Expression of cancer-associated fibroblast markers in advanced colorectal cancer

Nishishita, Rie; Morohashi, Satoko; Seino, Hiroko; Wu, Yunyan; Yoshizawa, Tadashi; Haga, Toshihiro; Saito, Kensuke; Hakamada, Kenichi; Fukuda, Shinsaku; Kijima, Hiroshi

doi:10.3892/ol.2018.8097

Cited by 38 publications

(42 citation statements)

References 21 publications

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“…To this end SW620 cells expressing luciferase were orthotopically injected alone or together with fibroblasts in the caecum of immunocompromised (NSG) mice. Fibroblasts and tumor cells were mixed and injected at a 1:1 ratio which is a realistic approximation of the average Cancer Associated Fibroblasts (CAF): epithelial cell ratio observed in human CRC, considering variability observed in different CRC subtypes, stages and intertumoral heterogeneity (Henry et al, 2007 ; Isella et al, 2015 ; Nishishita et al, 2018 ). Fibroblasts co-injected with tumor cells did not impact primary tumor growth (Supplementary Figure S3 ).…”

Section: Resultsmentioning

confidence: 99%

Characterization and In Vivo Validation of a Three-Dimensional Multi-Cellular Culture Model to Study Heterotypic Interactions in Colorectal Cancer Cell Growth, Invasion and Metastasis

Cattin

Ramont²,

Rüegg

2018

Front. Bioeng. Biotechnol.

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Colorectal cancer (CRC) is the third cause of cancer-related mortality in industrialized countries. Local invasion and metastasis formation are events associated with poor prognosis for which today there are no effective therapeutic options. Invasion and metastasis are strongly modulated by cells of the tumor microenvironment (TME), in particular fibroblasts and endothelial cells. Unraveling interactions between tumor cells and cells of the TME may identify novel mechanisms and therapeutic targets to prevent or treat metastasis. We report here the development and in vivo validation of a 3D tumor spheroid model to study the interactions between CRC cells, fibroblasts and endothelial cells in vitro. Co-cultured fibroblasts promoted SW620 and HCT116 CRC spheroid invasion, and this was prevented by the SRC and FGFR kinase inhibitors Dasatinib and Erdafitinib, respectively. To validate these findings in vivo, we injected SW620 cells alone or together with fibroblasts orthotopically in the caecum of mice. Co-injection with fibroblasts promoted lung metastasis growth, which was fully reversed by treatment with Dasatinib or Erdafitinib. Co-culture of SW620 or HCT116 CRC spheroids with endothelial cells suppressed spheroid growth while it had no effect on cancer cell migration or invasion. Consistent with this in vitro effect, co-injected endothelial cells significantly inhibited primary tumor growth in vivo. From these experiments we conclude that effects on cancer cell invasion and growth induced by co-cultured TME cells and drug treatment in the 3D spheroid model in vitro, are predictive of in vivo effects. The 3D spheroid model may be considered as an attractive model to study the effect of heterotypic cellular interactions and drug activities on cancer cells, as animal testing alternative. This model may be adapted and further developed to include different types of cancer and host cells and to investigate additional functions and drugs.

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Section: Resultsmentioning

confidence: 99%

Characterization and In Vivo Validation of a Three-Dimensional Multi-Cellular Culture Model to Study Heterotypic Interactions in Colorectal Cancer Cell Growth, Invasion and Metastasis

Cattin

Ramont²,

Rüegg

2018

Front. Bioeng. Biotechnol.

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“…Cancer-associated fibroblasts (CAFs) in the immediate vicinity of cancer cells play an important role in tumorigenesis in various physicochemical ways by reducing apoptosis and improving the proliferation, migration and viability of cancer cells [58,59]. CAFs residing in TME are heterogeneous cells with different origins, different functions (pro or anti-tumor activities) and different surface markers such as alpha-smooth muscle actin (α-SMA), myosin light chain 9 (MYL9), myosin light chain kinase (MYLK), matrix metalloproteinase 2 (MMP2), decorin (DCN) and collagen type I alpha 2 (COL1A2) [60][61][62][63].…”

Section: Cancer-associated Fibroblast (Cafs)mentioning

confidence: 99%

Tumor microenvironment complexity and therapeutic implications at a glance

et al. 2020

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The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices.

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“…Not exclusive to fibroblasts. 91,92 No which seem to be sensitive to factors such as CAF subtype (αSMA, FAP) or hypoxia (αSMA, POSTN). Another strength of the PDGFRs is that, unlike αSMA, they are surface-bound markers, allowing for flow cytometry-based sorting of viable fibroblast populations for long-term assays and cultures.…”

Section: Fibroblast Markersmentioning

confidence: 99%

In search of definitions: Cancer‐associated fibroblasts and their markers

Nurmik

Ullmann

Rodriguez

et al. 2019

Intl Journal of Cancer

470

428

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The tumor microenvironment has been identified as one of the driving factors of tumor progression and invasion. Inside this microenvironment, cancer‐associated fibroblasts (CAFs), a type of perpetually activated fibroblasts, have been implicated to have a strong tumor‐modulating effect and play a key role in areas such as drug resistance. Identification of CAFs has typically been carried based on the expression of various “CAF markers”, such as fibroblast activation protein alpha (FAP) and alpha smooth muscle actin (αSMA), which separates them from the larger pool of fibroblasts present in the body. However, as outlined in this Review, the expression of various commonly used fibroblast markers is extremely heterogeneous and varies strongly between different CAF subpopulations. As such, novel selection methods based on cellular function, as well as further characterizing research, are vital for the standardization of CAF identification in order to improve the cross‐applicability of different research studies in the field. The aim of this review is to give a thorough overview of the commonly used fibroblast markers in the field and their various strengths and, more importantly, their weaknesses, as well as to highlight potential future avenues for CAF identification and targeting.

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Expression of cancer-associated fibroblast markers in advanced colorectal cancer

Cited by 38 publications

References 21 publications

Characterization and In Vivo Validation of a Three-Dimensional Multi-Cellular Culture Model to Study Heterotypic Interactions in Colorectal Cancer Cell Growth, Invasion and Metastasis

Characterization and In Vivo Validation of a Three-Dimensional Multi-Cellular Culture Model to Study Heterotypic Interactions in Colorectal Cancer Cell Growth, Invasion and Metastasis

Tumor microenvironment complexity and therapeutic implications at a glance

In search of definitions: Cancer‐associated fibroblasts and their markers

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