Cancer associated fibroblasts in cancer pathogenesis

Franco, Omar E.; Shaw, Aubie; Strand, Douglas W.; Hayward, Simon W.

doi:10.1016/j.semcdb.2009.10.010

Cited by 340 publications

(300 citation statements)

References 57 publications

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“…Therefore, influences of tumor-associated acidic environments on the activity and function of these associated cells may in turn affect the progression of cancer itself. Cancer-associated fibroblasts is one of the most crucial components of the tumor microenvironment, which promotes the growth and invasion of cancer cells (52). We observed that acidic condition increased the expression of MMP2 and MMP9 in bone marrow stromal cells (data not shown).…”

Section: Discussionmentioning

confidence: 68%

The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells

Nishisho

Hata

Nakanishi

et al. 2011

Molecular Cancer Research

134

128

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Accumulating evidence indicates that the acidic microenvironments critically influence malignant behaviors of cancer including invasiveness, metastasis, and chemoresistance. Because the vacuolar-type H þ -ATPase (V-ATPase) has been shown to cause extracellular acidification by pumping protons, we studied the role of V-ATPase in distant metastasis. Real-time PCR analysis revealed that the high-metastatic B16-F10 melanoma cells strongly expressed the a3 isoform V-ATPase compared to the low-metastatic B16 parental cells. Consistent with this, B16-F10 cells created acidic environments in lung metastases by acridine orange staining and strong a3 V-ATPase expression in bone metastases by immunohistochemistry. Immunocytochemical analysis showed B16-F10 cells expressed a3 V-ATPase not only in cytoplasm but also plasma membrane, whereas B16 parental cells exhibited its expression only in cytoplasm. Of note, knockdown of a3 V-ATPase suppressed invasiveness and migration with reduced MMP-2 and MMP-9 expression in B16-F10 cells and significantly decreased lung and bone metastases, despite that tumor growth was not altered. Importantly, administration of a specific V-ATPase a3 inhibitor FR167356 reduced bone metastasis of B16-F10 cells. These results suggest that a3 V-ATPase promotes distant metastasis of B16-F10 cells by creating acidic environments via proton secretion. Our results also suggest that inhibition of the development of cancer-associated acidic environments by suppressing a3 V-ATPase could be a novel therapeutic approach for the treatment of cancer metastasis. Mol Cancer Res; 9(7); 845-55. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 68%

The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells

Nishisho

Hata

Nakanishi

et al. 2011

Molecular Cancer Research

134

128

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“…These data suggest that MSC conditioning with T 3 or T 4 and/or T 3 or T 4 treatment of patients could serve as an effective tool to enhance MSC migration and engraftment in tissue-engineering and gene-delivery approaches. At the same time, it should be taken into account that the stimulatory effect of iodothyronines, shown in our study, on the differentiation of MSCs towards CAFs that are known to support a microenvironment that drives tumour progression and metastasis, could enhance tumour growth (Franco et al 2010). However, depending on the approach used, MSCbased cancer gene therapy can include the destruction of exogenously applied engineered MSCs in the context of therapy, which is likely to overcome any endogenous tumour-promoting effects of adoptively applied MSCs.…”

Section: Discussionmentioning

confidence: 87%

Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3

Schmohl¹,

Müller²,

Wechselberger³

et al. 2015

Endocrine-Related Cancer

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To improve our understanding of non-genomic, integrin avb3-mediated thyroid hormone action in tumour stroma formation, we examined the effects of triiodo-L-thyronine (T 3 ), L-thyroxine (T 4 ) and integrin-specific inhibitor tetrac on differentiation, migration and invasion of mesenchymal stem cells (MSCs) that are an integral part of the tumour's fibrovascular network. Primary human bone marrow-derived MSCs were treated with T 3 or T 4 in the presence of hepatocellular carcinoma (HCC) cell-conditioned medium (CM), which resulted in stimulation of the expression of genes associated with cancer-associated fibroblast-like differentiation as determined by qPCR and ELISA. In addition, T 3 and T 4 increased migration of MSCs towards HCC cell-CM and invasion into the centre of three-dimensional HCC cell spheroids. All these effects were tetrac-dependent and therefore integrin avb3-mediated. In a subcutaneous HCC xenograft model, MSCs showed significantly increased recruitment and invasion into tumours of hyperthyroid mice compared to euthyroid and, in particular, hypothyroid mice, while treatment with tetrac almost completely eliminated MSC recruitment. These studies significantly improve our understanding of the anti-tumour activity of tetrac, as well as the mechanisms that regulate MSC differentiation and recruitment in the context of tumour stroma formation, as an important prerequisite for the utilisation of MSCs as gene delivery vehicles.

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“…One of the characteristics of the tumor stroma is the emergence of a mesenchymal-specific cell called myofibroblast (27). Both clinical and experimental data support the hypothesis that myofibroblasts may modulate growth, invasion and metastasis (28)(29)(30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 91%

Isolation and characterization of myofibroblast cell lines from oral squamous cell carcinoma

Sobral

Zecchin²,

Aquino³

et al. 2011

Oncol Rep

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Abstract. Oral squamous cell carcinoma (OSCC) invasion is followed by several stromal events such as inflammatory and immune cell infiltration, neo-vascularization, fibroblast activation and occasionally myofibroblast emergence. Our previous studies demonstrated that myofibroblasts in the stroma of OSCC are associated with a more aggressive behavior, leading to shorter patient overall survival. Therefore, we evaluated whether OSCC-associated myofibroblasts have different characteristics compared to OSCC-associated fibroblasts. OSCC myofibroblast cell lines were isolated, cultured and characterized on the basis of the expression of specific isoform · of smooth muscle actin (·-SMA) and of the excessive production of type I collagen. To assess the proliferative potential of the cell lines, growth curves were constructed, whereas the production and activity of matrix metalloproteinases (MMP) were analyzed by ELISA and enzymography, respectively. Myofibroblast clones were positive for ·-SMA and vimentin, and negative for pan-cytokeratin and CD34. In long time cultures, Western blotting, flow cytometry and ELISA analysis revealed constant ·-SMA expression and elevated production of type I collagen. There were no differences on proliferative potential between fibroblast and myofibroblast clones, but myofibroblast cells secreted significantly higher levels of MMP-1, -2, -9 and -13. Furthermore, MMP-2 gelatinolytic activity was significantly higher in myofibroblast clones. The results of this study suggest that myofibroblasts may contribute to OSCC invasion through elevation of MMP synthesis.

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Cancer associated fibroblasts in cancer pathogenesis

Cited by 340 publications

References 57 publications

The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells

The a3 Isoform Vacuolar Type H+-ATPase Promotes Distant Metastasis in the Mouse B16 Melanoma Cells

Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3

Isolation and characterization of myofibroblast cell lines from oral squamous cell carcinoma

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