Wang W, Goswami S, Lapidus K, Wells AL, Wyckoff JB, Sahai E et al.. Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 64: 8585-8594

Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cancer Research (Impact Factor: 9.33). 01/2005; 64(23):8585-94. DOI: 10.1158/0008-5472.CAN-04-1136
Source: PubMed

ABSTRACT We subjected cells collected using an in vivo invasion assay to cDNA microarray analysis to identify the gene expression profile of invasive carcinoma cells in primary mammary tumors. Expression of genes involved in cell division, survival, and cell motility were most dramatically changed in invasive cells indicating a population that is neither dividing nor apoptotic but intensely motile. In particular, the genes coding for the minimum motility machine that regulates beta-actin polymerization at the leading edge and, therefore, the motility and chemotaxis of carcinoma cells, were dramatically up-regulated. However, ZBP1, which restricts the localization of beta-actin, the substrate for the minimum motility machine, was down-regulated. This pattern of expression implicated ZBP1 as a suppressor of invasion. Reexpression of ZBP1 in metastatic cells with otherwise low levels of ZBP1 reestablished normal patterns of beta-actin mRNA targeting and suppressed chemotaxis and invasion in primary tumors. ZBP1 reexpression also inhibited metastasis from tumors. These experiments support the involvement in metastasis of the pathways identified in invasive cells, which are regulated by ZBP1.

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Available from: Sumanta Goswami, Sep 28, 2015
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    • "However, there are still promising candidates such as MT1-MMP (Chen et al., 1994; Chen, 1996; Sabeh et al., 2009). In addition, upstream players that induce invadopodia formation such as Mena INV , Arg, IL-6, EGFR, and faciogenital dysplasia protein Fgd1, are known to have increased expression levels in various cancers (Ayala et al., 2009; Clark et al., 2009; Li et al., 2010b; Wang et al., 2004, 2007; Gil-Henn et al., 2013). Thus both upstream regulators and structural components of invadopodia present vital opportunities for diagnosis and therapy. "
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    ABSTRACT: The leading cause of death in cancer patients is metastasis. Invasion is an integral part of metastasis and is carried out by proteolytic structures called invadopodia at the cellular level. In this introductory review, we start by evaluating the definition of invadopodia. While presenting the upstream signaling events involved, we integrate current models on invadopodia. In addition, we discuss the significance of invadopodia in 2D and 3D and in vivo. We finally point out technical challenges and conclude with open questions in the field.
    Turkish Journal of Biology 11/2014; 38(6):740-747. DOI:10.3906/biy-1404-110 · 1.34 Impact Factor
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    • "Several actin binding proteins are deregulated in cancer cell lines [28], [52], among them Profilin (PfnI), which was proposed as a tumor suppressor protein [27], [30]. PfnI expression levels are significantly down-regulated in various types of adenocarcinoma cells. "
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    ABSTRACT: Cellular motility is the basis for cancer cell invasion and metastasis. In the case of breast cancer, the most common type of cancer among women, metastasis represents the most devastating stage of the disease. The central role of cellular motility in cancer development emphasizes the importance of understanding the specific mechanisms involved in this process. In this context, tumor development and metastasis would be the consequence of a loss or defect of the mechanisms that control cytoskeletal remodeling. Profilin I belongs to a family of small actin binding proteins that are thought to assist in actin filament elongation at the leading edge of migrating cells. Traditionally, Profilin I has been considered to be an essential control element for actin polymerization and cell migration. Expression of Profilin I is down-regulated in breast and various other cancer cells. In MDA-MB-231 cells, a breast cancer cell line, further inhibition of Profilin I expression promotes hypermotility and metastatic spread, a finding that contrasts with the proposed role of Profilin in enhancing polymerization. In this report, we have taken advantage of the fluorescence recovery after photobleaching (FRAP) of GFP-actin to quantify and compare actin dynamics at the leading edge level in both cancer and non-cancer cell models. Our results suggest that (i) a high level of actin dynamics (i.e., a large mobile fraction of actin filaments and a fast turnover) is a common characteristic of some cancer cells; (ii) actin polymerization shows a high degree of independence from the presence of extracellular growth factors; and (iii) our results also corroborate the role of Profilin I in regulating actin polymerization, as raising the intracellular levels of Profilin I decreased the mobile fraction ratio of actin filaments and slowed their polymerization rate; furthermore, increased Profilin levels also led to reduced individual cell velocity and directionality.
    PLoS ONE 01/2014; 9(1):e85817. DOI:10.1371/journal.pone.0085817 · 3.23 Impact Factor
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    • "Most studies on MTLn3 mammary adenocarcinoma cells and many other tumor cell types that have addressed changes in the regulatory proteins that alter actin organization have focused on cofilin-1 [42,46,47,50], primarily because it was reported to be the major ADF/cofilin protein expressed in MTLn3 cells [54,55]. However, this determination used antibodies that had a much greater affinity toward cofilin than toward ADF. "
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    ABSTRACT: ADF/cofilin proteins are key modulators of actin dynamics in metastasis and invasion of cancer cells. Here we focused on the roles of ADF and cofilin-1 individually in the development of polarized migration of rat mammary adenocarcinoma (MTLn3) cells, which express nearly equal amounts of each protein. Small interference RNA (siRNA) technology was used to knockdown (KD) the expression of ADF and cofilin-1 independently. Either ADF KD or cofilin KD caused cell elongation, a reduction in cell area, a decreased ability to form invadopodia, and a decreased percentage of polarized cells after 180 s of epidermal growth factor stimulation. Moreover, ADF KD or cofilin KD increased the rate of cell migration and the time of lamellipodia protrusion but through different mechanisms: lamellipodia protrude more frequently in ADF KD cells and are more persistent in cofilin KD cells. ADF KD cells showed a significant increase in F-actin aggregates, whereas cofilin KD cells showed a significant increase in prominent F-actin bundles and increased cell adhesion. Focal adhesion area and cell adhesion in cofilin KD cells were returned to control levels by expressing exogenous cofilin but not ADF. Return to control rates of cell migration in ADF KD cells was achieved by expression of exogenous ADF but not cofilin, whereas in cofilin KD cells, expression of cofilin efficiently rescued control migration rates. Although ADF and cofilin have many redundant functions, each of these isoforms has functional differences that affect F-actin structures, cell adhesion and lamellipodial dynamics, all of which are important determinants of cell migration.
    BMC Cell Biology 10/2013; 14(1):45. DOI:10.1186/1471-2121-14-45 · 2.34 Impact Factor
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