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

Kahlert, Christoph; Pecqueux, Mathieu; Halama, Niels; Dienemann, Hendrik; Muley, Thomas; Pfannschmidt, Joachim; Lasitschka, Felix; Klupp, Fee; Schmidt, Thomas; Rahbari, Nuh N.; Reißfelder, Christoph; Kunz, Christina; Benner, Axel; Falk, Christine S.; Weitz, Jürgen; Koch, Moritz

doi:10.1038/bjc.2013.745

Cited by 34 publications

(27 citation statements)

References 28 publications

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“…Noteworthy, miR-215, miR-194, and miR-192 showed a more than 100-fold upregulation in the normal liver tissue compared to the normal lung tissue. These results are congruent with earlier data by our group [21] that indicate that the protein expression profile of colorectal metastases is dependent on the host tissue and might be strongly influenced by the surrounding host tissue.…”

Section: Discussionsupporting

confidence: 93%

A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival

Pecqueux

Liebetrau

Werft

et al. 2016

IJMS

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MicroRNAs are small non-coding RNAs with a length of 18–25 nucleotides. They can regulate tumor invasion and metastasis by changing the expression and translation of their target mRNAs. Their expression is substantially altered in colorectal cancer cells as well as in the adjacent tumor-associated stroma. Both of these compartments have a mutual influence on tumor progression. In the development of metastases, cancer cells initially interact with the host tissue. Therefore, compartment-specific expression signatures of these three locations—tumor, associated stroma, and host tissue—can provide new insights into the complex tumor biology of colorectal cancer. Frozen tissue samples of colorectal liver (n = 25) and lung metastases (n = 24) were laser microdissected to separate tumor cells and the adjacent tumor-associated stroma cells. Additionally, normal lung and liver tissue was collected from the same patients. We performed a microarray analysis in four randomly selected liver metastases and four randomly selected lung metastases, analyzing a total of 939 human miRNAs. miRNAs with a significant change >2-fold between the tumor, tumor stroma, and host tissue were analyzed in all samples using RT-qPCR (11 miRNAs) and correlated with the clinical data. We found a differential expression of several miRNAs between the tumor, the tumor-associated stroma, and the host tissue compartment. When comparing liver and lung metastases, miR-194 showed a 1.5-fold; miR-125, miR-127, and miR-192 showed a 2.5-fold; miR-19 and miR-215 a 3-fold; miR-145, miR-199-3, and miR-429 a 5-fold; miR-21 a 7-fold; and, finally, miR-199-5 a 12.5-fold downregulation in liver metastases compared to lung metastases. Furthermore miR-19, miR-125, miR-127, miR-192, miR-194, miR-199-5, and miR-215 showed a significant upregulation in the normal liver tissue compared to the normal lung tissue. Univariate analysis identified an association of poor survival with the expression of miR-125 (p = 0.05), miR-127 (p = 0.001), miR-145 (p = 0.005), miR-192 (p = 0.015), miR-194 (0.003), miR-199-5 (p = 0.008), miR-215 (p < 0.001), and miR-429 (p = 0.03) in the host liver tissue of the liver metastases. Colorectal liver and lung metastases have a unique miRNA expression profile. miRNA expression in the host tissue of colorectal liver metastases seems to be able to influence tumor progression and survival. These findings can be used in the development of tailored therapies.

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Section: Discussionsupporting

confidence: 93%

A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival

Pecqueux

Liebetrau

Werft

et al. 2016

IJMS

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“…MMP-9 cleaves collagen types IV, V, XI, and XIV (11)(12)(13). Other MMPs might also be up-regulated (14,15), although they were not identified.…”

Section: Discussionmentioning

confidence: 94%

Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue

Huizen

Braak

Doukas

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan WangChanges to extracellular matrix (ECM) structures are linked to tumor cell proliferation and metastasis. We previously reported that naturally occurring peptides of collagen type I are elevated in urine of patients with colorectal liver metastasis (CRLM). In the present study, we took an MS-based proteomic approach to identify specific collagen types that are up-regulated in CRLM tissues compared with healthy, adjacent liver tissues from the same patients. We found that 19 of 22 collagen-␣ chains are significantly up-regulated (p < 0.05) in CRLM tissues compared with the healthy tissues. At least four collagen-␣ chains were absent or had low expression in healthy colon and adjacent tissues, but were highly abundant in both colorectal cancer (CRC) and CRLM tissues. This expression pattern was also observed for six noncollagen colon-specific proteins, two of which (CDH17 and PPP1R1B/DARP-32) had not previously been linked to CRLM. Furthermore, we observed CRLM-associated up-regulation of 16 proteins (of 20 associated proteins identified) known to be required for collagen synthesis, indicating increased collagen production in CRLM. Immunohistochemistry validated that collagen type XII is significantly upregulated in CRLM. The results of this study indicate that most collagen isoforms are up-regulated in CRLM compared with healthy tissues, most likely as a result of an increased collagen production in the metastatic cells. Our findings provide further insight into morphological changes in the ECM in CRLM and help explain the finding of tumor metastasis-associated proteins and peptides in urine, suggesting their utility as metastasis biomarkers. 2 The abbreviations used are: ECM, extracellular matrix; CRC, colorectal cancer; CRLM, colorectal liver metastasis; IQR, interquartile range; FIB, liver fibrosis; IHC, immunohistochemistry; PEPD, Xaa-Pro dipeptidase; Hyp, hydroxyproline; iBAQ, intensity-based absolute quantification.

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“…The overall dependence of tumor angiogenesis on the expression of various MMPs is still in the spotlight of experimental and clinical cancer research, deeply focusing on unraveling the precise interrelations between different regulatory molecules and proteolytic activities of specific MMPs (Al Rawashdeh et al, 2014; Barillari et al, 2014; Depner et al, 2014; Gong et al, 2014; Kahlert et al, 2014; Zhang et al, 2014). In this review, however, we attempted to summarize the data on the mechanisms whereby various MMPs, characterized by different substrate specificities, e.g.…”

Section: Discussionmentioning

confidence: 99%

Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

2015

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Metastasis is a distinct stage of cancer progression that requires the development of angiogenic blood vessels serving as conduits for tumor cell dissemination. An accumulated body of evidence indicates that metastasis-supporting neovasculature should possess certain structural characteristics allowing for the process of tumor cell intravasation, an active entry of cancer cells into the vessel interior. It appears that the development of tumor vessels with lumens of a distinctive size and their structure supported by a discontinuous pericyte coverage, together constitute critical microarchitectural requirements to: (a) provide accessible points for vessel wall penetration by primary tumor cells; (b) provide enough lumen space for a tumor cell or cell aggregate upon intravasation; and (c) allow for sufficient rate of blood flow to carry away intravasated cells from the primary tumor to the next, proximal or distal site. This review will primarily focus on the functional roles of matrix metalloproteinases (MMPs), which catalytically trigger the development of an intravasation-sustaining neovasculature at the early stages of tumor growth and are also required for the maintenance of a metastasis-supporting state of blood vessels at later stages of cancer progression.

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

Abstract: 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.

Cited by 34 publications

References 28 publications

A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival

A Comprehensive MicroRNA Expression Profile of Liver and Lung Metastases of Colorectal Cancer with Their Corresponding Host Tissue and Its Prognostic Impact on Survival

Up-regulation of collagen proteins in colorectal liver metastasis compared with normal liver tissue

Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

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