The physical limits of cell migration in dense porous environments are dependent upon the available space and the deformability of the nucleus and are modulated by matrix metalloproteinases, integrins and actomyosin function.

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.Contributed by V. Craig Jordan, September 14, 2011 (sent for review June 21, 2011) In laboratory studies, acquired resistance to long-term antihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17β-estradiol (E 2 ) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E 2 paradoxically induces apoptosis. This finding is the basis for the clinical use of estrogen to treat advanced antihormone-resistant breast cancer. We interrogated E 2 -induced apoptosis by analysis of gene expression across time (2-96 h) in MCF-7 cell variants that were estrogen-dependent (WS8) or resistant to estrogen deprivation and refractory (2A) or sensitive (5C) to E 2 -induced apoptosis. We developed a method termed differential area under the curve analysis that identified genes uniquely regulated by E 2 in 5C cells compared with both WS8 and 2A cells and hence, were associated with E 2 -induced apoptosis. Estrogen signaling, endoplasmic reticulum stress (ERS), and inflammatory response genes were overrepresented among the 5C-specific genes. The identified ERS genes indicated that E 2 inhibited protein folding, translation, and fatty acid synthesis. Meanwhile, the ERS-associated apoptotic genes Bcl-2 interacting mediator of cell death (BIM; BCL2L11) and caspase-4 (CASP4), among others, were induced. Evaluation of a caspase peptide inhibitor panel showed that the CASP4 inhibitor z-LEVD-fmk was the most active at blocking E 2 -induced apoptosis. Furthermore, z-LEVD-fmk completely prevented poly (ADP-ribose) polymerase (PARP) cleavage, E 2 -inhibited growth, and apoptotic morphology. The up-regulated proinflammatory genes included IL, IFN, and arachidonic acid-related genes. Functional testing showed that arachidonic acid and E 2 interacted to superadditively induce apoptosis. Therefore, these data indicate that E 2 induced apoptosis through ERS and inflammatory responses in advanced antihormone-resistant breast cancer.aromatase inhibitor | antihormonal resistance | estrogen receptor | gene expression microarrays | selective estrogen receptor modulator E lucidation of the basic structure function relationships of synthetic estrogens based on either stilbene (1) or triphenylethylene (2) was a landmark achievement that continues to have major therapeutic implications to this day. The first successful chemical therapy for the treatment of any cancer was the use of high-dose synthetic estrogen for the treatment of metastatic breast cancer (3). Response rates for patients who were more than a decade beyond menopause were about 30%. Importantly, treatment near menopause was ineffective, and therefore, tumor responsiveness was related to the duration of estrogen deprivation. In 1970, Alexander Haddow commented that "the extraordinary extent of tumor regression observed in...

The surface of highly monodisperse magnetic iron oxide (γ-Fe 2 O 3 ) nanocrystals was thoroughly investigated by FTIR, NMR, and mass spectroscopy. The nanocrystals were prepared by a thermal decomposition method now widely used for the preparation of magnetic metal and metal oxide nanocrystals. This method takes advantage of oleic acid as a means to passivate the surface and render the particles stable with respect to aggregation or grain growth and keeps them highly dispersed in a variety of organic media. The nature of this surface in terms of ligand structure and the role of oleic acid during the synthesis remained somewhat undetermined until this report. We provide spectroscopic evidence of an oleic acid ligand structural change during γ-Fe 2 O 3 nanocrystal synthesis.

Aberrant activation of canonical Wingless-type MMTV integration site family (Wnt) signaling is pathognomonic of colorectal cancers (CRC) harboring functional mutations in either adenomatous polyposis coli or β-catenin. Coincident with Wnt cascade activation, CRCs also up-regulate the expression of Wnt pathway feedback inhibitors, particularly the putative tumor suppressor, Axin2. Because Axin2 serves as a negative regulator of canonical Wnt signaling in normal cells, recent attention has focused on the utility of increasing Axin2 levels in CRCs as a means to slow tumor progression. However, rather than functioning as a tumor suppressor, we demonstrate that Axin2 acts as a potent promoter of carcinoma behavior by up-regulating the activity of the transcriptional repressor, Snail1, inducing a functional epithelialmesenchymal transition (EMT) program and driving metastatic activity. Silencing Axin2 expression decreases Snail1 activity, reverses EMT, and inhibits CRC invasive and metastatic activities in concert with global effects on the Wnt-regulated cancer cell transcriptome. The further identification of Axin2 and nuclear Snail1 proteins at the invasive front of human CRCs supports a revised model wherein Axin2 acts as a potent tumor promoter in vivo.invasion | E-cadherin | basement membrane | GSK3β | tankyrase

Genomic characterization is beginning to define a molecular taxonomy for breast cancer; however, the molecular basis of invasion and metastasis remains poorly understood. We report a pivotal role for the fibroblast growth factor -inducible 14 (Fn14) receptor in this process. We examined whether Fn14 and its ligand tumor necrosis factor -like weak inducer of apoptosis (TWEAK) were expressed in breast tumors and whether deregulation of Fn14 levels affected malignant behavior of breast cancer cell lines. Analysis of TWEAK and Fn14 in publicly available gene expression data indicated that high Fn14 expression levels significantly correlated with several poor prognostic indicators (P < 0.05).

Current in vivo models for head and neck squamous cell carcinoma (HNSCC) have limitations in simulating some essential tumorigenic phenotypes, such as invasion. Most mouse models of human HNSCC are inadequate because tumor cells are injected directly into the connective tissue, thereby bypassing the basement membrane of the surface epithelium, the first barrier to invasion. In this manuscript, we establish the chick chorioallantoic membrane (CAM) assay as an in vivomodel of human HNSCC tumor progression. Using the CAM model of HNSCC, we investigated the role of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, in multiple aspects of HNSCC tumor progression. We found that knockdown of EZH2 reduced tumor size, angiogenesis, invasion, and metastasis of tumors produced by grafting human HNSCC cells onto the CAM. In addition, we demonstrate that EZH2 expression mediates a mesenchymal phenotype in HNSCC cell lines and mouse tumors. These findings demonstrate the advantages of the newly proposed CAM model of human HNSCC and highlight the emerging role of EZH2 in HSNCC tumor progression.

Purpose Invasion is the critical step in progression of a pre-cancerous lesion to squamous cell carcinoma of the head and neck (SCCHN). Invasion is regulated by multiple pro-inflammatory mediators. Tristetraprolin (TTP) is an mRNA degrading protein that regulates multiple pro-inflammatory mediators. TTP may serve as an excellent treatment target. Rap1 is a ras-like oncoprotein that induces critical signaling pathways. In this study, the role of rap1 in TTP-mediated invasion was investigated. Experimental Design Using complementary approaches we modulated TTP and altered expression of IL-6 and MMP2/9, which were quantified by ELISA and zymogram. Invasion was evaluated in vitro using the Oral-Cancer-Equivalent (OCE) 3D model and in vivo in the chick chorioallantoic membrane (CAM). The role of rap1 and p38 were established using knockdown strategies. Results Downregulation of TTP significantly increased invasion via secretion of MMP9/2 and IL-6. In the novel OCE and CAM invasion models of SCCHN, cells with downregulated TTP destroyed the basement membrane to invade the underlying connective tissue. Rap1 induces p38 mitogen activated protein kinase (p38)-mediated inactivation of TTP. Inactive TTP enhances transcript stability via binding to the 3′-UTR. High IL-6 and MMP9 are prognostic for poor clinical outcomes in SCCHN patients. Conclusions Targeting the rap1-p38-TTP cascade is an attractive novel treatment strategy in SCCHN to concurrently suppress multiple mediators of invasion.

Summary During development, wound repair and disease-related processes, such as cancer, normal, or neoplastic cell types traffic through the extracellular matrix (ECM), the complex composite of collagens, elastin, glycoproteins, proteoglycans, and glycosaminoglycans that dictate tissue architecture. Current evidence suggests that tissue-invasive processes may proceed by protease-dependent or protease-independent strategies whose selection is not only governed by the characteristics of the motile cell population, but also by the structural properties of the intervening ECM. Herein, we review the mechanisms by which ECM dimensionality, elasticity, crosslinking, and pore size impact patterns of cell invasion. This summary should prove useful when designing new experimental approaches for interrogating invasion programs as well as identifying potential cellular targets for next-generation therapeutics.