Metastasis: Tumor cells becoming MENAcing

Department of Biology and Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT), 77 Massachusetts Ave, Cambridge, MA 02138, USA.
Trends in cell biology (Impact Factor: 12.31). 11/2010; 21(2):81-90. DOI: 10.1016/j.tcb.2010.10.001
Source: PubMed

ABSTRACT During breast cancer metastasis cells emigrate from the primary tumor to the bloodstream, and this carries them to distant sites where they infiltrate and sometimes form metastases within target organs. These cells must penetrate the dense extracellular matrix comprising the basement membrane of the mammary duct/acinus and migrate toward blood and lymphatic vessels, processes that mammary tumor cells execute primarily using epidermal growth factor (EGF)-dependent protrusive and migratory activity. Here, we focus on how the actin regulatory protein Mena affects EGF-elicited movement, invasion and metastasis. Recent findings indicate that, in invasive migratory tumor cells, Mena isoforms that endow heightened sensitivity to EGF and increased protrusive and migratory abilities are upregulated, whereas other isoforms are selectively downregulated. This change in Mena isoform expression enables tumor cells to invade in response to otherwise benign EGF stimulus levels and could offer an opportunity to identify metastatic risk in patients.

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    • "is supported by in vivo imaging of mammary tumors, which demonstrates the following regarding motile tumor cells: they represent only a small percentage of tumor cells, they are distributed throughout the tumor, and they are found most commonly localized to precise areas within the tumor [5]. Furthermore, genes associated with metastasis are expressed early and are found in tumor cells throughout the tumor [2]. Also in support of the model is the observation that micrometastases are commonly genetically heterogeneous, indicating that the invasiveness and migration are not limited to stable gene alterations. "
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    ABSTRACT: Despite diagnostic advances, breast cancer remains the most prevalent cancer among women in the United States. The armamentarium of treatment options for metastatic disease is limited and mostly ineffective with regards to eradicating cancer. However, there have been novel findings in the recent literature that substantiate the function of the microenvironment in breast cancer progression and the support of metastasis to tertiary sites such as bone marrow. The uncovered significance of the microenvironment in the pathophysiology of breast cancer metastasis has served to challenge previously widespread theories and introduce new perspectives for the future research to eradicate breast cancer. This paper delineates the current understanding of the molecular mechanisms involved in the interactions between breast cancer cells and the microenvironment in progression, metastasis, and dormancy. The information, in addition to other mechanisms described in bone marrow, is discussed in the paper.
    02/2012; 2012(11):721659. DOI:10.1155/2012/721659
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    • "These cells are motile, chemotactic to EGF receptor ligands, nonapoptotic, and chemotherapy resistant. Key among the motility genes is Mena, an actin binding protein that regulates pathways involved in EGF-stimulated actin polymerization, chemotaxis , and cell migration (Gertler and Condeelis 2011; Roussos et al. 2011b). "
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    ABSTRACT: Although metastasis is a major cause of death from breast cancer, our ability to predict which tumors will metastasize is limited (American Cancer Society 2010). Proper assessment of metastatic risk and elucidating the underlying mechanisms of metastasis will help personalize therapy and may provide insight into potential therapeutic targets. Traditionally, histologic grading, staging, hormone receptors, HER2/Neu, and proliferation assays have been the gold standard on which oncologists based their treatment decisions. However, all of these are indirect measures of metastatic risk. Recent insights from intravital imaging directly address questions of mechanism and have led to a new way of using histologic and cytologic material to assess metastatic risk. This review describes the tumor microenvironment model of invasion and intravasation, as well as an emerging histopathologic application based on this model. In particular, the authors describe a new immunohistochemical approach to the assessment of metastatic risk based on the density of intravasation microenvironment sites called the tumor microenvironment of metastasis. In addition, they describe an isoform assay for the actin regulatory protein Mena using fine needle aspiration samples and the details about how these 2 assays may be applied in clinical practice in a synergistic way to assess the risk of metastasis.
    Journal of Histochemistry and Cytochemistry 01/2012; 60(3):168-73. DOI:10.1369/0022155411435153 · 2.40 Impact Factor
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    • "For example, trophoblast cells breach the endometrium to establish the placenta, and leukocytes cross the perivascular BM to reach sites of infection (Madsen and Sahai, 2010; Pollheimer and Knofler, 2005). The genetic networks that control invasive behavior are also thought to be co-opted by tumor cells during metastasis (Gertler and Condeelis, 2011). Cell invasion requires the integration of multiple cellular processes, including attachment to BM, remodeling of the actin cytoskeleton, and physical breaching of BM barriers (Rowe and Weiss, 2008; Yilmaz and Christofori, 2009). "
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    ABSTRACT: Cell invasion through basement membrane is a specialized cellular behavior critical for many developmental processes and leukocyte trafficking. Invasive cellular behavior is also inappropriately co-opted during cancer progression. Acquisition of an invasive phenotype is accompanied by changes in gene expression that are thought to coordinate the steps of invasion. The transcription factors responsible for these changes in gene expression, however, are largely unknown. C. elegans anchor cell (AC) invasion is a genetically tractable in vivo model of invasion through basement membrane. AC invasion requires the conserved transcription factor FOS-1A, but other transcription factors are thought to act in parallel to FOS-1A to control invasion. Here we identify the transcription factor HLH-2, the C. elegans ortholog of Drosophila Daughterless and vertebrate E proteins, as a regulator of AC invasion. Reduction of HLH-2 function by RNAi or with a hypomorphic allele causes defects in AC invasion. Genetic analysis indicates that HLH-2 has functions outside of the FOS-1A pathway. Using expression analysis, we identify three genes that are transcriptionally regulated by HLH-2: the protocadherin cdh-3, and two genes encoding secreted extracellular matrix proteins, mig-6/papilin and him-4/hemicentin. Further, we show that reduction of HLH-2 function causes defects in polarization of F-actin to the invasive cell membrane, a process required for the AC to generate protrusions that breach the basement membrane. This work identifies HLH-2 as a regulator of the invasive phenotype in the AC, adding to our understanding of the transcriptional networks that control cell invasion.
    Developmental Biology 07/2011; 357(2):380-91. DOI:10.1016/j.ydbio.2011.07.012 · 3.64 Impact Factor
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