MMP Secretion Rate and Inter-invadopodia Spacing Collectively Govern Cancer Invasiveness

Kumar, Sandeep; Das, Alakesh; Barai, Amlan; Sen, Shamik

doi:10.1016/j.bpj.2017.11.3777

Cited by 43 publications

(39 citation statements)

References 54 publications

(70 reference statements)

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“…In vitro , knockdown of N‐WASP, an invadosome component that promotes trafficking of MMP‐14 to invadopodia, abolishes invadopodia formation and lung metastasis in breast cancer cells . Recent experiments using gels of varying matrix stiffness show that an increase in ECM stiffness increases the density of invadopodia on tumour cells and consequently, increases ECM degradation . However, a balance must be achieved between ECM degradation and invadopodia penetration because excessive ECM degradation actually destabilises invadopodia and impairs motility.…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis

Conlon

Murray

2019

The Journal of Pathology

145

101

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This review aims to provide an overview of recent developments regarding the roles of MMPs in tumour invasion and metastasis. Much of the mortality burden belonging to cancer relates to its ability to invade adjacent tissue and form metastases at distant sites. This would not be possible without remodelling of the ECM, a process which is enabled by the functions of MMPs. Recent studies provide a better understanding of the importance of the biophysical nature of the ECM, how this influences cancer cell motility, and how MMPs act to modify matrix stiffness. The regulation of MMPs and the role of immune cell generated MMPs has also become better understood. All of this provides a framework for the therapeutic targeting of MMPs and recent advances in the development of selective MMPs inhibitors are also reviewed.

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Section: Introductionmentioning

confidence: 99%

“…However, a balance must be achieved between ECM degradation and invadopodia penetration because excessive ECM degradation actually destabilises invadopodia and impairs motility. Therefore, cancer cells must finely tune the spacing of invadopodia in order to optimise the creation of pores for movement .…”

Section: Introductionmentioning

confidence: 99%

Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis

Conlon

Murray

2019

The Journal of Pathology

145

101

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“…They have been shown to play significant roles in mammary gland branch patterning (Wiseman and Werb, 2002). Their interaction dynamics in the context of mammary morphogenesis and elsewhere has been proposed to act through reaction-diffusion (Grant et al, 2004; Hoshino et al, 2012; Kumar et al, 2018; Skaalure et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

Pally

Pramanik

Bhat

2019

Preprint

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Equal contribution.The progression of cancer in the breast involves multiple reciprocal interactions between malignantly transformed epithelia, surrounding untransformed but affected stromal cells, and the extracellular matrix (ECM) that is remodelled during the process. A quantitative understanding of the relative contribution of such interactions to phenotypes associated with cancer cells can be arrived at through the construction of increasingly complex experimental and computational models. Herein, we introduce a multiscale 3D organo-and patho-typic model that approximates, to an unprecedented extent, the histopathological complexity of a tumor disseminating into its surrounding stromal milieu via both bulk and solitary motility dynamics. End-point and time-lapse microscopic observations of this model allow us to study the earliest steps of cancer invasion as well as the dynamical interactions between the epithelial and stromal compartments. We then construct an agent-based Cellular Potts model that incorporates constituents of the experimental model, as well as places them in similar spatial arrangements. The computational model, which comprises adhesion between cancer cells and the matrices, cell proliferation and apoptosis, and matrix remodeling through reaction-diffusion-based morphogen dynamics, is first trained to phenocopy controls run with the experimental model, wherein one or the other matrices have been removed. The trained computational model successfully predicts phenotypes of the experimental counterparts that are subjected to pharmacological treatments (inhibition of N-linked glycosylation and matrix metalloproteinase activity) and scaffold modulation (alteration of collagen density). Our results suggest that specific permissive regimes of cell-cell and cell-matrix adhesions operating in the context of a reaction-diffusionregulated ECM dynamics, promote multiscale invasion of breast cancer cells and determine the extent to which they migrate through their surrounding stroma. Preparation of cancer cell clusters:Normal/cancer cells were trypsinized using 1:5 diluted 0.25% Trypsin & 0.02% EDTA (HiMedia, TCL007). 30,000 cells per 200 μ L of defined medium (Blaschke et al., 1994) supplemented with 4% rBM (Corning, 354230) were cultured on 3% polyHEMA (Sigma, P3932) coated 96 well plate for 48 hours in a 37 o C humidified incubator with 5% carbon dioxide. 3D invasion assay:rBM-coated clusters were collected into 1.5 mL tubes, centrifuged briefly and supernatant is removed. Acid-extracted rat tail collagen (Gibco, A1048301) was neutralized on ice in the presence of 10X DMEM with 0.1N NaOH such that the final concentration of the collagen is 1 mg/mL. Pellet of clusters was resuspended in 50 μ L of neutralized collagen and seeded in 8-well chambered cover glass (Eppendorf 0030742036) and supplemented with defined medium. 3D cultures were grown in a 37 o C humidified incubator with 5% carbon dioxide. Processing of 3D invasive clusters:3D invasion cultures were washed with phosphate buffered saline pH 7...

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“…Matrix metalloproteinases (MMPs) are involved in many physiological processes including embryogenesis and wound healing [ 49 ]. In addition, MMPs mediate cell penetration, leading proteins to pass the extracellular matrix (ECM) [ 50 ]. Presumably, MMP-2 also plays a major role in epithelial cell migration in the human eye lens.…”

Section: Discussionmentioning

confidence: 99%

Decorin, Tenascin C, Total Antioxidant, and Total Oxidant Level Changes in Patients with Pseudoexfoliation Syndrome

Oruc

Keser

Yusufoğlu

et al. 2018

Journal of Ophthalmology

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Purpose Pseudoexfoliation syndrome (PEX) is an eye disease that develops under the influence of regional population differences, genetic factors, age, and environmental factors and is characterized by visualization of a gray-white fibrogranular substance in the lens anterior capsule and/or pupil margin during anterior segment examination. The underlying biochemical mechanisms of the disease have not yet been fully elucidated. Therefore, this study was designed to show the changes in aqueous humor and blood serum levels of matrix metalloproteinases (decorin and tenascin C), total antioxidants (TAS), and total oxidants (TOS) in both cataract patients who have unilateral PEX material and cataract patients who do not have unilateral PEX material. Methods Biological samples were simultaneously collected from 22 cataract patients who had unilateral pseudoexfoliation (PEX patients) and 22 cataract patients who did not have unilateral pseudoexfoliation (control patients). From the collected biological samples, decorin (DEC) and tenascin C (TN-C) were measured with the enzyme-linked immunosorbent assay (ELISA) method, and TAS and TOS were measured with an autoanalyzer. Results When decorin, tenascin C, and TOS values of PEX patients were compared with those of control patients, there was a statistically significant increase in all three parameters. Conversely, TAS values showed a statistically significant decrease in PEX patients compared to controls. DEC, TN-C, TAS values, and TOS values were significantly higher in aqueous fluid than in blood in both the PEX patient and control groups. Conclusions We suggest that parameters such as DEC, TN-C, TAS, and TOS play a role in the etiopathology of pseudoexfoliation syndrome. Thus, bringing these increased levels of extracellular proteins and TOS and decreased levels of TAS back to within physiological limits can mediate the reorganization of the blood-aqueous fluid barrier and slow the progression of pseudoexfoliation syndrome.

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MMP Secretion Rate and Inter-invadopodia Spacing Collectively Govern Cancer Invasiveness

Cited by 43 publications

References 54 publications

Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis

Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis

An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

Decorin, Tenascin C, Total Antioxidant, and Total Oxidant Level Changes in Patients with Pseudoexfoliation Syndrome

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