Synthetic Polyamine BPA‐C8 Inhibits TGF‐β1‐Mediated Conversion of Human Dermal Fibroblast to Myofibroblasts and Establishment of Galectin‐1‐Rich Extracellular Matrix in Vitro

Mifkova, Alzbeta; Kodet, Ondřej; Szabó, Pavol; Kučera, Jan; Dvořánková, Barbora; André, Sabine; Koripelly, Girish; Gabius, Hans‐Joachim; Lehn, Jean-Maríe; Smetana, Karel

doi:10.1002/cbic.201402087

Cited by 11 publications

(8 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As indicated above, the ACFs resemble normal dermal fibroblasts of a healthy individual stimulated by TGF-β1. Therefore, it may be hypothesized that therapeutic attenuation of TGF-β activity ( 38 , 39 ), blocking of transition of fibroblasts to myofibroblasts ( 39 ) and/or therapeutic blockade of their function ( 40 ) may be used to prevent resistance to B-Raf inhibitor therapy in the future. Mechanistically, this blockade would disrupt bi-directional cross-talk between the melanoma cells and stromal fibroblasts which allow the tumors to amplify a drug-resistant niche.…”

Section: Discussionmentioning

confidence: 99%

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

et al. 2018

Self Cite

View full text Add to dashboard Cite

The incidence of malignant melanoma is rapidly increasing and current medicine is offering only limited options for treatment of the advanced disease. For B-Raf mutated melanomas, treatment with mutation-specific drug inhibitors may be used. Unfortunately, tumors frequently acquire resistance to the treatment. Tumor microenvironment, namely cancer-associated fibroblasts, largely influence this acquired resistance. In the present study, fibroblasts were isolated from a patient suffering from acrolentiginous melanoma (Breslow, 4.0 mm; Clark, IV; B-Raf V600E mutated). The present study focused on the expression of structural and functional markers of fibroblast activation in melanoma-associated fibroblasts (MAFs; isolated prior to therapy initiation) as well as in autologous control fibroblasts (ACFs) of the same patient isolated during B-Raf inhibitor therapy, yet before clinical progression of the disease. Analysis of gene transcription was also performed, as well as DNA methylation status analysis at the genomic scale of both isolates. MAFs were positive for smooth muscle actin (SMA), which is a marker of myofibroblasts and the hallmark of cancer stoma. Surprisingly, ACF isolated from the distant uninvolved skin of the same patient also exhibited strong SMA expression. A similar phenotype was also observed in control dermal fibroblasts (CDFs; from different donors) exclusively following stimulation by transforming growth factor (TGF)-β1. Immunohistochemistry confirmed that melanoma cells potently produce TGF-β1. Significant differences were also identified in gene transcription and in DNA methylation status at the genomic scale. Upregulation of SMA was observed in ACF cells at the protein and transcriptional levels. The present results support recent experimental findings that tumor microenvironment is driving resistance to B-Raf inhibition in patients with melanoma. Such an activated microenvironment may be viable for the growth of circulating melanoma cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Deregulation of the microenvironment during the wound healing results in delayed healing in venous ulcers or in diabetic foot syndrome [ 50 , 51 ]. Part of granulation tissue fibroblasts is transformed to the myofibroblasts due to activity of TGF-β1/3 and/or galectin-1 [ 52 , 53 ]. Myofibroblasts are very active in formation of extracellular matrix and contribute to the reduction of wound size by their contractibility.…”

Section: Escs and Wound Healingmentioning

confidence: 99%

“…Modification of local inflammatory environment in tumor stroma is also behind effect of drugs such as imiquimode or non-steroidal anti-inflammatory drugs. Specific targeting of CAFs is not recently in clinical use, however, early preclinical data are promising [ 53 ].…”

Section: Malignant Melanoma: Microenvironment In Non-keratinocyticmentioning

confidence: 99%

Cancer Microenvironment: What Can We Learn from the Stem Cell Niche

Lacina

Plzák

Kodet

et al. 2015

IJMS

Self Cite

View full text Add to dashboard Cite

Epidermal stem cells (ESCs) are crucial for maintenance and self- renewal of skin epithelium and also for regular hair cycling. Their role in wound healing is also indispensable. ESCs reside in a defined outer root sheath portion of hair follicle—also known as the bulge region. ECS are also found between basal cells of the interfollicular epidermis or mucous membranes. The non-epithelial elements such as mesenchymal stem cell-like elements of dermis or surrounding adipose tissue can also contribute to this niche formation. Cancer stem cells (CSCs) participate in formation of common epithelial malignant diseases such as basal cell or squamous cell carcinoma. In this review article, we focus on the role of cancer microenvironment with emphasis on the effect of cancer-associated fibroblasts (CAFs). This model reflects various biological aspects of interaction between cancer cell and CAFs with multiple parallels to interaction of normal epidermal stem cells and their niche. The complexity of intercellular interactions within tumor stroma is depicted on example of malignant melanoma, where keratinocytes also contribute the microenvironmental landscape during early phase of tumor progression. Interactions seen in normal bulge region can therefore be an important source of information for proper understanding to melanoma. The therapeutic consequences of targeting of microenvironment in anticancer therapy and for improved wound healing are included to article.

show abstract

“…In addition, previous studies have revealed that galectin-1 plays a role in the desmoplastic reaction associated with PC (22). Furthermore, it has been reported that TGF-β1 alone or TGF-β1 together with galectin-1 induces the transition of human dermal fibroblasts to myofibroblasts (23) and that galectin-1 may promote the TGF-β1-induced differentiation of fibroblasts by sustaining nuclear localization of Smad2 in pulmonary fibrotic diseases (17). however, it is not known whether galectin-1 plays a fibrogenic role in CP/PC and which is the related underlying mechanism.…”

Section: Galectin-1 Expression In Activated Pancreatic Satellite Cellmentioning

confidence: 94%

Galectin-1 expression in activated pancreatic satellite cells promotes fibrosis in chronic pancreatitis/pancreatic cancer via the TGF-β1/Smad pathway

Tang

Zhang

et al. 2018

Oncol Rep

View full text Add to dashboard Cite

Chronic pancreatitis/pancreatic cancer (CP/PC) is characterized by fibrous connective tissue proliferation induced by activated pancreatic stellate cells (PSCs). Galectin-1 is upregulated in activated PSCs and is important for the continuing activation of PSCs. The aim of this study was to evaluate the effect of galectin-1 derived from activated PSCs on the progression of fibrosis in CP/PC. To this end, the expression of desmin, α-SMA, galectin-1, fibronectin and collagen type I in normal pancreatic, CP and PC tissues, as well as quiescent/activated PSCs, was investigated. The proliferation rate and migration ability of control, galectin-1-overexpressing and galectin-1-silenced PSCs were also evaluated, as well as the mRNA and protein expression of fibronectin, collagen type I, α-SMA, tissue inhibitors of metalloproteinases (TIMP)-1, MMP-2, Smad2 and TGF-β1. Furthermore, the effect of adding a TGF-β1 receptor inhibitor on the expression of these proteins was examined. The results revealed that the expression profile of desmin, α-SMA, galectin-1, fibronectin and collagen type I in the normal pancreas was similar to that of quiescent PSCs and the expression profile in CP/PC tissues was similar to that of activated PSCs. Furthermore, galectin-1-overexpressing PSCs exhibited a significantly higher proliferation rate and migration ability, while galectin-1-silenced PSCs exhibited a significantly lower proliferation rate and migration ability than the control PSCs. The expression of fibronectin, collagen type I, α-SMA, MMP-2 and TIMP-1 was also significantly higher in the galectin-1-overexpressing PSCs than the control PSCs and this effect was found to be mediated by the TGF-β1/Smad pathway. The trends in the expression of these factors were reversed in the galectin-1-silenced PSCs. From these findings, it can be concluded that overexpression of galectin-1 promotes PSC activity (proliferation and migration) and stimulates fibrosis by increasing extracellular matrix synthesis and decreasing the MMP/TIMP ratio via the TGF-β1/Smad pathway. Thus, galectin-1 may be a novel candidate for reversing or halting fibrosis progression in CP/PC.

show abstract

Synthetic Polyamine BPA‐C8 Inhibits TGF‐β1‐Mediated Conversion of Human Dermal Fibroblast to Myofibroblasts and Establishment of Galectin‐1‐Rich Extracellular Matrix in Vitro

Cited by 11 publications

References 36 publications

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

Microenvironment‑driven resistance to B‑Raf inhibition in a melanoma patient is accompanied by broad changes of gene methylation and expression in distal fibroblasts

Cancer Microenvironment: What Can We Learn from the Stem Cell Niche

Galectin-1 expression in activated pancreatic satellite cells promotes fibrosis in chronic pancreatitis/pancreatic cancer via the TGF-β1/Smad pathway

Contact Info

Product

Resources

About