Illuminating the metastatic process
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.
- SourceAvailable from: Kozo Kaibuchi
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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). "
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 · 8.36 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    . 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]. "
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.04/2014; 2(1):45-56.
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- "The invasion and metastasis of cancer cells are landmark events that involve many changes in cellular behavior, and lead to different steps of the metastatic cascade [3,4]. One of the most crucial steps in the metastatic cascade is the acquisition of invasive capabilities, including turnover of cell-cell junctions, degradation of the cell matrix, and activation of pathways that control cytoskeletal dynamics in cancer cells. "
ABSTRACT: Recent evidence indicates that long noncoding RNAs (lncRNAs) play a critical role in the regulation of cellular processes, such as differentiation, proliferation and metastasis. These lncRNAs are found to be dysregulated in a variety of cancers. BRAF activated non-coding RNA (BANCR) is a 693-bp transcript on chromosome 9 with a potential functional role in melanoma cell migration. The clinical significance of BANCR, and its' molecular mechanisms controlling cancer cell migration and metastasis are unclear. Expression of BANCR was analyzed in 113 non-small cell lung cancer (NSCLC) tissues and seven NSCLC cell lines using quantitative polymerase chain reaction (qPCR) assays. Gain and loss of function approaches were used to investigate the biological role of BANCR in NSCLC cells. The effects of BANCR on cell viability were evaluated by MTT and colony formation assays. Apoptosis was evaluated by Hoechst staining and flow cytometry. Nude mice were used to examine the effects of BANCR on tumor cell metastasis in vivo. Protein levels of BANCR targets were determined by western blotting and fluorescent immunohistochemistry. BANCR expression was significantly decreased in 113 NSCLC tumor tissues compared with normal tissues. Additionally, reduced BANCR expression was associated with larger tumor size, advanced pathological stage, metastasis distance, and shorter overall survival of NSCLC patients. Reduced BANCR expression was found to be an independent prognostic factor for NSCLC. Histone deacetylation was involved in the downregulation of BANCR in NSCLC cells. Ectopic expression of BANCR impaired cell viability and invasion, leading to the inhibition of metastasis in vitro and in vivo. However, knockdown of BANCR expression promoted cell migration and invasion in vitro. Overexpression of BANCR was found to play a key role in epithelial-mesenchymal transition (EMT) through the regulation of E-cadherin, N-cadherin and Vimentin expression. We determined that BANCR actively functions as a regulator of EMT during NSCLC metastasis, suggesting that BANCR could be a biomarker for poor prognosis of NSCLC.Molecular Cancer 03/2014; 13(1):68. DOI:10.1186/1476-4598-13-68 · 4.26 Impact Factor