Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions

Alexander, Jennifer I.; Cukierman, Edna

doi:10.1016/j.ceb.2016.05.002

Cited by 129 publications

(119 citation statements)

References 181 publications

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“…We believe that the increase in activated fibroblasts (myofibroblast) was a crucial contributor to collagen reorganization. These myofibroblasts express α-SMA, and they are the major source of various ECM components, including fibrillar collagens 21. Consistently, we found significantly increased numbers of α-SMA-positive myofibroblasts in the stroma of gastric cancer.…”

Section: Discussionsupporting

confidence: 83%

Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis

Zhou¹,

Ji²,

Xiao³

et al. 2017

J. Cancer

130

128

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Collagen components in the tumor microenvironment substantially influence cancer pathogenesis and progression. Nevertheless, in gastric cancer, collagen status and its prognostic role remain unclear. Using picrosirius red staining and immunohistochemistry, we found that collagen deposition was significantly increased in gastric cancer when compared with non-neoplastic tissues, and in cancer stroma, more immature collagen components were present, suggesting a qualitative change. Furthermore, the morphology of collagen fibers could be weakly, moderately or strongly changed in gastric cancer; when weakly or moderately changed, they appeared similar to normal collagen fibers, except for a higher linearization and density; when strongly changed, they were thicker and less eosinophilic, sharply differently from their normal counterparts. In addition, we found abundant myofibroblasts and elevated expression of lysyl oxidase-like 2 (the enzyme that mediates crosslinking of collagen molecules) in cancer stroma, which might contribute to the increased collagen deposition and crosslinking. Last, five collagen architectural parameters (alignment, density, width, length and straightness) were analyzed with second harmonic generation imaging, a highly specific technology for detection of collagen fibers, and our data indicated that all the parameters were significantly increased in the tumor microenvironment. Of the five parameters, collagen width was the most powerful parameter in predicting 5-year overall survival, and increased collagen width was associated with reduced survival. The prognostic value of collagen width was superior to traditional clinicopathological parameters, and this was validated in two unrelated gastric cancer cohorts that contained 225 and 151 patients. Collectively, the collagen status (content, maturity, morphology and architecture) was profoundly reorganized in the tumor microenvironment of gastric cancer, and collagen width could serve as a valuable prognostic indicator.

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Section: Discussionsupporting

confidence: 83%

Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis

Zhou¹,

Ji²,

Xiao³

et al. 2017

J. Cancer

130

128

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“…In this regard, concepts of dynamic reciprocity, often employed in the context of wound remodeling or the tumor microenvironment [90,91], offer a novel avenue to explore the design of HSC culture platforms. Therefore, we developed a culture system that takes advantage of paracrine signaling from niche-associated mesenchymal stromal cells (MSCs).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cell remodeling of a gelatin hydrogel microenvironment defines an artificial hematopoietic stem cell niche

Gilchrist

Lee

et al. 2018

Preprint

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We identify a combination of an initially low-diffusivity (autocrine dominated) hydrogel and a 1:1 HSCP:MSC seeding ratio as conducive to enhanced HSC population maintenance. Further, gene expression and serial mechanical testing data suggests that MSC-mediated matrix remodeling is significant for the long-term HSC culture, reducing HSC autocrine feedback and potentially enhancing MSC-mediated paracrine signaling over 7-day culture in vitro. This work demonstrates the design of an HSC culture system that couples initial hydrogel properties, MSC co-culture, and concepts of dynamic reciprocity mediated by MSC remodeling to achieve enhanced HSC maintenance.

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“…Extracellular matrix deposition, contraction, and remodelling are common to diseases such as tissue fibrosis, diabetes, and tissue aging and importantly are salient features of almost all solid tumours . Prior to and during malignant transformation and tumour expansion, the host stroma typically initiates a desmoplastic stromal response . This response leads to a significant deposition and remodelling of the ECM within and surrounding the tumour.…”

Section: Background and Rationalementioning

confidence: 99%

The Mini‐Organo: A rapid high‐throughput 3D coculture organotypic assay for oncology screening and drug development

et al. 2019

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Background The use of in vitro cell cultures is a powerful tool for obtaining key insights into the behaviour and response of cells to interventions in normal and disease situations. Unlike in vivo settings, in vitro experiments allow a fine‐tuned control of a range of microenvironmental elements independently within an isolated setting. The recent expansion in the use of three‐dimensional (3D) in vitro assays has created a number of representative tools to study cell behaviour in a more physiologically 3D relevant microenvironment. Complex 3D in vitro models that can recapitulate human tissue biology are essential for understanding the pathophysiology of disease. Aim The development of the 3D coculture collagen contraction and invasion assay, the “organotypic assay,” has been widely adopted as a powerful approach to bridge the gap between standard two‐dimensional tissue culture and in vivo mouse models. In the cancer setting, these assays can then be used to dissect how stromal cells, such as cancer‐associated fibroblasts (CAFs), drive extracellular matrix (ECM) remodelling to alter cancer cell behaviour and response to intervention. However, to date, many of the published organotypic protocols are low‐throughput, time‐consuming (up to several weeks), and work‐intensive with often limited scalability. Our aim was to develop a fast, high‐throughput, scalable 3D organotypic assay for use in oncology screening and drug development. Methods and results Here, we describe a modified 96‐well organotypic assay, the “Mini‐Organo,” which can be easily completed within 5 days. We demonstrate its application in a wide range of mouse and human cancer biology approaches including evaluation of stromal cell 3D ECM remodelling, 3D cancer cell invasion, and the assessment of efficacy of potential anticancer therapeutic targets. Furthermore, the organotypic assay described is highly amenable to customisation using different cell types under diverse experimental conditions. Conclusions The Mini‐Organo high‐throughput 3D organotypic assay allows the rapid screening of potential cancer therapeutics in human and mouse models in a time‐efficient manner.

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Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions

Cited by 129 publications

References 181 publications

Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis

Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis

Mesenchymal stromal cell remodeling of a gelatin hydrogel microenvironment defines an artificial hematopoietic stem cell niche

The Mini‐Organo: A rapid high‐throughput 3D coculture organotypic assay for oncology screening and drug development

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