Clinical Relevance of the Expression of mRNA of MMP-7, MMP-9, TIMP-1, TIMP-2 and CEA Tissue Samples from Colorectal Liver Metastases

Sutnar, A; Pešta, Martin; Liška, Václav; Třeška, Vladislav; Skalický, T; Kormunda, Stanislav; Topolčan, Ondřej; Černý, Rudolf; Holubec, Luboš

doi:10.1159/000110897

Cited by 26 publications

(13 citation statements)

References 17 publications

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“…These results are consistent with previous reports that show stroma-restricted expression of the MMPs in human liver metastases of colorectal cancer (21,22). Abundant expression of MMP2 or MMP9 is associated with poor prognosis and high mortality of colon cancer patients (23)(24)(25)(26)(27). Although selective inhibitors of MMP2/9 significantly block mouse liver metastasis of colon cancer and prolong the survival of tumor-bearing mice (28), clinical trials for MMP inhibitors have failed because of severe side effects such as musculoskeletal pain and inflammation (29)(30)(31).…”

Section: Discussionsupporting

confidence: 93%

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Kitamura

Fujishita

Loetscher

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

139

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Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CCchemokine ligands CCL9 and CCL15, respectively, and recruit CD34 + Gr-1 − immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.C olon cancer is one of the leading causes of cancer-related deaths (1). Although most primary tumors can be resected surgically, colorectal cancer frequently spreads to the liver, which is responsible for the high mortality of the disease (2). For successful metastasis, cancer cells need to invade surrounding tissues, penetrate microvessels, survive in circulation, disseminate to distant organs, form micrometastases, and expand into macrometastases. To progress through these steps, tumor cells often acquire the capability of survival and invasion by activating metastatic signaling pathways or inactivating metastasis suppressor genes (2, 3). In addition to these cell autonomous changes, tumor stromal cells, especially bone marrow-derived myeloid cells, actively participate in early steps of the metastatic cascade in some mouse models (4). For example, tumor-associated macrophages (TAMs) promote migration and intravasation of mammary tumor cells (5, 6). Bone marrow-derived cells that express myeloid cell marker CD11b and granulocyte marker Gr-1 (CD11b + Gr-1 + ) also promote metastasis of breast cancer cells, likely through promotion of intravasation and suppression of immune responses (7). Furthermore, CD11b + myeloid cells that express vascular endothelial growth factor receptor 1 (VEGFR1) accumulate at the metastatic sites before the arrival of lung cancer and melanoma cells and foster the dissemination of the cancer cells (8). These reports suggest that bone marrow-derived myeloid cells can help cancer epithelium in early steps of metastasis. It remains to be determined whether therapeutics targeting such myeloid cells can prevent cancer metastasis (9).As a model for invasive colon cancer, we previously constructed cis-Apc +/Δ716 Smad4 +/− (Apc/Smad4) mice that develop intestinal adenocarcinomas with marked invasions by loss of Apc and Smad4 tumor suppressor genes in the intestinal epithelium (10, 11). In the Apc/Smad4 tumors, we reported that the invading cancer epithelium is associated with immature myeloid cells (iMCs) that express myeloid progenitor cell marker CD34 and CD11b (12). Because these iMCs do not express Gr-1 or VEGFR1, they belong to a different subc...

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Section: Discussionsupporting

confidence: 93%

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Kitamura

Fujishita

Loetscher

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

139

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“…Patients having high tissular CEA content in tumors or nonneoplasic mucosa presented a 2-year survival rate of 65.9% (5) . LORENZI et al (25) affirmed that apical expression for tissular CEA presented a significant relationship with degree of differentiation of the neoplasm while diffuse cellular or cytoplasmic expression of this antigen frequently indicates neoplasms extending beyond the intestinal wall and invading lymphatic veins. Studies by NAKAGOE et al (20) analyzing the prognostic value of CEA levels in tumoral tissue, normal colonic mucosa and pre-operative CEA sera in patients with resected colorectal carcinoma, concluded that high CEA levels in neoplasic tissue was the sole independent predictor of adverse evolution following colorectal carcinoma resection.…”

Section: Discussionmentioning

confidence: 99%

“…CEA can also be detected and quantitatively measured in colorectal tumor tissue and normal mucosa (1,2,3,4,5,9,17,12,13,18,26) , but its role in the management of colorectal cancer remains controversial (4,11,20) . Some authors have reported that elevated CEA concentrations within the tumor are correlated with advanced stage (3,4,7,18,22,25,26) , whereas other studies have not reached this conclusion (5,16,20) . In addition, COSIMELLI et al (5) reported that elevated CEA concentrations within colorectal cancer was a predictor for local and distant tumor recurrence after surgery, independent of other recognized prognostic variables (stage and histological grade).…”

Section: Introductionmentioning

confidence: 98%

“…Several small-scale retrospective studies have demonstrated that CRC patients with high preoperative levels of CEA have a worse prognosis than those with low levels (8,30) . Preoperative CEA thus has the potential to supply prognostic data independent of the traditional staging systems in patients with CRC (6,7,8,19,21,25,28) . CEA can also be detected and quantitatively measured in colorectal tumor tissue and normal mucosa (1,2,3,4,5,9,17,12,13,18,26) , but its role in the management of colorectal cancer remains controversial (4,11,20) .…”

Section: Introductionmentioning

confidence: 99%

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Prognostic value of carcinoembryonic antigen distribution in tumor tissue of colorectal carcinoma

Nazato

Matos

Waisberg

et al. 2009

Arq. Gastroenterol.

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-Context -Carcinoembryonic antigen (CEA) can be detected in colorectal tumor tissue but its role in the survival of patients remains controversial. Objective -To characterize the expression of tissue CEA using immunohistochemical staining in colorectal tumors and to analyze the relationship between this finding and preoperative plasmatic level of CEA, morphologic features and survival of patients operated with curative intent for colorectal carcinoma. Method -Forty-seven patients were included in the study: 18 (38.3%) males and 29 (61.7%) females, with a mean age of 67.8 ± 9.7 years (37 to 84 years). Immediately before laparotomy, pre-operative serum levels of CEA were obtained where normal levels were considered ≤2.5 ng/mL for non-smokers, and ≤5.0 ng/mL for smokers. CEA immunohistochemical studies were carried out using anti-human CEA monoclonal mouse antibody. The expression of immunostaining for each neoplasia was classified according to the pattern of CEA tissular distribution into apical or cytoplasmic. The variables considered for the statistical analysis were plasmatic preoperative CEA level, location of the lesion within the large intestine, lesion diameter, lymph node involvement, Duke's classification, vein invasion, grade of cellular differentiation, survival and pattern of CEA tissular distribution. The statistical models utilized were Spearman's correlation and the Mann-Whitney, Kruskal-Wallis and Student t tests. Patients' survival was analyzed using the KaplanMeier method. Results -The mean preoperative CEA value was 15.4 ± 5.5 ng/mL (0.2 to 92.1 ng/mL). The neoplasm was located in the colon in 29 (61.7%) and in the rectum in 18 (38.3%) patients. Eight (17.0%) patients were classified as Duke's stage A, 22 (46.8%) as stage B and 17 (36.2%) as stage C. On immunohistochemical studies, the pattern of CEA tissular distribution was apical in 33 (70.2%) patients and cytoplasmic in 14 (29.8%) patients. Patients with apical patterns presented a mean sera CEA level of 15.5 ± 6.5 ng/mL while those with cytoplasmic pattern attained a mean sera CEA level of 15.1 ± 7.3 ng/mL, with no significant difference between these values (P = 0.35). Apical distribution of CEA occurred in 6 (12.8%) Duke A, 18 (38.2%) Duke B and 9 (12.2%) Duke C patients, while cytoplasmic CEA tissular distribution was observed in 2 (4.2%) Duke A, 3 (6.4%) Duke B and 9 (19.1%) Duke C patients. Patients with Duke B neoplasms presented significantly more apical CEA tissular distribution patterns (P = 0.049) than subjects with cytoplasmic CEA tissular patterns. The apical CEA tissular distribution pattern in neoplasms was significantly more frequent in neoplasms with no lymph node compromise compared to the cytoplasmic pattern (P = 0.50). However, no significant differences were seen between apical and cytoplasmic CEA tissular distribution patterns in terms of colon or rectal site (P = 0.21), lesion diameter across greatest axis (P = 0.19), vein invasion (P = 0.13) or degree of cellular differentiation (P = 0.19). Of the 47 patients...

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“…Classical and proliferative tumour markers and matrix metalloproteinases and their tissue inhibitors refl ect the features of malignancy and are useful in prediction of prognosis in patients with colorectal liver metastases (4). There is very limited information about their physiological functions during regeneration and healing of liver parenchyma after any type of liver surgery for malignancy.…”

mentioning

confidence: 99%

Matrix metalloproteinases and their inhibitors in correlation to proliferative and classical tumour markers during surgical therapy of colorectal liver metastases

Liška

Sutnar²,

Holubec³

et al. 2012

BLL

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Abstract:Objectives: Classical and proliferative tumour markers and matrix metalloproteinases and their tissue inhibitors refl ect the features of malignancy and are useful in prediction of prognosis in patients with colorectal liver metastases. There is very limited information about their physiological functions during regeneration and healing of liver parenchyma after any type of liver surgery for malignancy. Methods: The presented study included the patients, who underwent following surgical procedures for CLM, benign liver lesions and inguinal hernias: Group A: 22 patients with inguinal hernias, Group B: 26 patients with benign liver lesions, Group C: 30 patients with colorectal liver metastases (CLM) who were treated by radiofrequency ablation, Group D: 41 patients with CLM who underwent a radical surgical therapy -resection, and Group E: 22 patients with inoperable CLM who underwent an explorative laparotomy without any surgical procedure. Results: The preoperative and postoperative serum levels of CEA, CA 19-9, TK, TPA, TPS, MMP-2, MMP-9, TIMP-1, and TIMP-2 were statistically analyzed and compared within the groups to estimate the infl uence of a surgical procedure type. These results refl ect the infl uence of surgical procedure on the serum levels of studied tumour markers during operation. Conclusions: It was the fi rst description using these types of comparison to all metalloproteinases, their inhibitors, and proliferative and classical tumour markers. It could help us to estimate the critical relations of these tumour markers in prognoses of disease free survival or overall survival in patients after a surgical procedure for CLM (Tab. 5, Ref. 26). Full Text in PDF www.elis.sk.

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Clinical Relevance of the Expression of mRNA of MMP-7, MMP-9, TIMP-1, TIMP-2 and CEA Tissue Samples from Colorectal Liver Metastases

Cited by 26 publications

References 17 publications

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model

Prognostic value of carcinoembryonic antigen distribution in tumor tissue of colorectal carcinoma

Matrix metalloproteinases and their inhibitors in correlation to proliferative and classical tumour markers during surgical therapy of colorectal liver metastases

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