway activation. 33 Moreover, the uPA gene appears to act as a direct target gene of b-catenin.…”

Section: Discussionmentioning

confidence: 99%

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Zlobec

Minoo

Baumhoer

et al. 2007

Cancer

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BACKGROUND. The heterogeneity of stage II colon cancer underlines the need for identifying high‐risk, lymph node‐negative patients. The objective of this study was to define a multimarker prognostic model of 5‐year survival in patients with lymph node‐negative, mismatch repair (MMR)‐proficient colorectal cancer (CRC). METHODS. Immunohistochemistry for 13 tumor markers was performed on 587 lymph node‐negative, MMR‐proficient CRC samples by using a tissue microarray. Immunoreactivity was evaluated semiquantitatively. A receiver‐operating characteristic‐based approach was used to detect clinically relevant tumor markers and to determine cutoff scores for tumor positivity. Univariate and multivariate analyses stratified by pathologic T3 (pT3) or pT4 tumor classification were performed. RESULTS. In univariate analysis, the absence of CD8+ tumor infiltrating lymphocytes (TILs) (P < .001), loss of p27 (P = .006), positive urokinase‐type plasminogen activator (uPA) expression (P = .002), and positive uPA receptor (uPAR) expression (P = .037) were associated with an adverse prognosis. In multivariate analysis, CD8 (P = .001), p27 (P = .031), and uPA (P = .014) were independent prognostic factors. The multimarker phenotype of negative CD8, loss of p27, and positive uPA expression led to significantly worse survival compared with all other combinations of these features. Stratified by pT3 or pT4 stage, CD8 (P = .006) and uPA (P = .011) had independent prognostic value. Combined CD8 negativity and uPA positivity led to a more adverse prognosis in both patients with pT3 tumors and patients with pT4 tumors (P < .001). No difference was observed in the length of survival between patients with pT3 tumors who had CD8 negativity and uPA positivity and patients with pT4 tumors (P = .267). CONCLUSIONS. The multimarker phenotype of the absence of CD8+ TILs, loss of p27, and positive uPA expression was predictive of an adverse prognosis in patients with lymph node‐negative, MMR‐proficient CRC. The current findings suggested that a subgroup of patients with high‐risk, lymph node‐negative pT3 tumors should be considered for adjuvant therapy. Cancer 2008. © 2007 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Zlobec

Minoo

Baumhoer

et al. 2007

Cancer

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“…Bootstrap is a well-established computational statistic method to estimate the reliability of estimator. 23 It can be used to estimate the distribution of an estimator, e.g., the error rate of a classifier, based on N observed cases X 5 {X 1 , X 2 , . .…”

Section: Discussionmentioning

confidence: 99%

“…It is involved in localizing and promoting cell-surface plasminogen activation, plasmin formation and localized degradation of the extracellular matrix. 42 Overexpression of UPAR has been found in many cancers 23,[43][44][45][46] including pancreatic cancer, and contributes to tumor invasion and metastasis. 24,25 Recent studies by Ellis and colleagues have shown that pancreatic metastatic disease is dependent upon the UPA/ UPAR system, and that system activation and subsequent metastases is (i) mediated by insulin growth factor-1, hepatocyte growth (Table I).…”

Section: Discussionmentioning

confidence: 99%

Accurate discrimination of pancreatic ductal adenocarcinoma and chronic pancreatitis using multimarker expression data and samples obtained by minimally invasive fine needle aspiration

Chen

Zheng

Robbins

et al. 2007

Intl Journal of Cancer

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To augment cytological diagnosis of pancreatic ductal adenocarcinoma (PDAC) in tissue samples obtained by minimally invasive endoscopic ultrasound-guided fine needle aspiration, we investigated whether a small set of molecular markers could accurately distinguish PDAC from chronic pancreatitis (CP). Expression levels of 29 genes were first determined by quantitative real-time RT-PCR in a training set of tissues in which the final diagnosis was PDAC (n 5 20) or CP (n 5 10). Using receiver operator characteristic curve analysis, we determined that the single gene with the highest diagnostic accuracy for discrimination of CP vs. PDAC in the training study was urokinase plasminogen activator receptor (UPAR; AUC value 5 0.895, 95% CI 5 0.728-0.976). In the set of test tissues (n 5 14), the accuracy of UPAR decreased to 79%. However, we observed that the addition of 6 genes (EPCAM2, MAL2, CEA5, CEA6, MSLN and TRIM29; referred to as the 6-gene classifier) to UPAR resulted in high accuracy in both training and testing sets. Excluding 3 samples (out of 44; 7%) for which results of the UPAR/6-gene classifier were ''undefined,'' the accuracy of the UPAR/6-gene classifier was 100% in training samples (n 5 29), 92% in 12 test samples (p 5 0.004 that results were randomly generated; p 5 0.046 that the UPAR/6-gene classifier was comparable to UPAR alone; v 2 test), 100% in 3 samples for which the initial cytological diagnosis was ''suspicious'' and 98% (40/41) overall. Our results provide evidence that molecular marker expression data can be used to augment cytological analysis. ' 2006 Wiley-Liss, Inc.Key words: chronic pancreatitis; pancreatic ductal adenocarcinoma; urokinase plasminogen activator receptor; diagnostic accuracy Although the incidence of pancreatic ductal adenocarcinoma (PDAC) is only 1-2% and relatively low compared to other cancers, nearly all patients die from PDAC within 1-2 years.

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“…11,12 In our previous work, we have reported the relationship between integrin atb6 and MMP-9 in colon cancer. We reported that atb6 expression in colon cancer cells lead to the increase in secretion of MMP-9 and that this secretion paralleled the level of cell-surface atb6 expression.…”

mentioning

confidence: 99%

“…10 Urokinase plasminogen activator (uPA )is found in cellular structures at the leading edge of migrating cells that are involved in adhesion, migration, invasion and intravasation and is considered to be a marker for malignancy in colon cancer. 11,12 In our previous work, we have reported the relationship between integrin atb6 and MMP-9 in colon cancer. We reported that atb6 expression in colon cancer cells lead to the increase in secretion of MMP-9 and that this secretion paralleled the level of cell-surface atb6 expression.…”

mentioning

confidence: 99%

Suppression of integrin αυβ6 by RNA interference in colon cancer cells inhibits extracellular matrix degradation through the MAPK pathway

Wang

Zhang

et al. 2008

Intl Journal of Cancer

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Integrin atb6 plays a very important role in the progression of colon cancer cells and is now defined as a novel, independent prognostic indicator for aggressive colon cancer in humans. Herein, we use the RNA interfering technology to downregulate the expression of atb6 in colon cancer cells. Our data demonstrate that plasmid vector based shRNA can effectively down-regulate atb6 expression in protein and mRNA levels. Supression of integrin atb6 inhibits the phosphorylation and nonphosphorylation level of ERK1/2, the secretion of uPA, pro-MMP-9 and pro-MMP-2 in tumor conditioned medium, and more important, inhibits MAPKdependent [ 3 H] labeled collagen IV degradation via the plasminogen activation cascade. Our study demonstrates in vitro that supression of integrin atb6 inhibits extracellular matrix degradation through the MAPK pathway. ' 2008 Wiley-Liss, Inc.Key words: colon cancer; integrin atb6; MAP kinase; RNA interference Cancer cell invasion and metastasis are regarded as multistep phenomena, involving the proteolytic degradation of the extracellular matrix (ECM), altered cell adhesion and the physical movement of cancer cells. Such migratory and tissue remodeling events involve complex interactions between integrins and matrix degrading protease systems, such as the plasminogen activation system.1 The integrins provide direct links with the ECM, functioning as bidirectional transducers of extra-and intracellular signals, and thus potentially modulating cancer cell invasion. 2Integrin atb6 is restrictedly distributed to epithelial cells. It is primarily expressed during fetal development and wound healing. Upregulation of the integrin atb6 is found in some epithelial carcinomas, most notably in orally-derived squamous cell carcinomas, [3][4][5] where the receptor typically displays a focally localized distribution at the infiltrating edge of tumor islands. Recently, the most compelling finding is that atb6 is defined as a novel, independent prognostic indicator for aggressive colon cancer and gastric carcinoma in humans. 6,7 The integrin atb6 may serve to identify patients that are at higher risk of developing metastatic disease and emerges as an attractive new candidate as a therapeutic target for metastatic colon carcinoma.Many proteinases are capable of degrading ECM components, but the proteinase system primarily responsible for ECM degradation in vivo are matrix metalloproteinases (MMPs) and plasminogen activator (PA) systems.8,9 MMP-2 and MMP-9 have been implicated to play a role in colorectal cancer progression, invasion and metastasis in animal models and patients.10 Urokinase plasminogen activator (uPA )is found in cellular structures at the leading edge of migrating cells that are involved in adhesion, migration, invasion and intravasation and is considered to be a marker for malignancy in colon cancer. 11,12 In our previous work, we have reported the relationship between integrin atb6 and MMP-9 in colon cancer. We reported that atb6 expression in colon cancer cells lead to the increase in secret...

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Quantitative expression of protein markers of plasminogen activation system in prognosis of colorectal cancer

Abstract: uPA and uPAR may be independent predictors of liver metastasis, patient overall survival and cancer-specific survival after resection of colorectal tumors.

Cited by 66 publications

References 22 publications

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Accurate discrimination of pancreatic ductal adenocarcinoma and chronic pancreatitis using multimarker expression data and samples obtained by minimally invasive fine needle aspiration

Suppression of integrin αυβ6 by RNA interference in colon cancer cells inhibits extracellular matrix degradation through the MAPK pathway

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