Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment

Bu, Luke; Baba, Hideo; Yoshida, Naoya; Miyake, Keisuke; Yasuda, Tadahito; Uchihara, Tomoyuki; Tan, Patrick; Ishimoto, Takatsugu

doi:10.1038/s41388-019-0765-y

Cited by 256 publications

(217 citation statements)

References 133 publications

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“…The predictive value for estimating patient outcome through molecular subtype assignment (using the molecular prognostic signatures identified by Konecny et al [13]) showed a median survival difference of two years depending on whether the tumor epithelium or stroma and/or mixed tissue is sampled; notably the contribution of the stromal microenvironment to the mesenchymal signature has been recently described [20,22]. Taken together, these observations provide evidence for the existence of a pathological ovarian stroma and the proposed role of cancer-associated fibroblasts contributing to disease development and/or progression [23][24][25][26]. Assignment of the cryopulverized tissue in our study to a particular subtype was less clear due to profound signal averaging of the proteome (Figure 4).…”

Section: Discussionmentioning

confidence: 81%

Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens

Hunt

Bateman

Hood

et al. 2019

Preprint

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A series of 200 consecutive thin sections were generated from a high-grade serous ovarian tumor and laser microdissected four spatially separated "core" regions of tumor epithelium, along with tumor epithelium, stroma or whole tissue harvests at 200 µm intervals. These distinct tissue collections were analyzed by quantitative proteomics and RNA-Seq. Unsupervised analyses revealed co-clustering of tumor cores with enriched tumor epithelium, which were distinct from the enriched stroma and whole tumor collections. Strong correlations in protein and transcript abundance in tumor epithelium and stromal collections from neighboring thin sections were decreased in samples harvested just hundreds of microns apart. Stroma (mesenchymal) and tumor epithelium (differentiated) displayed a distinct association with ovarian cancer prognostic molecular sub-types with a 2-year difference in median survival. These data reveal substantial tumor microenvironment protein and transcript expression heterogeneity that directly bear on prognostic signatures and underscore the need to enrich cellular subpopulations for expression profiling.

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Section: Discussionmentioning

confidence: 81%

Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens

Hunt

Bateman

Hood

et al. 2019

Preprint

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“…Disorders of functions and cancer-related pathways are common in cancers [25,26]. Regarding GO and KEGG enrichment analyses, COL5A2 was involved in the extracellular matrix, focal adhesion, and PI3K-Akt signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

The TCGA and GEO databases identify COL5A2 as a poorly prognostic gene in patients with advanced gastric cancer

Tan

Chen

Xing

et al. 2020

Preprint

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Background Gastric cancer (GC) metastasis determines the prognosis of patients, and exploring the molecular mechanism of GC metastasis is expected to provide a theoretical basis for clinical treatment. Recent studies have shown that extracellular matrix protein is closely related to GC metastasis. This study aimed to explore the expression profile and role of COL5A2 (Collagen V-type α2), as an extracellular matrix protein, in GC. Methods The expression, overall survival and progression-free survival data of COL5 family members were extracted from The Cancer Genome Atlas(TCGA)database, respectively. Paraffin immunohistochemistry and RT-qPCR in GC and matched normal tissues were used to analyze the expression of the target genes. Weighted gene co-expression network analysis of the GSE62229 database was performed out to identify modules and associated genes, and the functions were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Results COL5A2 was selected as our research target in the TCGA database, and was also verified in the GSE62229 and GSE15459 datasets. COL5A2 was upregulated in GC tissues by paraffin immunohistochemistry and RT-qPCR. The analysis of clinicopathological characteristics showed a significant difference in the Borrmann type (P = 0.036), histological type (P = 0.013) and T stage(P = 0.011). The prognosis of patients with low COL5A2 expression was better than that of patients with high COL5A2 expression. GSEA results showed that the TCGA and GSE62229 samples were significantly enriched in several well-known cancer-related pathways, such as the TGF-β, MAPK, and JAK2 signaling pathways. Conclusion COL5A2 was most closely related to advanced GC among COL5 family members. High COL5A2 expression is associated with a poor prognosis in GC, and may be a novel therapeutic target for GC.

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“…A growing piece of evidence now shows that these cells are recruited from the stroma by cancer cells to promote ECM remodeling, neoangiogenesis, proliferation, invasion, migration, and metastasis, and mediate drug resistance mechanisms through the secretion of various growth factors, chemokines, and cytokines [19,20]. Among these reactive stromal cells, CAFs are the most described and mainly derived from healthy fibroblasts, although they could also originate from mesenchymal stem/stromal cells (MSCs), adipocytes, endothelial cells, epithelial cells, or stellate cells [21]. They also share many similarities with wound healingrelated myofibroblasts and differentiate when exposed to molecules such as transforming growth factor-beta, fibroblast growth factor 2, and platelet-derived growth factor [22].…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors

Roy

Magne

Vaillancourt-Audet

et al. 2020

BioMed Research International

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Cancer research has considerably progressed with the improvement of in vitro study models, helping to understand the key role of the tumor microenvironment in cancer development and progression. Over the last few years, complex 3D human cell culture systems have gained much popularity over in vivo models, as they accurately mimic the tumor microenvironment and allow high-throughput drug screening. Of particular interest, in vitrohuman 3D tissue constructs, produced by the self-assembly method of tissue engineering, have been successfully used to model the tumor microenvironment and now represent a very promising approach to further develop diverse cancer models. In this review, we describe the importance of the tumor microenvironment and present the existing in vitro cancer models generated through the self-assembly method of tissue engineering. Lastly, we highlight the relevance of this approach to mimic various and complex tumors, including basal cell carcinoma, cutaneous neurofibroma, skin melanoma, bladder cancer, and uveal melanoma.

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Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment

Cited by 256 publications

References 133 publications

Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens

Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens

The TCGA and GEO databases identify COL5A2 as a poorly prognostic gene in patients with advanced gastric cancer

Human Organ-Specific 3D Cancer Models Produced by the Stromal Self-Assembly Method of Tissue Engineering for the Study of Solid Tumors

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