Illuminating the metastatic process

Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
Nature Reviews Cancer (Impact Factor: 29.54). 11/2007; 7(10):737-49. DOI: 10.1038/nrc2229
Source: PubMed

ABSTRACT Until recently most studies of metastasis only measured the end point of the process--macroscopic metastases. Although these studies have provided much useful information, the details of the metastatic process remain somewhat mysterious owing to difficulties in studying cell behaviour with high spatial and temporal resolution in vivo. The use of luminescent and fluorescent proteins and developments in optical imaging technology have enabled the direct observation of cancer cells spreading from their site of origin and arriving at secondary sites. This Review will describe recent advances in our understanding of the different steps of metastasis gained from cellular resolution imaging, and how these techniques can be used in preclinical drug evaluation.

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    • "Metastasis of a primary tumor to different tissues and organs is generally the cause of cancer-related death. During cancer progression, invasion of cancer cells is the first step required for metastasis (Thiery, 2002; Sahai, 2007). Numerous studies have postulated that invasion into the surrounding stroma requires cancer cells with epithelial cell morphology to undergo a phenotypic conversion termed the epithelial-mesenchymal transition (EMT), wherein they lose their intercellular adhesion ability and acquire mesenchymal morphology and increased invasion potential (Thiery, 2002; Hanahan and Weinberg, 2011; Scheel and Weinberg, 2012). "
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    ABSTRACT: For collective invasion, cancer cells form cohesive groups comprised of leading cells (LCs) at the forefront and following cells (FCs) at the rear. However, the molecular mechanisms that define LCs and FCs remain elusive. Here, we demonstrated that LCs, but not FCs, upregulated the expression of integrin β1 after the loss of intercellular adhesion. The LC-specific expression of integrin β1 was posttranscriptionally regulated by the TRIM27/MRTF-B complex in response to the loss of intercellular adhesion, thereby regulating the stability and translation of integrin β1 mRNA via microRNA-124 in LCs. Accordingly, depletion of TRIM27 and MRTF-B abrogated the upregulation of integrin β1 in LCs and blocked the invasion of cancer cell groups in vitro and in vivo. Therefore, our findings revealed that the specific function of LCs was defined by intrinsic mechanisms related to the presence of the cell's free surface, providing insights into the regulation of intratumor heterogeneity.
    Cell Reports 04/2014; 7(4). DOI:10.1016/j.celrep.2014.03.068 · 7.21 Impact Factor
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    • "At the preclinical level, priority should be given to research that aims to identify and validate novel therapeutic targets that block cancer metastasis in vivo. With modern intravital imaging techniques, each step of the metastatic cascade can be quantitatively visualized in vivo [25] [32] [34] [80]. Modern gene silencing techniques continue to allow researchers to conduct genome wide screens to identify the genes that control metastatic dissemination of cancer from the primary tumor [81-84]. "
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    ABSTRACT: Metastasis is the main cause of prostate cancer-associated deaths. While significant progress has been made in the treatment of primary tumors, efficient therapies that target the metastatic spread of prostate cancer are far from clinical reality. To efficiently treat cancer we need be able to impede its spread. Unfortunately, the majority of current therapeutics approved to treat metastatic cancer were originally selected based on their ability to inhibit primary tumor growth. This inherent flaw precludes these therapies from efficiently targeting the development of secondary metastatic lesions, a process that is distinct from that of primary tumor progression. In this review we will summarize the conceptual, cellular and molecular targets that should be considered to design effective anti-metastatic therapies.
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    • "EMBO Mol Med (2013) 5, 1523–1536 INTRODUCTION One of the hallmarks of an aggressive tumour is its propensity to form metastases, and the understanding of this process is highly relevant to cancer treatment. The dissemination of cancer cells from primary tumours to form distant metastases is a highly regulated process consisting of invasion, intravasation, transit in the blood or lymph, extravasation and growth at a new site (Chaffer & Weinberg, 2011; Hanahan & Weinberg, 2011; Olson & Sahai, 2009; Sahai, 2007; Yilmaz & Christofori, 2009). The epithelial to mesenchymal transition (EMT) converts epithelial cells into migratory and invasive cells and is a fundamental event in both morphogenesis and cancer progression (Nieto, 2011; Nieto & Cano, 2012). "
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    ABSTRACT: The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression.
    EMBO Molecular Medicine 10/2013; 5(10):1523-1536. DOI:10.1002/emmm.201302847 · 8.25 Impact Factor
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