Comparative Profiling of Primary Colorectal Carcinomas and Liver Metastases Identifies LEF1 as a Prognostic Biomarker

Lin, Albert Y.; Chua, Mei-Sze; Choi, Yoon‐La; Yeh, William; Kim, Young H.; Azzi, Raymond L.; Adams, Gregg A.; Sainani, Kristin L.; Rijn, Matt van de; So, Samuel; Pollack, Jonathan R.

doi:10.1371/journal.pone.0016636

Cited by 57 publications

(55 citation statements)

References 49 publications

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“…LEF-1, a member of the LEF1/TCF transcription factor family involved in the Wnt pathway, is a DNA binding transcription factor that functions by recruiting β-catenin to Wnt target genes for regulation. It has recently been reported that levels of LEF1 are markedly correlated with tumor cell invasion and patient prognosis (31)(32)(33)(34). Certain members of the MMP family (MMP-2, -7, -9 and -26) have been identified as downstream target-genes of the LEF1/ TCF complex.…”

Section: Discussionmentioning

confidence: 99%

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1

et al. 2012

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Abstract. The invasive behavior of glioblastoma multiforme (GBM) cells is one of the most important reasons for the poor prognosis of this cancer. For invasion, tumor cells must acquire an ability to digest the extracellular matrix and infiltrate the normal tissue bordering the tumor. Preventing this by altering effector molecules can significantly improve a patient's prognosis. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. The expression levels of miR-218 correlate with the invasive potential of GBM cells. In this study, we found that miR-218 expression was low in glioma tissues, especially in GBM. The data showed an inverse correlation in 60 GBM tissues between the levels of miR-218 and MMP mRNAs (MMP-2, -7 and -9). Additionally, ectopic expression of miR-218 suppressed the invasion of GBM cells whereas inhibition of miR-218 expression enhanced the invasive ability. Numerous members of the MMP family are downstream effectors of the Wnt/LEF1 pathway. Target prediction databases and luciferase data showed that LEF1 is a new direct target of miR-218. Importantly, western blot assays demonstrated that miR-218 can reduce protein levels of LEF1 and MMP-9. We, therefore, hypothesize that miR-218 directly targets LEF1, resulting in reduced synthesis of MMP-9. Results suggest that miR-218 is involved in the invasive behavior of GBM cells and by targeting LEF1 and blocking the invasive axis, miR-218-LEF1-MMPs, it may be useful for developing potential clinical strategies. IntroductionGBM (WHO-grade IV) is the most malignant and frequent brain tumor and has the worst prognosis of any cancer. Despite advances in treatment by surgery combined with radiotherapy or chemotherapy, patients with GBM have a mean survival of only 14.6 months (1). Therefore, new therapeutic targets are urgently needed. A formidable difficulty in treating GBM is that tumor cells diffuse and infiltrate the normal peripheral tissue, therefore it is not possible to completely dissect out and remove the tumor. Degradation of extracellular matrix (ECM) is the defining step in tumor cell invasion and members of the matrix metalloproteinase family (MMPs) have crucial roles in regulating this process (2-4). Thus, understanding and blocking the invasive process may be an effective strategy for treating GBM.The recent discovery of miRNAs is a major advance. Accumulating evidence suggests that miRNAs are involved in multiple biological functions, including cell invasion, by altering the expression of multiple target genes. They bind to the 3' untranslated region (UTR) of target messenger RNAs (mRNAs) to suppress translation or induce degradation of these mRNAs. The roles different miRNAs play have been recently expounded in numerous human tumors as detailed below.Accumulated evidence shows that downregulation of miR-218 can enhance tumor cell invasion and proliferation in several kinds of solid tumors (5,6). In this study, we have identifi...

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Section: Discussionmentioning

confidence: 99%

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1

et al. 2012

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“…Two studies used home-made cDNA microarrays [8], [13], one used the Agilent human 1A platform [9], and the last one used home-spotted chips using the Sigma human Oligolibrary [11]. Because these platforms did not use Affymetrix probes, we first converted our probe signature into a gene signature.…”

Section: Resultsmentioning

confidence: 99%

“…The red and green bars bellow the heatmap indicate the hepatic metastasis samples from the GIST and the SCC respectively. C) Normal liver tissues (light blue), primary tumors (green) and hepatic metastases (red) were clustered using the 24 genes of our 33-gene signature present in Lin et al [8] study. D) Normal colon tissues (blue), primary tumors (green), hepatic metastases (red) and peritoneal carcinomatosis (orange) were clustered using the 32 genes of our 33-gene signature present in Kleivi et al [9] study.…”

Section: Supporting Informationmentioning

confidence: 99%

“…Three studies focused on the development of diagnostic and prognostic markers and did not try to identify gene signatures able to differentiate metastatic from primary cancer tissues [6]–[8]. Two studies presented gene signatures associated with metastatic disease containing more than 400 genes.…”

Section: Introductionmentioning

confidence: 99%

“…This suggests that heterogeneity between patients is higher than between a primary tumor and its metastases. Finally, the three gene signatures published so far [9], [13], [14] share only few genes [8], underlining the difficulty of extracting pertinent data from the background due to human diversity, cancer heterogeneity and the use of different microarray platforms.…”

Section: Introductionmentioning

confidence: 99%

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Specific Extracellular Matrix Remodeling Signature of Colon Hepatic Metastases

et al. 2013

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To identify genes implicated in metastatic colonization of the liver in colorectal cancer, we collected pairs of primary tumors and hepatic metastases before chemotherapy in 13 patients. We compared mRNA expression in the pairs of patients to identify genes deregulated during metastatic evolution. We then validated the identified genes using data obtained by different groups. The 33-gene signature was able to classify 87% of hepatic metastases, 98% of primary tumors, 97% of normal colon mucosa, and 95% of normal liver tissues in six datasets obtained using five different microarray platforms. The identified genes are specific to colon cancer and hepatic metastases since other metastatic locations and hepatic metastases originating from breast cancer were not classified by the signature. Gene Ontology term analysis showed that 50% of the genes are implicated in extracellular matrix remodeling, and more precisely in cell adhesion, extracellular matrix organization and angiogenesis. Because of the high efficiency of the signature to classify colon hepatic metastases, the identified genes represent promising targets to develop new therapies that will specifically affect hepatic metastasis microenvironment.

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Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies

et al. 2013

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Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis displayed increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demonstrate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. Conclusion: The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of targetable antigens. (HEPATOLOGY 2014;59:924-934) See Editorial on Page 757 D espite its great promise, clinically used targeted cancer therapy is unfortunately showing only limited success at a very high cost. 1 This failure is partly explained by the high level of genetic heterogeneity of malignant lesions and the fact that carcinogenesis is an evolutionally driven process that recapitulates Darwin's theory of selection of the fittest. 2 In such an unfavorable context, targeted therapy protocols are reaching only a subpopulation of tumor cells, leading to a punctual increase in the selective pressure, fueling resistance to therapy, and thus failing to cure the patient. 3 The notion of tumor heterogeneity and the apparent random distribution of tumor cells harboring different mutations are supported by recent genetic studies. [4][5][6] However, the lack of information at the protein level limits the understanding of how genetic Abbreviations: CRC, colorectal cancer; MALDI, matrix assisted laser desorption ionization; MS, mass spectrometry. From the

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Comparative Profiling of Primary Colorectal Carcinomas and Liver Metastases Identifies LEF1 as a Prognostic Biomarker

Cited by 57 publications

References 49 publications

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1

MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1

Specific Extracellular Matrix Remodeling Signature of Colon Hepatic Metastases

Organized proteomic heterogeneity in colorectal cancer liver metastases and implications for therapies

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