collagen invasion
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2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 738-738
Author(s):  
Kenneth H. Yu ◽  
Brian McCarthy ◽  
William H. Isacoff ◽  
Brandon Cooper ◽  
Andrew Bartlett ◽  
...  

738 Background: Pancreatic adenocarcinoma (PDAC) is for most patients a refractory disease. Modern cytotoxic chemotherapeutics (C) are not yet optimal for inducing responses and extending life. We are developing a blood-based pharmacogenomic (PGx) assay profiling circulating tumor and invasive cells (CTICs) to predict sensitivity and resistance to C. Methods: The PGx assay was studied in two cohorts of patients (pts) presenting for frontline C therapy of metastatic PDAC. Cohort 1 is from an ongoing prospective study (planned n=80); pts are enrolled prior to receiving either FOLFIRINOX or gemcitabine (Gem)/nab-paclitaxel (Nab-P). Cohort 2 (n=50) consists of pts enrolled prior to receiving bespoke combinations of C agents informed by the assay. 6 mL of peripheral blood was collected from pts at baseline and while on C therapy. CTICs were isolated by previously described collagen invasion assay, total RNA was extracted and gene-expression analysis was performed. PGx models for seven C agents used in PDAC were applied, and correlated to treatment received. Pts were classified as sensitive if C received were predicted to be effective and resistant if not. Objective endpoints were PFS and OS. Results: Cohort 1 patients who received sensitive first-line C combinations experienced significantly longer time to progression (TTP) v resistant (Table). In Cohort 2, the PGx assay was predictive of TTP and OS when used across multiple lines of therapy, with a two-year survival of 38%. Greater OS was observed in Cohort 2 pts receiving heterogenous C regimens more highly correlated to those predicted by the PGx assay. Conclusions: The PGx assay has promising predictive performance in both standard and personalized C regimens. A prospective, directed trial comparing these approaches is warranted. Clinical trial information: NCT03033927. [Table: see text]


PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0160108 ◽  
Author(s):  
Christine A. Fiddler ◽  
Helen Parfrey ◽  
Andrew S. Cowburn ◽  
Ding Luo ◽  
Gerard B. Nash ◽  
...  
Keyword(s):  

2013 ◽  
Vol 305 (3) ◽  
pp. F382-F389 ◽  
Author(s):  
Tania Marchbank ◽  
Asif Mahmood ◽  
Raymond J. Playford

Pancreatic secretory trypsin inhibitor (PSTI) is expressed in most bladder carcinomas, where its pathophysiological relevance is unclear. Using recombinant normal sequence PSTI/tumor-associated trypsin inhibitor (TATI), a variant associated with familial pancreatitis (N34S), an active site-inactivated variant (R18/V19), and immunoneutralization and RNA interference-mediated knockdown techniques, we investigated the actions of PSTI/TATI on cell migration (wounding monolayers), collagen invasion (gel invasion assays), and proliferation (Alamar blue) on 253J, RT4, and HT1376 human bladder carcinoma cell lines. All three forms of PSTI/TATI stimulated migration twofold, and normal sequence PSTI/TATI showed synergistic promigratory effects when added with EGF. Addition of structurally unrelated soybean trypsin inhibitor had no promigratory activity. Similar results were seen using collagen invasion assays, although the active site mutated variant had no proinvasive activity, probably due to reduced Akt2 activation. PSTI/TATI did not stimulate proliferation despite acting, at least partially, through the EGF receptor, as effects of PSTI/TATI were truncated by the addition of an EGF receptor blocking antibody or the tyrosine kinase inhibitor tyrphostin. Cell lines produced endogenous PSTI/TATI, and PSTI/TATI RNA interference knockdown or the addition of PSTI/TATI, EGF receptor, or tyrphostin blocking agents reduced migration and invasion below baseline. PSTI/TATI induced phosphorylation of the EGF receptor, ERK1 and ERK2, Akt2 and Akt3, JNK1, MKK3, and ribosomal protein S6 kinase 1. This profile was more limited than that induced by EGF and did not include Akt1, probably explaining the lack of proproliferative activity. Our findings of autocrine stimulation and synergistic responses between EGF and PSTI/TATI at concentrations found in urine and tissue suggest that PSTI/TATI has pathophysiological relevance.


Sexual Health ◽  
2013 ◽  
Vol 10 (6) ◽  
pp. 593
Author(s):  
Erin Isaacson Wechsler ◽  
Sharof Tugizov ◽  
Joel Palefsky

Background The nucleotide analogue cidofovir has been shown to be effective in treating precancerous HPV-associated lesions located in the respiratory tract, cervix, vulva and anus. Cidofovir has been shown to have a 51% efficacy in the short-term treatment of high-grade perianal squamous intraepithelial lesions in HIV-infected persons. Less is known about the effect of cidofovir in treating more advanced stages of HPV-associated disease such as invasive cancer. Methods: We established an immortalised anal keratinocyte cell line (AKC2) following transfection of the HPV-16 genome into primary anal keratinocytes and long-term culture. AKC2 cells were invasive using in vitro collagen invasion assays. To determine the effect of cidofovir on invasion, AKC2 cells were treated for up to 7 days with different concentrations of cidofovir (10, 25 and 50 µg mL–1) and studied using the collagen invasion assays. Untreated cells served as a control. Results: We detected a decrease in invasion of AKC2 cells (50%, 70% and 90% decrease) with 10, 25 and 50 µg mL–1 cidofovir, respectively. Cellular toxicity was not detected in any of the cidofovir-treated samples. Preliminary data suggest that cidofovir directly or indirectly impairs the formation of actin filaments and cellular filopodia, which are known to play a role in cellular invasion. Conclusions: Cidofovir inhibits invasion of HPV-16-transformed anal keratinocytes potentially through affecting pathways that are involved in actin filament formation. Cidofovir could potentially be useful as an adjuvant treatment for invasive anal cancers, and its mechanism of action in inhibiting cellular invasion requires further study.


2012 ◽  
Vol 448 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Heather J. Spence ◽  
Paul Timpson ◽  
Hao Ran Tang ◽  
Robert H. Insall ◽  
Laura M. Machesky

The Scar (suppressor of cAMP receptor)/WAVE [WASP (Wiskott–Aldrich syndrome protein) verprolin homologous] complex plays a major role in the motility of cells by activating the Arp2/3 complex, which initiates actin branching and drives protrusions. Mammals have three Scar/WAVE isoforms, which show some tissue-specific expression, but their functions have not been differentiated. In the present study we show that depletion of Scar/WAVE3 in the mammalian breast cancer cells MDA-MB-231 results in larger and less dynamic lamellipodia. Scar/WAVE3-depleted cells move more slowly but more persistently on a two-dimensional matrix and they typically only show one lamellipod. However, Scar/WAVE3 appears to have no role in driving invasiveness in a three-dimensional Matrigel™ invasion assay or a three-dimensional collagen invasion assay, suggesting that lamellipodial persistence as seen in two-dimensions is not crucial in three-dimensional environments.


2007 ◽  
Vol 407 (2) ◽  
pp. 171-177 ◽  
Author(s):  
Yi I. Wu ◽  
Hidayatullah G. Munshi ◽  
Scott J. Snipas ◽  
Guy S. Salvesen ◽  
Rafael Fridman ◽  
...  

The transmembrane collagenase MT1-MMP (membrane-type 1 matrix metalloproteinase), also known as MMP-14, has a critical function both in normal development and in cancer progression, and is subject to extensive controls at the post-translational level which affect proteinase activity. As zymogen activation is crucial for MT1-MMP activity, an α1-PI (α1-proteinase inhibitor)-based inhibitor was designed by incorporating the MT1-MMP propeptide cleavage sequence into the α1-PI reactive-site loop (designated α1-PIMT1) and this was compared with wild-type α1-PI (α1-PIWT) and the furin inhibitory mutant α1-PIPDX. α1-PIMT1 formed an SDS-stable complex with furin and inhibited proMT1-MMP activation. A consequence of the loss of MT1-MMP activity was the activation of proMMP-2 and the inhibition of MT1-MMP-mediated collagen invasion. α1-PIMT1 expression also resulted in the intracellular accumulation of a glycosylated species of proMT1-MMP that was retained in the perinuclear region, leading to significantly decreased cell-surface accumulation of proMT1-MMP. These observations suggest that both the subcellular localization and the activity of MT1-MMP are regulated in a coordinated fashion, such that proMT1-MMP is retained intracellularly until activation of its zymogen, then proMT1-MMP traffics to the cell surface in order to cleave extracellular substrates.


2006 ◽  
Vol 149 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Luis Enrique Arias-Romero ◽  
Ma. de Jesús Almáraz-Barrera ◽  
Juan Daniel Díaz-Valencia ◽  
Arturo Rojo-Domínguez ◽  
Rosaura Hernandez-Rivas ◽  
...  

2003 ◽  
pp. 081-089 ◽  
Author(s):  
Marc E Bracke ◽  
Tom Boterberg ◽  
Erik A Bruyneel ◽  
Marc M Mareel

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